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Federico PIACENTINI
Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto
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Pubblicazioni
2024
- Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer
[Articolo su rivista]
Dieci, M. V.; Conte, P.; Bisagni, G.; Bartolini, S.; Frassoldati, A.; Generali, D.; Piacentini, F.; Griguolo, G.; Tagliafico, E.; Braso Maristany, F.; Chic, N.; Pare, L.; Miglietta, F.; Vicini, R.; D'Amico, R.; Balduzzi, S.; Prat, A.; Guarneri, V.
abstract
Background: Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. Methods: A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. Results: Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P =. 005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P =. 001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P =. 042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. Conclusions: The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.
2024
- Real-World Data and Clinical Implications of Next-Generation Sequencing (NGS)-Based Analysis in Metastatic Breast Cancer Patients
[Articolo su rivista]
Canino, F; Tornincasa, A; Bettelli, S; Manfredini, S; Barbolini, M; Moscetti, L; Omarini, C; Toss, A; Tamburrano, F; Antonelli, G; Baglio, F; Belluzzi, L; Martinelli, G; Natalizio, S; Ponzoni, O; Dominici, M; Piacentini, F.
abstract
Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical-pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.
2023
- Adjuvant Endocrine Therapy in Premenopausal Women With Hormone Receptor-Positive Early-Stage Breast Cancer: Risk Stratification in a Real-World Setting
[Articolo su rivista]
D'Onofrio, Raffaella; Omarini, Claudia; Toss, Angela; Sperduti, Isabella; Piacentini, Federico; Barbolini, Monica; Cortesi, Laura; Barbieri, Elena; Pettorelli, Elisa; Chiavelli, Chiara; Dominici, Massimo; Moscetti, Luca
abstract
Background: Ovarian function suppression (OFS) and hormone therapy (HT) represent an adjuvant option in premenopausal hormone receptor-positive early breast cancer (HR+EBC). The SOFT-TEXT trials showed improved outcomes upon receiving aromatase inhibitors (AIs)/OFS.
Methods: In order to estimate the magnitude of absolute improvements, we conducted a retrospective study applying composite risk (CR) to 237 premenopausal HR+EBC patients.
Results: Overall, 119 of these received tamoxifen (T)/OFS and 118 received AIs/OFS. The median age was 45 years (ys). After a median follow up of 65 months, recurrence was 6.7% in T patients and 10.2% in AI ones. CR (cutoff: 2.67) and ET duration (five-year cutoff) was found to have a significant impact on DFS. Invasive disease-free survival (IDFS) at 5 ys amounted to 82.9% for a CR>2.67 and 95% with CR
2023
- Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer.
[Articolo su rivista]
Enrique Fein, Luis; Lucas Kaen, Diego; Dario Kowalyszyn, Ruben; Varela, Mirta; Luis Lerzo, Guillermo; Wong, Vanessa; M Boyle, Frances; Fox, Peter; Kannourakis, George; Mccarthy, Nicole; Murray, Nicholas; Okera, Meena; van der Westhuizen, Andre; Bae, Susie; Goodwin, Annabel; Morris, Michelle; Quaghebeur, Claire; Canon, Jean-Luc; Dirix, Luc; Duhoux, Francois; Fontaine, Christel; Papadimitriou, Konstantinos; Mates, Mihaela; Niraula, Saroj; C Pezo, Rossanna; Puchyr, Martina; Linda Yu, Joanne; Wu, Xinhong; Chen, Wenyan; Pang, Danmei; Zang, Aimin; Wang, Jingfen; Jiang, Ou; Wu, Zhiyong; Dalenc, Florence; Stefani, Laetitia; Luporsi, Elisabeth; Petit, Thierry; Hardy-Bessard, Anne-Claire; Peron, Julien; Monceau-Baroux, Lucie; Meynard, Guillaume; Christophe Thery, Jean; Harbeck, Nadia; Tio, Joke; Schneeweiss, Andreas; Wuelfing, Pia; Schem, Christian; Tesch, Hans; A Fasching, Peter; Park-Simon, Tjoung-Won; Reinisch, Mattea; Wimberger, Pauline; Braun, Michael; Hegewisch-Becker, Susanna; Witzel, Isabell; Lux, Michael; Van Mackelenbergh, Marion; Wiebke Fischer, Dorothea; Fischer, Holger; Marmé, Frederik; Griesshammer, Martin; B Al-Farhat, Yousuf; Arkosy, Peter; Csoszi, Tibor; Papai, Zsuzsanna; Laszlo Rubovszky, Gabor; Horvath, Zsolt; Peretz, Tamar; Drumea, Karen; Lubovsky, Shlomit; Itay, Amit; Kuchuk, Iryna; Yerushalmi, Rinat; Yousef, Samih; Kornev, Gleb; Goldvaser, Hadar; Tokar, Margarita; Coltelli, Luigi; Biganzoli, Laura; Montemurro, Filippo; Orditura, Michele; De Giorgi, Ugo; Zambelli, Alberto; Rota Caremoli, Elena; Piacentini, Federico; Angelo Colleoni, Marco; Tonini, Giuseppe; Battelli, Nicola; Tagliaferri, Pierosandro; Inoue, Kenichi; Hara, Fumikata; Iwata, Hiroji; Yasojima, Hiroyuki; Mizuno, Toshiro; Nakayama, Takahiro; Itoh, Mitsuya; Osaki, Akihiko; Taira, Tetsuhiko; Watanabe, Kenichi; Toyama, Tatsuya; Yamamoto, Yutaka; Yamashita, Toshinari; Yanagita, Yasuhiro; Aogi, Kenjiro; Saji, Shigehira; Takahashi, Masato; Nakamura, Seigo; Takada, Masahiro; Toi, Masakazu; Nakamura, Rikiya; Hee Park, Yeon; Shim, Byoung-Yong; Hong Seo, Jae; Uk Park, Keon; Hoon Sim, Sung; Hee Lee, Moon; Jin Choi, Young; Hae Jung, Kyung; Hyun Kim, Jee; Yun Kang, Seok; Luzgardo Alvarez Barreda, Renzo; L Gomez, Henry; I Nowecki, Zbigniew; Kubiatowski, Tomasz; J Wysocki, Piotr; Zurawski, Bogdan; A Frolova, Mona; Tarasova, Anna; Zhukova, Lyudmila; V Krivorotko, Petr; Kirtbaya, Dmitry; Vahidovna Orlova, Rashida; Cortegoso, Alexandra; Guerrero Zotano, Angel; Ciruelos Gil, Eva; Martinez Garcia, Maria; Oliveira, Mafalda; Ramos, Manuel; Ruiz-Borrego, Manuel; Morales Murillo, Serafin; Stradella, Agostina; Vazquez Fernandez, Silvia; Gion Cortes, Maria; Cruz-Jurado, Josefina; Calvo Plaza, Isabel; Sanchez Rovira, Pedro; Poveda Velasco, Andres; Angel Garcia Saenz, Jose; Antonio Virizuela Echaburu, Juan; Juan Illarramendi Mañas, Jose; Jerez Gilarranz, Yolanda; Zamora Aunon, Pilar; Cantos, Blanca; Mele Olive, Mireia; de la Haba, Juan; Ribelles, Nuria; Lu, Yen-Shen; Wang, Hwei-Chung; Chen, Shin-Cheh; Tseng, Ling-Ming; Chung, Wei-Pang; Chung, Chi-Feng; Rau, Kun-Ming; Feng, Yin-Hsun; J Howell, Sacha; Esther Una Cidon, Maria; Sheri, Amna; C Turner, Nicholas; Mcgrath, Sophie; John Nelmes, Daniel; Braybrooke, Jeremy; Waters, Simon; A McGoldrick, Trevor; H Blau, Sibel; Graff, Stephanie; Mozayen, Mohammad; P Hamilton, Erika; L Hart, Lowell; Landry, Chrystal; Sharma, Ruby; Sharma, Priyanka; Thara, Eddie; S Marathe, Omkar; J Irvin, William; R Daniel, Brooke; Gudena, Vinay; Cao, Yu; O Ademuyiwa, Foluso; Coluzzi, Paul; H Rak-Tkaczuk, Katherine; Neidhart, Jeffrey; Klein, Paula; Mina, Lida; Zhao, Qing; S Rugo, Hope; O'Shaughnessy, Joyce; Sideras, Konstandinos; V Giridhar, Karthik
abstract
Background: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited.
Methods: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed.
Results: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.
Conclusions: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.).
2023
- Correction: Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation (British Journal of Cancer, (2023), 128, 2, (266-274), 10.1038/s41416-022-02050-8)
[Articolo su rivista]
Dieci, M. V.; Carbognin, L.; Miglietta, F.; Canino, F.; Giorgi, C. A.; Cumerlato, E.; Amato, O.; Massa, D.; Griguolo, G.; Genovesi, E.; Garufi, G.; Giannarelli, D.; Tornincasa, A.; Trudu, L.; Michieletto, S.; Saibene, T.; Lo Mele, M.; Fassan, M.; Zarrilli, G.; Piacentini, F.; Bria, E.; Guarneri, V.
abstract
The original version of this article contained an error in the funding section. This work was supported by RSF-2017- 00000557 funding from Veneto Region (Italy). Role of the funder/sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The original article has been corrected.
2023
- Incorporating weekly carboplatin in anthracycline and paclitaxel-containing neoadjuvant chemotherapy for triple-negative breast cancer: propensity-score matching analysis and TIL evaluation
[Articolo su rivista]
Dieci, M. V.; Carbognin, L.; Miglietta, F.; Canino, F.; Giorgi, C. A.; Cumerlato, E.; Amato, O.; Massa, D.; Griguolo, G.; Genovesi, E.; Garufi, G.; Giannarelli, D.; Tornincasa, A.; Trudu, L.; Michieletto, S.; Saibene, T.; Lo Mele, M.; Fassan, M.; Zarrilli, G.; Piacentini, F.; Bria, E.; Guarneri, V.
abstract
Background The generation of data capturing the risk-benefit ratio of incorporating carboplatin (Cb) to neoadjuvant chemotherapy (NACT) for triple-negative breast cancer (TNBC) in a clinical practice setting is urgently needed. Tumour-infiltrating lymphocytes (TILs) have an established role in TNBC receiving NACT, however, the role of TIL dynamics under NACT exposure in patients receiving the current standard of care is largely uncharted. Methods Consecutive TNBC patients receiving anthracycline-taxane [A-T] +/- Cb NACT at three Institutions were enrolled. Stromal-TILs were evaluated on pre-NACT and residual disease (RD) specimens. In the clinical cohort, propensity-score-matching was used to control selection bias. Results In total, 247 patients were included (A-T = 40.5%, A-TCb = 59.5%). After propensity-score-matching, pCR was significantly higher for A-TCb vs A-T (51.9% vs 34.2%, multivariate: OR = 2.40, P = 0.01). No differences in grade >= 3 haematological toxicities were observed. TILs increased from baseline to RD in the overall population and across A-T/A-TCb subgroups. TIL increase from baseline to RD was positively and independently associated with distant disease-free survival (multivariate: HR = 0.43, P = 0.05). Conclusions We confirmed in a clinical practice setting of TNBC patients receiving A-T NACT that the incorporation of weekly Cb significantly improved pCR. In addition, A-T +/- Cb enhanced immune infiltration from baseline to RD. Finally, we reported a positive independent prognostic role of TIL increase after NACT exposure.
2023
- Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2â € "Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial
[Articolo su rivista]
Conte, P.; Bisagni, G.; Piacentini, F.; Sarti, S.; Minichillo, S.; Anselmi, E.; Aieta, M.; Gebbia, V.; Schirone, A.; Musolino, A.; Garrone, O.; Beano, A.; Rimanti, A.; Giotta, F.; Turletti, A.; Miglietta, F.; Dieci, M. V.; Vicini, R.; Balduzzi, S.; D'Amico, R.; Guarneri, V.
abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2â € "positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.
2023
- Pathologic response and survival after neoadjuvant chemotherapy with or without pertuzumab in patients with HER2-positive breast cancer: the Neopearl nationwide collaborative study
[Articolo su rivista]
Fabbri, A; Nelli, F; Botticelli, A; Giannarelli, D; Marrucci, E; Fiore, C; Virtuoso, A; Scagnoli, S; Pisegna, S; Alesini, D; Sini, V; Orlandi, A; Fabi, A; Piacentini, F; Moscetti, L; D'Auria, G; Gamucci, T; Mazzotta, M; Pizzuti, L; Vici, P; Cretella, E; Scavina, P; La Cesa, A; Persano, M; Atzori, F; Ruggeri, Em
abstract
Purpose: Clinical trials have shown a significant increase in pathologic complete response (pCR) with the addition of pertuzumab to neoadjuvant chemotherapy for patients with early-stage HER-2 positive breast cancer. To date, limited studies have examined comparative outcomes of neoadjuvant pertuzumab in real-world setting. The Neopearl study aimed to assess comparative real-life efficacy and safety of neoadjuvant pertuzumab for these patients.
Methods: We conducted a nationwide retrospective analysis involving 17 oncology facilities with a certified multidisciplinary breast cancer treatment committee. We identified patients with HER-2 positive stage II-III breast cancer treated with neoadjuvant chemotherapy based on trastuzumab and taxanes with or without pertuzumab. All patients underwent breast surgery and received a comprehensive cardiologic evaluation at baseline and after neoadjuvant treatment. Patients who received the combination of pertuzumab, trastuzumab, and chemotherapy constituted case cohort (PTCT), whereas those treated with trastuzumab and chemotherapy accounted for control cohort (TCT). The pCR rate and 5-year event free survival (EFS) were the primary outcomes. Secondary end-points were rates of conversion from planned modified radical mastectomy (MRM) to breast conservation surgery (BCS) and cardiotoxicities.
Results: From March 2014 to April 2021, we included 271 patients, 134 (49%) and 137 (51%) in TCT and PTCT cohort, respectively. Positive axillary lymph nodes and stage III were more frequent in PTCT cohort. The pCR rate was significantly increased in patients who received pertuzumab (49% vs 62%; OR 1.74, 95%CI 1.04-2.89) and with HER-2 enriched subtypes (16% vs 85%; OR 2.94, 95%CI 1.60-5.41). After a median follow-up of 5 years, the 5-year EFS was significantly prolonged only in patients treated with pertuzumab (81% vs 93%; HR 2.22, 95%CI 1.03-4.79). The same analysis performed on propensity score matched population showed concordant results. On univariate analysis, only patients with positive lymph nodes were found to benefit from pertuzumab for both pCR and 5-year EFS. The rates of conversion from MRM to BCS and cardiologic toxicities did not differ between the cohorts.
Conclusion: Our findings support previous data on improved outcomes with the addition of pertuzumab to trastuzumab-based neoadjuvant chemotherapy. This benefit seems to be more significant in patients with clinically positive lymph nodes.
2023
- Personalized Systemic Therapies in Hereditary Cancer Syndromes
[Articolo su rivista]
Mastrodomenico, L.; Piombino, C.; Ricco, B.; Barbieri, E.; Venturelli, M.; Piacentini, F.; Dominici, M.; Cortesi, L.; Toss, A.
abstract
Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades.
2023
- Targeting PI3K/AKT/mTOR Pathway in Breast Cancer: From Biology to Clinical Challenges
[Articolo su rivista]
Cerma, K.; Piacentini, F.; Moscetti, L.; Barbolini, M.; Canino, F.; Tornincasa, A.; Caggia, F.; Cerri, S.; Molinaro, A.; Dominici, M.; Omarini, C.
abstract
Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20-40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era.
2023
- Thromboembolism and Adjuvant Endocrine Therapy (AET) in Hormone Receptor-Positive Early Breast Cancer (EBC): Did Treatment Evolution Change Incidence of the Adverse Event? A Meta-Analysis
[Articolo su rivista]
D'Onofrio, R.; Sperduti, I.; Piacentini, F.; Barbolini, M.; Omarini, C.; Toss, A.; Cortesi, L.; Barbieri, E.; Canino, F.; Dominici, M.; Moscetti, L.
abstract
: The adjuvant endocrine therapy (AET) of HR+ EBC has been changing in recent years. Aromatase inhibitors (AIs) as an upfront strategy (or as part of a switch strategy) have been added to the choice of Tamoxifen (T) alone. Increased TE risk is well known in T-treated patients, while AIs have shown a reduced TE rate. By adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) to AIs, an increase in TE rate has been shown. We conducted this meta-analysis to evaluate the impact of the AETs on TE incidence. Twelve randomized phase III trials were included. Four trials evaluated the upfront strategy, 6 assessed the switch and 2 the combination with a CDK4/6 inhibitor. The new AETs did not significantly modify or affect the rate of TE events (OR 0.847, 95% CI, 0.528-1.366, P = .489). The OR for CDK4/6 inhibitor plus ET vs. ET was 3.635 (P = .002). Excluding the CDK4/6 inhibitors, the overall OR for AIs vs. T was 0.628 (P < .001), while it was 0.781 (P = .151) for switching T vs. continuing T for 5 years, and 0.52 (P < .0001) for the upfront strategies with AIs. The AIs alone or plus CDK4/6 inhibitors did not affect the rate of TE events. AIs as an upfront strategy is the safest AET, associated with the lowest TE incidence. The switch strategy increases TE rate, whereas the addition of CDK4/6 to the standard AET was shown to significantly increase TE events. The results of the currently ongoing trials with CDK4/6 inhibitors will help obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and clarify the weight of TE adverse events in the benefit/risk balance of this new adjuvant strategy.
2022
- Carcinoid Crisis: A Misunderstood and Unrecognized Oncological Emergency
[Articolo su rivista]
Bardasi, C.; Benatti, S.; Luppi, G.; Garajova, I.; Piacentini, F.; Dominici, M.; Gelsomino, F.
abstract
Carcinoid Crisis represents a rare and extremely dangerous manifestation that can occur in patients with Neuroendocrine Tumors (NETs). It is characterized by a sudden onset of hemodynamic instability, sometimes associated with the classical symptoms of carcinoid syndrome, such as bronchospasm and flushing. Carcinoid Crisis seems to be caused by a massive release of vasoactive substances, typically produced by neuroendocrine cells, and can emerge after abdominal procedures, but also spontaneously in rare instances. To date, there are no empirically derived guidelines for the management of this cancer-related medical emergency, and the available evidence essentially comes from single-case reports or dated small retrospective series. A transfer to the Intensive Care Unit may be necessary during the acute setting, when the severe hypotension becomes unresponsive to standard practices, such as volemic filling and the infusion of vasopressor therapy. The only effective strategy is represented by prevention. The administration of octreotide, anxiolytic and antihistaminic agents represents the current treatment approach to avoid hormone release and prevent major complications. However, no standard protocols are available, resulting in great variability in terms of schedules, doses, ways of administration and timing of prophylactic treatments.
2022
- COVID-related disruption in mammographic screening: a year later.
[Articolo su rivista]
Toss, A; Callegari, V; Cortesi, G; Civallero, M; Armocida, C; Piacentini, F.
abstract
2022
- Homologous recombination deficiency, RB-loss gene signatures, intrinsic subtype and response to neoadjuvant treatment in HR+/HER2- early breast cancer: a correlative analysis of two phase II trials
[Poster]
Griguolo, Gaia; Miglietta, Federica; Paré, Laia; Generali, Daniele G.; Frassoldati, Antonio; Musolino, Antonino; Spazzapan, Simon; Vernaci, Grazia; Giarratano, Tommaso; Lo Mele, Marcello; Bisagni, Giancarlo; Piacentini, Federico; Tagliafico, Enrico; Cagossi, Katia; Schiavi, Francesca; Pinato, Claudia; Prat, Aleix; Guarneri, Valentina; Dieci, Maria Vittoria
abstract
Background: Hormone-receptor (HR)+/HER2- breast cancer (BC) is a biologically heterogeneous disease. Homologous recombination deficiency (HRD) and BRCA mutations have been previously reported to be associated with worse outcomes in HR+/HER2- metastatic BC patients receiving CDK4/6 inhibitors and endocrine therapy. Here, we assess the relation between HRD and RB-loss signatures, intrinsic subtyping, the PAM50-based chemo-endocrine score, and response to chemotherapy-based therapy and endocrine treatment in HR+/HER2- early BC. Methods: GIADA is a multicentric neoadjuvant phase II trial that treated premenopausal patients with Luminal B (LumB)-like BC (HR-positive, HER2-negative, with Ki67>20% and/or histologic Grade 3) with a combination of chemotherapy, immunotherapy and endocrine treatment. Expression of 758 genes on baseline tumor samples from all 43 patients was quantified by nCounter platform. The LETLOB phase II trial randomized postmenopausal women with clinical stage II-IIIA HR+/HER2- BC to neoadjuvant letrozole + lapatinib or letrozole + placebo for 6 months (Guarneri, JCO 2014). Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 out of 92 pts enrolled. Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. A published HRD signature (Peng, Nat Commun 2014) and a signature of RB loss (RBsig), previously reported to potentially predict resistance to CDK4/6 inhibitors in HR+/HER2- BC (Malorni, Oncotarget 2016) were computed. The PAM50 based chemo-endocrine score (CES) was calculated using published definition (Prat, CCR 2017). Higher values of CES indicate increased endocrine sensitivity, while lower values indicate chemosensitivity. Association between genomic signatures was assessed through Pearson’s correlation coefficient. Association of genomic signatures with pCR was assessed through logistic regression and association with PEPI scores was assessed through Kruskal-Wallis test. Results: HRD signature levels were significantly higher in non-luminal (Basal-like and HER2-enriched) tumors as compared to Luminal (A or B) tumors (p>0.001 in the GIADA trial, p=0.021 in the LETLOB trial). Moreover, higher levels of HRD signature were associated with higher levels of RB-loss signature (Pearson correlation 0.355, p=0.020 in the GIADA trial; Pearson correlation 0.942, p< 0.001 in the LETLOB trial), higher levels of Basal-like signature (Pearson correlation 0.502, p< 0.001 in the GIADA trial; Pearson correlation 0.373, p=0.002 in the LETLOB trial) and lower levels of CES (Pearson correlation -0.422, p=0.005 in the GIADA trial; Pearson correlation -0.763, p< 0.001 in the LETLOB trial), indicative of higher chemosensitivity. In the GIADA trial, higher levels of HRD signature (p=0.018) and RBloss signature (p=0.073) and lower levels of CES (p=0.007) were associated with higher pCR rates after chemo, endocrine and immunotherapy. In the LETLOB trial, lower levels of HRD signature (p=0.068) and RBloss signature (p=0.042) and higher levels of CES (p=0.050) were associated with higher sensitivity to endocrine treatment (lower PEPI scores, 0 vs 1-3 vs 4 or more, after neoadjuvant letrozole). Conclusions: In HR+/HER2- early BC, HRD gene signatures, RB-loss gene signatures and non-luminal (especially Basal-like) intrinsic subtyping are associated with each other and associated with higher sensitivity to chemotherapy-based therapy and lower sensitivity to endocrine treatment. These observations might help correctly tailor systemic therapy, including biologic agents, in patients with HR+/HER2- early and advanced BC.
2022
- Ocular Toxicity in Breast Cancer Management: Manual for The Oncologist
[Articolo su rivista]
Canino, F.; Omarini, C.; Cerma, K.; Moscetti, L.; Tornincasa, A.; Trudu, L.; Dominici, M.; Piacentini, F.
abstract
Ocular adverse events are common to many antineoplastic agents, although often misunderstood. In most cases, they are easily manageable, but sometimes they require instrumental diagnostics and specific treatments. There are currently no international guidelines for the management of these toxicities. In this review we summarized the main ocular adverse events related to the antineoplastic agents used in the treatment of breast cancer, analyzing their clinical presentation and management, trying to provide a useful tool to be used in clinical practice.
2022
- Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts
[Poster]
Dieci, Maria Vittoria; Bisagni, Giancarlo; Bartolini, Stefania; Frassoldati, Antonio; Giulio Generali, Daniele; Piacentini, Federico; Griguolo, Gaia; Tagliafico, Enrico; Brasó-Maristany, Fara; Chic, Nuria; Porra, Francesca; Vicini, Roberto; D’Amico, Roberto; Balduzzi, Sara; Prat, Aleix; Conte, Pierfranco; Guarneri, Valentina
abstract
Background: All intrinsic molecular subtypes are represented among HER2-positive breast cancer, with implications on clinical outcome and treatment sensitivity. The impact of molecular subtypes on the pattern and site of relapse is largely unexplored.
Methods: 677 patients with HER2-positive early breast cancer from the Shorther trial (n=437), the CherLOB trial (n=84) and two Institutional cohorts (Istituto Oncologico Veneto IRCCS Padova n=39 and Hospital Clinic Barcelona n=117) were included. Only patients with available PAM50 intrinsic molecular subtyping were considered. We analyzed the incidence of distant relapse (at any site and at specific sites) as the first event. Cumulative incidence was estimated according to competing risk analysis (Fine and Gray’s method). Competing risk regression was used to calculate the subdistribution Hazard Ratios (subHR) and their 95% Confidence Interval (CI).
Results: The distribution of molecular subtypes was: 130 LumA (19%), 75 LumB (11%), 347 HER2-e (51%), 46 Basal (7%), 79 Normal (12%). Median follow up was 8.4 years (95%CI 8.2-8.6). The 10-yr cumulative incidence rates of distant relapse as first event were: LumA 7.9%, LumB 14.8%, HER2-e 14.7%, Basal 15.5%, Normal 10.4% (HER2-e vs LumA: SubHR 2.21, 95%CI 1.05-4.64, p=0.037). Table 1 shows the 5-yr and 10-yr cumulative incidence rates of distant metastases at specific sites (as first event) according to intrinsic subtype. HER2-e enriched and Basal tumors were more prone as compared to other subtypes to develop brain and lung metastasis as first event, respectively. Isolated brain metastases without extracranial disease occurred only in patients with HER2-e tumors. All brain metastases as first event occurred within 5 years from diagnosis. Bone-only disease as first event was less frequent in HER2-e and Basal subtype (subHR HER2-e vs LumA: 0.32, 95%CI 0.10-10.4. p=0.058). Next, we analyzed the frequency of site-specific first metastasis among patients who experienced a distant metastasis as first event (n=77). Lung metastases were more frequent in Basal tumors (LumA 25.0%, LumB 20.0%, HER2-e 24.4%, Basal 71.4%, Normal 0.0%, p=0.037) and bone metastases were more frequent in Luminal tumors (LumA 100.0%, LumB 60.0%, HER2-e 31.1%, Basal 42.9%, Normal 57.1%, p=0.006). Among 45 HER2-e patients with a first distant relapse, 25.6% were diagnosed with a brain metastasis and 15.6% had brain-only disease. Conclusions: Molecular subtypes influence the metastatic behaviour of clinically HER2-positive breast cancer. These results, if further validated, may have implication in planning personalized monitoring strategies.
2022
- Predictive factors for relapse in triple-negative breast cancer patients without pathological complete response after neoadjuvant chemotherapy
[Articolo su rivista]
Toss, A.; Venturelli, M.; Civallero, M.; Piombino, C.; Domati, F.; Ficarra, G.; Combi, F.; Cabitza, E.; Caggia, F.; Barbieri, E.; Barbolini, M.; Moscetti, L.; Omarini, C.; Piacentini, F.; Tazzioli, G.; Dominici, M.; Cortesi, L.
abstract
IntroductionTriple-negative breast cancer (TNBC) patients who do not obtain pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) present higher rate of relapse and worse overall survival. Risk factors for relapse in this subset of patients are poorly characterized. This study aimed to identify the predictive factors for relapse in TNBC patients without pCR after NACT. MethodsWomen with TNBC treated with NACT from January 2008 to May 2020 at the Modena Cancer Center were included in the analysis. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of relapse. ResultsWe identified 142 patients with a median follow-up of 55 months. After NACT, 62 patients obtained pCR (43.9%). Young age at diagnosis (<50 years) and high Ki-67 (20%) were signi!cantly associated with pCR. Lack of pCR after NACT resulted in worse 5-year event-free survival (EFS) and overall survival (OS). Factors independently predicting EFS in patients without pCR were the presence of multifocal disease [hazard ratio (HR), 3.77; 95% CI, 1.45-9.61; p=0.005] and residual cancer burden (RCB) III (HR, 3.04; 95% CI, 1.09-9.9; p=0.04). Neither germline BRCA status nor HER2-low expression were associated with relapse. DiscussionThese data can be used to stratify patients and potentially guide treatment decision-making, identifying appropriate candidates for treatment intensi!cation especially in neo-/adjuvant setting.
2022
- Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer.
[Articolo su rivista]
Viansone, A; Pellegrino, B; Omarini, C; Pistelli, M; Boggiani, D; Sikokis, A; Uliana, V; Zanoni, D; Tommasi, C; Bortesi, B; Bonatti, F; Piacentini, F; Cortesi, L; Camisa, R; Sgargi, P; Michiara, M; Musolino, A.
abstract
Background: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients.
Materials and methods: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status.
Results: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7).
Conclusions: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.
2022
- Reply to comments on: Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients
[Articolo su rivista]
Del Re, M.; Omarini, C.; Diodati, L.; Palleschi, M.; Meattini, I.; Crucitta, S.; Lorenzini, G.; Isca, C.; Fontana, A.; Livi, L.; Piacentini, F.; Fogli, S.; De Giorgi, U.; Danesi, R.
abstract
2022
- Role of Intrinsic Subtype Analysis with PAM50 in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A Systematic Review.
[Articolo su rivista]
Canino, F; Piacentini, F; Omarini, C; Toss, A; Barbolini, M; Vici, P; Dominici, M; Moscetti, L.
abstract
Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated.
2022
- Statins increase pathological response in locally advanced rectal cancer treated with chemoradiation: a multicenter experience.
[Articolo su rivista]
Caputo, F; Santini, C; Casadei-Gardini, A; Cerma, K; Bardasi, C; Garajovà, I; Lattanzi, E; Passardi, A; Rapposelli, Ig; Spallanzani, A; Salati, M; Bonetti, Lr; Gelmini, R; Meduri, B; Piccoli, M; Pecchi, A; Benatti, S; Piacentini, F; Dominici, M; Luppi, G; Gelsomino, F.
abstract
Aims: To investigate the influence of various concomitant medications on outcomes in patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. Materials & methods: The authors retrospectively identified 246 patients from 2003 to 2018, collecting demographic and clinicopathological data of interest. Odds ratio (OR) was used to assess the association between concomitant drugs and outcomes. Results: The authors found an association between statins and a Dworak regression grade of 3-4 (OR = 8.78; p = 0.01). Furthermore, statins were significantly associated with more frequent chemoradiation-related toxicity (OR = 2.39; p = 0.0098) and chemotherapy dose reduction or discontinuation (OR = 2.26; p = 0.03). Conclusion: Despite higher frequency of radiotherapy and chemotherapy interruption or dose reduction, the concomitant use of statins during neoadjuvant chemoradiation proved to be associated with better tumor regression.
2022
- Successes and failures of angiogenesis blockade in gastric and gastro-esophageal junction adenocarcinoma
[Articolo su rivista]
Salati, M.; Caputo, F.; Bocconi, A.; Cerri, S.; Baldessari, C.; Piacentini, F.; Dominici, M.; Gelsomino, F.
abstract
Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients’ outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach.
2022
- T-DM1 efficacy in trastuzumab-pertuzumab pre-treated HER2 positive metastatic breast cancer patients: a meta-analysis.
[Articolo su rivista]
Omarini, C; Piacentini, F; Sperduti, I; Cerma, K; Barbolini, M; Canino, F; Nasso, C; Isca, C; Caggia, F; Dominici, M; Moscetti, L.
abstract
Background: Current guidelines consider T-DM1 the standard 2nd line therapy for HER2 positive metastatic breast cancer (MBC) patients following trastuzumab (T) + pertuzumab (P) and taxane 1st line treatment. Despite this, there are no prospective studies supporting this sequence.
Methods: We performed a meta-analysis using real world data to determine the efficacy of T-DM1 after 1st line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the EMILIA phase III pivotal trial.
Results: Seven studies were eligible. The meta-analysis showed a combined 1-year PFS risk difference for T-DM1 efficacy after TP in 2nd or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p = 0.07), with low heterogeneity among studies (I2 0.01%, p = 0.836). Considering the four studies on T-DM1 in 2nd line setting, 1-year PFS risk was -0.034 (95% CI -0.207 - 0,139; p = 0.701) (I2 0.01%, p = 0.91).
Conclusion: Overall, the efficacy of T-DM1 after TP seems to be similar to that previously reported in the EMILIA trial. In the second line setting, data are not mature enough to confirm T-DM1 efficacy in TP pre-treated population.
2021
- Abemaciclib: eventi avversi e riduzione di dose.
[Capitolo/Saggio]
Piacentini, F
abstract
La paziente è una donna di 64 anni, in stato post-menopausale dall’età di 51 anni, in ottime condizioni
cliniche generali (ECOG performance status (PS)=0).
Non riporta significativa familiarità per neoplasie, in particolare per carcinoma mammario e/o ovarico.
In anamnesi: insufficienza renale cronica in stadio III in follow-up nefrologico, ipercolesterolemia con
ateromasia carotidea controllata con statine, intolleranza glucidica in dietoterapia. Dopo oltre cinque
anni dal termine del trattamento chemio e ormonoterapico adiuvante per carcinoma mammario endocrino-
sensibile, le vengono diagnosticate metastasi scheletriche e linfonodali da carcinoma mammario
a fenotipo luminal-A like
2021
- Adding weekly carboplatin to
sequential anthracycline and
paclitaxel-based chemotherapy as
neoadjuvant treatment for triple
negative breast cancer (TNBC)
patients: a propensity scorematched
study
[Abstract in Rivista]
Dieci, M. V.; Carbognin, L.; Cumerlato, E.; Canino, F.; Griguolo, G.; Giorgi, C. A.; Amato, O.; Genovesi, E.; Garufi, G.; Giannarelli, D.; Tornincasa, A.; Trudu, L.; Michieletto, S.; Saibene, T.; Conte, P.; Piacentini, F.; Bria, E.; Guarneri, V.
abstract
Background: The addition of carboplatin (Cb) to neoadjuvant
anthracycline and taxane -based chemotherapy for
TNBC increases pathological complete response (pCR)
rate at the cost of worse hematologic toxicity. However,
treatment schedules and doses adopted in randomized trials
were not always consistent with current clinical practice.
We evaluated the role of adding weekly Cb (wCb) to
neoadjuvant sequential anthracycline and paclitaxel.
Methods: Clinicopathological data of TNBC (ER &
PgR<10%) patients treated at three Institutions (Istituto
Oncologico Veneto IOV-IRCCS – Padova, Policlinico
Gemelli – Roma, AOUI – Modena) were retrieved. Patients
should have received sequential treatment with anthracycline-
based chemotherapy and weekly paclitaxel (A/wP)
with or without wCb. Propensity score was used to control
selection bias. Variables considered for matching were:
age (continuous), cT (cT1 vs cT2 vs cT3-4), cN (pos vs
neg), histologic grade (2 vs 3), BRCA status (mutated vs
non informative or unknown). A caliper width of 0.2 was
applied for matching. Binary logistic regression was used
to test the association of Cb treatment with pCR (ypT0/is
ypN0). Cox regression was used for survival analyses.
Results: 247 patients were included: 60% treated with A/
wP+wCb, 40% with A/wP. Main characteristics: median
age 51 yrs, ductal histology 95%, histologic grade 3 95%,
cT1 18%, cT2 66%, cT3-4 16%, cN+ 51%, BRCA
mutated 13%. After propensity score matching, pCR rate
was significantly higher for A/wP+wCb vs A/wP in logistic
regression analysis corrected for matching variables:
47% vs 33% (OR 2.14 95%CI 1.08-4.23, p=0.029).
Grade⩾3 neutropenia was more frequent with wCb (35%
vs 47%). The achievement of pCR was significantly
10 Tumori Journal 107(2S)
associated with improved disease-free survival (HR 0.26,
95%CI 0.11-0.63, p=0.003). No difference in disease-free
survival was observed comparing A/wP+wCb vs A/wP:
HR 1.50, 95%CI 0.79-2.85, p=0.220.
Conclusions: The relative and absolute positive effect on
pCR of adding wCb to sequential A/wP in a clinical practice
setting is in line with data from randomized trials
adopting different treatment schedules. Inclusion of wCb
increases the risk of hematologic toxicity. Additional data
are needed to clarify the impact on long-term survival.
These results support the conditional positive GRADE
recommendation for Cb inclusion in neoadjuvant chemotherapy
for TNBC provided by the AIOM Guidelines on
Breast Cancer.
2021
- Adjuvant exemestane or
tamoxifen plus ovarian
suppression in premenopausal
women: single institution
analysis
[Abstract in Rivista]
D'Onofrio, R.; Piacentini, F.; Barbolini, M.; Isca, C.; Nasso, C.; Caggia, F.; Dominici, M.; Moscetti, L.; Omarini, C.
abstract
Background: The combined analysis of data from TEXT
and SOFT trials shows that among premenopausal women
with hormone receptor-positive (HR+) breast cancer
(BC), adjuvant endocrine therapy (AET) with exemestane
(EXE) plus ovarian function suppression (OFS) improved
disease-free survival compared to tamoxifen (TAM) plus
OFS. We conducted a single institution analysis to compare
the activity and safety of both treatment strategies.
Patients And Methods: The data on tumor and patient’s
characteristics of premenopausal women treated with AET
from January 2014 to December 2018 in our institution
were retrospectively collected. Treatment toxicities were
graded according to CTCAE v5. Survival data were analyzed
by Kaplan Meier curves and log rank test.
Results: 237 patients were included in the study: 120 on
TAM / OFS and 117 on EXE/OFS. Notably, 43 patients
(18%) started AET in 2014 (before TEXT/SOFT data):
93% of these were treated with TAM/OFS versus only 7%
with EXE/OFS. Women on EXE/OFS had more high-risk
early BC compared to those on TAM/OFS (STAGE III
23,9% vs 6,6%; luminal B-like 34,2% vs 21,6%; T> 2 cm
68,4% vs 32,5%; nodal status positive 66,6% vs 36,6% -
all p value <0,01). According with risk of relapse, the
number of patients pre-treated with chemotherapy was
higher in EXE/OFS group (79,5% versus 37,5%, p value
<0,001) than TAM/OFS one. Extended therapy was
accepted by 50% of patients in the TAM/OFS group and
47% in the EXE/OFS group. Any grade adverse events
(AE) were observed in 77 (64%) and 101 (86%) patients in
TAM/OFS and EXE/OFS group, respectively. In particular,
the incidence of G3 AEs was significantly higher in the
EXE/OFS group and mainly represented by muscoloskeletal
symptoms, osteoporosis and hypertension. Eighteen
(15,4%) women discontinued EXE and switched to an
alternate ET (TAM or NSAI) due to treatment toxicity. No
statistically significant difference in terms of relapse freesurvival
was observed between the two groups.
A – Breast Cancer 27
Conclusions: In our analysis, the choice of the AET is
driven mainly from the risk of relapse. EXE/OFS represents
the main choice in the high-risk patients as per SOFT/
TEXT trials results. TAM/OFS represent the main chose
antecedent to the SOFT/TEXT results (2014/2015).The
frequency and the grade of AEs were higher in EXE group
than TAM one. The AET should be proposed based on
both, risk of relapse and treatment toxicity profile. An
update analysis will be presented at the meeting.
2021
- Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature
[Articolo su rivista]
Isca, Chrystel; Piacentini, Federico; Mastrolia, Ilenia; Masciale, Valentina; Caggia, Federica; Toss, Angela; Piombino, Claudia; Moscetti, Luca; Barbolini, Monica; Maur, Michela; Dominici, Massimo; Omarini, Claudia
abstract
2021
- Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients.
[Articolo su rivista]
Del Re, M; Omarini, C; Diodati, L; Palleschi, M; Meattini, I; Crucitta, S; Lorenzini, G; Isca, C; Fontana, A; Livi, L; Piacentini, F; Fogli, S; De Giorgi, U; Danesi, R.
abstract
Background: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients.
Patients and methods: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as 'no concomitant PPIs' if no PPIs were administered during palbociclib treatment, and as 'concomitant PPIs' if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice.
Results: A total of 112 patients were enrolled in the study; 56 belonged to the 'no concomitant PPIs' group and 56 to the 'concomitant PPIs' group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P < 0.0001). Multivariate analysis confirmed concomitant PPIs as the only independent predictive factor for shorter PFS (P = 0.0002). PFS was significantly longer in estrogen-sensitive mBC with no concomitant PPIs compared with patients taking PPIs or estrogen-resistant patients, with and without PPIs (P < 0.0001). No correlation with adverse events was found when considering grade >2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale].
Conclusions: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP).
2021
- Drug-drug interactions between
palbociclib and proton pump
inhibitors may significantly
affectclinical outcome of
metastatic breast cancer
patients
[Abstract in Rivista]
Del Re, M.; Omarini, C.; Diodati, L.; Palleschi, M.; Meattini, I.; Crucitta, S.; Isca, C.; Fogli, S.; Bleve, S.; Lorenzini, G.; Fontana, A.; Livi, L.; Piacentini, F.; De Giorgi, U.
abstract
Background: Proton pump inhibitors (PPIs) are widely
used in cancer patients to mitigate adversegastroesophageal
events polypharmacy-associated. However, drugdrug
interactions (DDIs) atabsorption level should be
considered as it may affect clinical outcome. Palbociclib is
a weak basewith pH-dependent solubility that rapidly
decreases as pH increases above 4.5 (Clin Pharmacol
DrugDev 2017;6:614-6).
The current study was aimed at investigating the effect of
concomitant PPIs on palbociclibprogression free survival
(PFS) in metastatic breast cancer (mBC) patients.
Materials and methods: ER+, HER-2- mBC patients
candidate to palbociclib as first line treatment were
enrolled in thisretrospective observational study. Patients
were defined as “no concomitant PPIs” if no PPI wereadministered
during palbociclib, and as “concomitant PPIs”
if the administration of PPIs covered theentire or not less
than 2/3 of treatment with palbociclib. All clinical interventions
were madeaccording to clinical practice.
Results: A total of 112 patients were enrolled; 56 belonged
to “no concomitant PPIs” during palbociclibtreatment and
55 to the "concomitant PPIs” group. Seventy-one patients
were endocrine sensitive(ES) and were administered palbociclib
+ letrozole and 43 were endocrine resistant (ER)
and weretreated with palbociclib + fulvestrant. The most
prescribed PPI was lansoprazol. Patients werestratified
according to PFS, showing that patients taking PPIs had a
shorter PFS compared to patientsassuming palbociclib +
hormone-therapy alone (14 vs 38 months, p<0.0001).
Multivariate analysisconfirmed the use of concomitant
PPIs as the only independent predictive factor for shorter
PFS(p=0.0002). PFS was significantly longer in ES mBC
with no concomitant PPIs compared to patientstaking PPIs
or ER patients with and without PPIs (p<0.0001). No correlation
with adverse events wasfound considering G>2
hematological toxicities.
Conclusions: The present study demonstrates that concomitant
use of PPIs in mBC patients treated withpalbociclib
A – Breast Cancer 13
has a detrimental effect on PFS. Therefore, it is recommended
to prescribe PPI withcaution in these patients, or
administering H2-antagonists or PPI for very short periods.
2021
- Immune microenvironment and intrinsic subtyping in hormone receptor-positive/HER2-negative breast cancer.
[Articolo su rivista]
Griguolo, G; Dieci, Mv; Paré, L; Miglietta, F; Generali, Dg; Frassoldati, A; Cavanna, L; Bisagni, G; Piacentini, F; Tagliafico, E; Cagossi, K; Ficarra, G; Prat, A; Conte, P; Guarneri, V.
abstract
Little is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2- breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2- early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.
2021
- Next Generation Sequencing
(NGS): a possible game changer in
metastatic breast cancer
[Abstract in Rivista]
Barbolini, M.; Omarini, C.; Moscetti, L.; Canino, F.; Trudu, L.; Tornincasa, A.; Caggia, F.; Bettelli, S.; Manfredini, S.; Isca, C.; Molinaro, A.; Dominici, M.; Piacentini, F.
abstract
Background: NGS has been introduced into the clinics
with the aim of sequencing long and complex genes for
tumor sample, in order to identify driver and/or targetable
alterations. Several companies and academic centers have
implemented NGS assays to guide treatment decisions,
even though there are no clear recommendations from scientific
societies about their use in daily clinical practice.
Patients and methods: Since 2019 NGS analysis was performed
in 32 MBC patients’ tissues at Modena Cancer
Center, as for clinical judgement during the course of
MBC. Oncomine™ was mainly used for the assay. The
aim was to define the PI3K mutational status, since
Alpelisib - an a-subunit selective PI3K inhibitor - had
shown to improve PFS in PI3K mutated HR+/HER2-
MBC patients in SOLAR-1 and BYLIEVE trials.
Results: Twenty (62%) NGS analysis were performed on
MBC samples, the other (13) on primary breast cancer.
Table1 summarize the clinical-pathological characteristics
of patients. At least 1 mutation was found in 25 (78%)
samples. A PI3K mutation was detected in 14 (44%) cases,
with E542K as the most frequent. In 10 out of 14 cases,
PI3K mutation was associated with other gene mutations.
FGFR3, FGFR4 mutations and FGFR2 amplification were
described in 4, 2 and one patients respectively. Two
patients showed AKT1 mutation, in one case was associated
with PTEN mutation. Two of the patients with PI3K
mutation were treated with Alpelisib + Fulvestrant. The
patient with FGFR1 amplification was eligible for a phase
II clinical trial.
Conclusions: NGS performed in this cohort of MBC
patients allowed therapeutic decisions in about 10% of
cases. Although PI3K mutational status for eligibility to
Alpelisib can be cheaply studied by RT-PCR, NGS assay
can provide wider information about other gene mutations,
useful for patients’ selection for clinical trials. In the
era of precision medicine, knowing the mutational status
of MBC early in patient history can change the therapeutic
algorithm.
2021
- Palbociclib in a patient with HR+/HER2- advanced breast cancer and HIV1 infection: A case report
[Articolo su rivista]
Canino, F.; Moscetti, L.; Borghi, V.; Dominici, M.; Piacentini, F.
abstract
The use of drugs that affect the cell cycle represents one of the common strategies for the control of some unrelated pathologies, such as chronic viral HIV infections or cancer. The authors report the case of a patient followed for a hormone receptor-positive (HR+)/HER2 negative (HER2-) advanced breast cancer, treated with hormone therapy and CDK 4/6 inhibitors, and a concomitant HIV infection under antiretroviral treatment. The authors consider the function of the sterile alpha motif and HD domain-containing protein-1 (SAMHD1) enzyme, its implications in the control of viral replication and the correlation between its activity and the mechanism of action of the CDK 4/6 inhibitor palbociclib.
2021
- Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).
[Articolo su rivista]
Pellegrino, B; Cavanna, L; Boggiani, D; Zamagni, C; Frassoldati, A; Schirone, A; Caldara, A; Rocca, A; Gori, S; Piacentini, F; Berardi, R; Brandes, Aa; Foglietta, J; Villa, F; Todeschini, R; Tognetto, M; Naldi, N; Bortesi, B; Montemurro, F; Ardizzoni, A; Boni, L; Musolino, A
abstract
Background: The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance.
Patients and methods: This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen.
Results: From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS.
Conclusions: The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity.
2021
- Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens
[Poster]
Viansone, Alessandro; Omarini, Claudia; Boggiani, Daniela; Sikokis, Angelica; Uliana, Vera; Pellegrino, Benedetta; Piacentini, Federico; Michiara, Maria; Musolino, Antonino
abstract
Background: HER2-amplified breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinico-histological characteristics and prognosis of this subgroup of patients. Materials and Methods: Using a retrospective matched cohort design, we collected data from 728 women who were diagnosed with breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinical and histological characteristics of the primary tumor, time to relapse, and survival were analyzed by BRCA and HER2 status. Results: One hundred and twenty HER2-positive, BRCA mutated cases were evaluated with respect to three control groups: HER2-positive, BRCA wild-type (n=136); HER2-negative, BRCA-mutated (n=226); HER2-negative, BRCA wild-type (n=246). Breast cancers with hormone receptor-negative status or high histologic grade (odds ratio=1.7; 95% confidence interval [CI]: 1.0-2.9) were more likely HER2-positive, with no restriction by BRCA mutation status. Disease-free and overall survival for HER2-positive, BRCA mutated cases were lower than those for the other subgroups. An interaction between BRCA mutations and HER2-positive status was found for poorer overall survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Germline BRCA mutations confer worse prognosis in patients with HER2-positive breast cancer. Ongoing trials testing novel therapeutic approaches (e.g. anti-HER2 therapies combined with PARP inhibitors) are warranted
2021
- Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe
[Articolo su rivista]
Moscetti, L.; Sperduti, I.; Frassoldati, A.; Musolino, A.; Nasso, C.; Toss, A.; Omarini, C.; Dominici, M.; Piacentini, F.
abstract
In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician.
2021
- Quality of life of therapies
for hormone receptor positive
advanced/metastatic breast
cancer (HR+/HER2- mBC):
regulatory aspects and clinical
impact in Europe
[Abstract in Rivista]
Moscetti, ; Sperduti, I.; Frassoldati, A.; Musolino, A.; Nasso, C.; Toss, A.; Omarini, C.; Dominici, M.; Piacentini, F.
abstract
Background: In recent years the number of trials that
incorporated health related quality of life (HRQoL) data
has increased. The impact of HRQoL on the regulatory
decision making in the European regulatory context and on
clinical practice is not well established. We conduct an
analysis of the role of QoL data extracted from the pivotal
trials of the drugs approved for HR+/HER2- mBC, to discuss
their impact on the regulatory decision making in the
European regulatory context and the possible impact on
clinical practice.
Methods: We identified all products approved for mBC by
the European Medicines Agency (EMA) based on the
European public assessment reports (EPARs) that are publicly
available on the agency’s website.The following substances
has been evaluated: letrozole, anastrozole,
exemestane, fulvestrant, ribociclib, palbociclib, abemaciclib,
alpelisib. The results of the HRQoL analysis form the
pivotal trials have been collected and a metanalysis has
been performed to evaluate the impact of experimental
drugs if compared to the standard treatments. All the
EPARs available from the EMA website have been checked
to verify the presence of the HRQoL in the discussion and
in the benefit risk assessment. The related summary of
medicine products characteristics (SmPCs) have been verified
to evaluate the presence of the HRQoL data in the
section 5.1
Results: 7 out of the 9 active substances taken in account
in the current analysis incorporated the HRQoL data in the
description of the result of the pivotal trials. Seventeen
trial has been identified, in fourteen the QoL was included
as a secondary endpoint. A global improvement in the
global QoL, considering the Time To deterioration >10,
was observed, pointing out the consistency of the efficacy
of the new substances if compared to the standard treatment.
As regards the approval process from the analysis of
the EMA documents, the HRQoL were reported quite
shortly and contained and discussed in the EPARs of
eleven trials in the approval process and cited in three
cases in the EPARs and summary of medicine products
characteristics (SmPC).
Conclusions: An effort should be done from all the stakeholders
to increase the visibility of the HRQoL results in
order to allow an increasing consideration in the approval
process to make QoL data more easily and visibly available
for the clinician and the patients. The evaluation should
be reflected in the SmPC in order to increase the amount of
information provided to the physician.
2021
- TDM-1 efficacy in trastuzumab-pertuzumab pre-treated HER2 positive metastatic breast cancer patients: A meta-analysis
[Abstract in Atti di Convegno]
Omarini, Claudia; Piacentini, Federico; Sperduti, Isabella; Cerma, Krisida; Barbolini, Monica; Canino, Fabio; Nasso, Cecilia; Dominici, Massimo; Moscetti, Luca
abstract
Background: Based on the results reported in Emilia trial population, current guidelines consider TDM-1 the standard second-line therapy for HER2 positive metastatic breast cancer (MBC) patients. Despite that, there are no prospective studies supporting the efficacy of TDM-1 following trastuzumab (T) + pertuzumab (P) and taxane first-line treatment. Currently, only real-world data have investigated this sequence with controversial results Methods: We performed a meta-analysis of the available real world data to determine the efficacy of TDM-1 after first-line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the phase III Emilia trial (T pre-treated population). Results: Seven studies were eligible, in three of them data were from sub-group population analysis. The meta-analysis showed a combined 1-years PFS risk difference for TDM-1 efficacy after TP in second or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p=0.07) , with low heterogeneity among studies (I2 < 0.0001, p =0.836). Considering the four studies on TDM-1 in second-line setting, 1-years PFS risk was -0.034 (95% CI -0.207 – 0,139; p=0.701) (I2 < 0.0001, p =0.91). Conclusions: Results from the meta-analysis show that the efficacy of TDM-1 after TP double-block seems to be similar to the previously reported in Emilia trial. In the second line setting, available data are not mature enough to confirm TDM-1 efficacy in TP pre-treated population. Currently, TP pretreated patients should receive TDM-1 as indicated in the guidelines.
2021
- TDM-1 efficacy in trastuzumabpertuzumab
pre-treated HER2
positive metastatic breast cancer
patients: a meta-analysis
[Abstract in Rivista]
Omarini, C.; Piacentini, F.; Sperduti, I.; Cerma, K.; Barbolini, M.; Canino, F.; Nasso, C.; Isca, C.; Caggia, F.; Dominici, M.; Moscetti, L.
abstract
Background: Based on the results reported in Emilia trial
population, current guidelines consider TDM-1 the standard
2nd line therapy for HER2 positive metastatic breast
cancer (MBC) patients. Despite that, there are no prospective
studies supporting the efficacy of TDM-1 following
trastuzumab (T) + pertuzumab (P) and taxane 1st line
treatment. Currently, only real-world data have investigated
this sequence with controversial results.
Methods: We performed a meta-analysis of the available
real world data to determine the efficacy of T-DM1 after 1st
line TP in HER2 positive MBC patients. We used a random-
effect model to find differences in the rate of 1-year
progression free survival (PFS) between TP pre-treated
population and the phase III Emilia trial (T pre-treated
population).
Results: Seven studies were eligible, in three of them data
were from sub-group population analysis. The meta-analysis
showed a combined 1-years PFS risk difference for
TDM-1 efficacy after TP in 2nd or more lines of -0.122, with
lower and upper limits of -0.253 and 0.010, respectively
(p=0.07), with low heterogeneity among studies (I2 <
0.0001, p =0.836). Considering the four studies on TDM-1
in 2nd line setting, 1-years PFS risk was -0.034 (95% CI
-0.207 – 0,139; p=0.701) (I2 < 0.0001, p =0.91).
Conclusions: Results from the meta-analysis show that
the efficacy of TDM-1 after TP double-block seems to be
similar to the previously reported in Emilia trial. In the
second line setting, available data are not mature enough
to confirm TDM-1 efficacy in TP pre-treated population.
Currently, TP pretreated patients should receive T-DM1 as
indicated in the guidelines.
2021
- The growing skyline of advanced hepatocellular carcinoma treatment: A review.
[Articolo su rivista]
Schipilliti, F. M.; Garajova, I.; Rovesti, G.; Balsano, R.; Piacentini, F.; Dominici, M.; Gelsomino, F.
abstract
Hepatocellular carcinoma (HCC) is the main type of liver cancer. In the majority of cases, HCC is diagnosed at the advanced stage, leading to poor prognosis. In recent years, many efforts have been devoted to investigating potential new and more effective drugs and, indeed, the treatment armamentarium for advanced HCC has broadened tremendously, with targeted- and immune-therapies, and probably the combination of both, playing pivotal roles. Together with new established knowledge, many issues are emerging, with the role of neoadjuvant/adjuvant settings, the definition of the best transitioning time from loco-regional treatments to systemic therapy, the identification of potential predictive biomarkers, and radiomics being just some of the topics that will have to be further explored in the next future. Clearly, the current COVID-19 pandemic has influenced the management of HCC patients and some considerations about this topic will be elucidated.
2021
- The Prognostic Role of Early Skeletal Muscle Mass Depletion in Multimodality Management of Patients with Advanced Gastric Cancer Treated with First Line Chemotherapy: A Pilot Experience from Modena Cancer Center
[Articolo su rivista]
Rimini, M; Pecchi, A; Prampolini, F; Bussei, C; Salati, M; Forni, D; Martelli, F; Valoriani, F; Canino, F; Bocconi, A; Gelsomino, F; Reverberi, L; Benatti, S; Piacentini, F; Menozzi, R; Dominici, M; Luppi, G; Spallanzani, A
abstract
Background: Few data about the link between nutritional status and survival are available in the metastatic gastric cancer (GC) setting. The aim of this work was to evaluate the prognostic role of tissue modifications during treatment and the benefit of a scheduled nutritional assessment in this setting. Methods: Clinical and laboratory variables of 40 metastatic GC patients treated at Modena Cancer Center were retrieved: 20 received a nutritional assessment on the oncology’s discretion, the other 20 received a scheduled nutritional assessment at baseline and every 2–4 weeks. Anthropometric parameters were calculated on Computed Tomography (CT) images at the baseline and after 3 months of chemotherapy. Results: A correlation between baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS), Lymphocyte to Monocyte Ratio (LMR), C-reactive protein (PCR), Prognostic Nutritional Index (PNI) and Overall survival (OS) was highlighted. Among the anthropometric parameters, early skeletal muscle mass depletion (ESMMD) >10% in the first months of treatment significantly impacted on mOS (p = 0.0023). A link between ESMMD and baseline LDH > 460 U/L, baseline CRP > 2.2 mg/dL and weight decrease during treatment emerged. Patients evaluated with a nutritional scheduled support experienced a mean gain in subcutaneous and visceral fat of 11.4% and 10.21%, respectively. Conclusion: We confirm the prognostic impact of ESMMD > 10% during chemotherapy in metastatic GC. The prognostic role of a scheduled nutritional assessment deserves further confirmation in large prospective trials.
2021
- The Role of Exosomes in Breast Cancer Diagnosis.
[Articolo su rivista]
Piombino, C; Mastrolia, I; Omarini, C; Candini, O; Dominici, M; Piacentini, F; Toss, A.
abstract
The importance of molecular re-characterization of metastatic disease with the purpose of monitoring tumor evolution has been acknowledged in numerous clinical guidelines for the management of advanced malignancies. In this context, an attractive alternative to overcome the limitations of repeated tissue sampling is represented by the analysis of peripheral blood samples as a 'liquid biopsy'. In recent years, liquid biopsies have been studied for the early diagnosis of cancer, the monitoring of tumor burden, tumor heterogeneity and the emergence of molecular resistance, along with the detection of minimal residual disease. Interestingly, liquid biopsy consents the analysis of circulating tumor cells, circulating tumor DNA and extracellular vesicles (EVs). In particular, EVs play a crucial role in cell communication, carrying transmembrane and nonmembrane proteins, as well as metabolites, lipids and nucleic acids. Of all EVs, exosomes mirror the biological fingerprints of the parental cells from which they originate, and therefore, are considered one of the most promising predictors of early cancer diagnosis and treatment response. The present review discusses current knowledge on the possible applications of exosomes in breast cancer (BC) diagnosis, with a focus on patients at higher risk.
2021
- Thromboembolism (TE) and adjuvant endocrine therapy (AET) in hormone receptor positive (HR+) early breast cancer (EBC): Did the evolution of treatment change the incidence of the adverse event? A metanalysis
[Abstract in Atti di Convegno]
Moscetti, Luca; Omarini, Claudia; Sperduti, Isabella; Canino, Fabio; Barbolini, Monica; Nasso, Cecilia; Toss, Angela; Dominici, Massimo; Piacentini, Federico
abstract
Background: The AET of HR+ EBC has been changing in the recent years. Aromatase inhibitors (AI) as upfront, or in a planned switch strategy after Tamoxifen (T), have been added to the choice of T alone. An increased risk of TE is well known in the T treated patients while AIs have showed a reduced rate of TE. Recently, adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) abemaciclib to AIs, has showed a positive impact in the high risk HR+ EBC subgroups, but we are seeing an increase of the TE rate. We conducted this meta-analysis to evaluate the impact of the new AETs on the incidence of TE if compared to the standard monotherapy. Methods: We performed a meta-analysis of the randomized phase III trials comparing the experimental AETs and the endocrine standard therapy. A random-effect model to find differences in the rate of TE events between the experimental treatments and the standard therapy has been used. Results: Twelve phase III trials were included. Five trials evaluated the upfront strategy, 6 studies the switch and one the combination with a CDK4/6inhibitor (i.e. abemaciclib). Overall, the new AETs did not significantly modify or affect the rate of TE events (OR 0.708, 0.444-1.130, p = 0.148) with high heterogeneity among studies (I2 87, p < 0.0001). Excluding the abemaciclib trial, the incidence of TE is reduced (OR 0.609, 0.462-0.802, p < 0.0001) with a moderate heterogeneity among the studies (I2 59, p < 0.006). Considering the upfront strategies with AIs, the TE events are reduced (OR 0.507, 0.394-0.651, p < 0.0001) but they are not if we consider the trials in which T is used upfront before AIs (OR 0.762, 0.546-1.065, p = 0.112). Conclusions: Overall, the new treatments (AIs alone or plus CDK4/6 inhibitors) did not affect the rate in TE events. AIs as upfront strategy is the safest AETs of HR+ EBC, being associated to the lowest incidence of TE. The switch strategy increases the TE rate whereas the addition of abemaciclib to the standard AET showed to significantly increase the TE events. The results of the currently ongoing trials with the CDK4/6 inhibitors will help to obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and to clarify the weight of the TE adverse events in the balance of benefit/risk of this new adjuvant strategy.
2021
- Trastuzumab-lapatinib as neoadjuvant therapy for HER2-positive early breast cancer: Survival analyses of the CHER-Lob trial
[Articolo su rivista]
Guarneri, V.; Dieci, M. V.; Griguolo, G.; Miglietta, F.; Girardi, F.; Bisagni, G.; Generali, D. G.; Cagossi, K.; Sarti, S.; Frassoldati, A.; Gianni, L.; Cavanna, L.; Pinotti, G.; Musolino, A.; Piacentini, F.; Cinieri, S.; Prat, A.; Conte, P.
abstract
Aim: The Cher-LOB randomised phase II study showed that the combination of lapatinib-trastuzumab plus chemotherapy increases pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here, we report the post hoc survival analysis as per treatment arm, pCR and biomarkers. Methods: The Cher-LOB study randomised 121 patients with human epidermal growth factor receptor 2–positive, stage II–IIIA breast cancer. A specific protocol to collect recurrence-free survival (RFS) and overall survival (OS) data was designed. Tumour-infiltrating lymphocytes (TILs) and PAM50-intrinsic subtyping were evaluated at baseline. Results: At 9-year median follow-up, a trend towards RFS improvement with lapatinib-trastuzumab over trastuzumab was observed (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.18–1.05). Combining treatment arms, pCR was significantly associated with both RFS (HR 0.12, 95% CI 0.03–0.49) and OS (HR 0.12, 95% CI 0.03–0.49). TILs were significantly associated with RFS (HR = 0.978 for each 1% increment). Luminal-A subtype was a significant and independent predictor of improved RFS as compared with other PAM50-based intrinsic subtypes at the multivariate analysis including the most relevant clinicopathologic variables (HR 0.29, 95% CI 0.09–0.94, p = 0.040). Conclusions: Cher-LOB trial survival analysis confirmed the prognostic role of pCR and TILs and showed a signal for a better outcome with lapatinib-trastuzumab over trastuzumab. Trial registration: NCT00429299.
2021
- Two-month stop in mammographic screening significantly impacts on breast cancer stage at diagnosis and upfront treatment in the COVID era
[Articolo su rivista]
Toss, A; Isca, C; Venturelli, M; Nasso, C; Ficarra, G; Bellelli, V; Armocida, C; Barbieri, E; Cortesi, L; Moscetti, L; Piacentini, F; Omarini, C; Andreotti, A; Gambini, A; Battista, R; Dominici, M; Tazzioli, G
abstract
The present analysis aims to evaluate the consequences of a 2-month interruption of mammographic screening on breast cancer (BC) stage at diagnosis and upfront treatments in a region of Northern Italy highly affected by the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus.
2020
- A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation
[Articolo su rivista]
Prat, A; Guarneri, V; Paré, L; Griguolo, G; Pascual, T; Dieci, Mv; Chic, N; González-Farré, B; Frassoldati, A; Sanfeliu, E; Cejalvo, Jm; Muñoz, M; Bisagni, G; Brasó-Maristany, F; Urso, L; Vidal, M; Brandes, Aa; Adamo, B; Musolino, A; Miglietta, F; Conte, B; Oliveira, M; Saura, C; Pernas, S; Alarcón, J; Llombart-Cussac, A; Cortés, J; Manso, L; López, R; Ciruelos, E; Schettini, F; Villagrasa, P; Carey, La; Perou, Cm; Piacentini, F; D'Amico, R; Tagliafico, E; Parker, Js; Conte, P
abstract
Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer.
Methods: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data.
Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1).
Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.
2020
- Cancer treatment during the coronavirus disease 2019 pandemic: Do not postpone, do it!
[Articolo su rivista]
Omarini, C.; Maur, M.; Luppi, G.; Narni, F.; Luppi, M.; Dominici, M.; Longo, G.; Piacentini, F.
abstract
At the end of January 2020, a novel betacoronavirus, known as severe acute respiratory syndrome coronavirus 2, progressively spread in Italy. Patients with cancer are considered more prone to infections because of the immunosuppressive status due to both malignancy and anticancer treatments. From the first Italian government restrictions (23rd February), Modena Cancer Center adopted practical health vigilance recommendations to minimise the risk of exposure to the virus without overlooking cancer management. From 23rd February to 31st March 2020, 1257 patients on active anticancer treatment for oncological or haematological malignancies attended our institution. All the staff activities were rescheduled following our practical coronavirus disease 2019 (COVID-19) guideline. During this period, we have tallied 9 cases of COVID-19 infection (0.71%) in patients with cancer and 3 cases (1.66%) in health workers. The mortality rate of our patients with cancer was 22%, consistent with the data reported in the literature. In conclusion, following our practical health vigilance recommendations, physicians should be confident in maintaining life-saving anticancer treatment without exceedingly increasing the risk of nosocomial COVID-19 infection. The high rate of mortality suggested that all patients on active anticancer treatment with flu-like symptoms have to be carefully screened for COVID-19 infection.
2020
- Clinical Prognosticators in Patients Treated with CDK 4/6 Inhibitors for Hormone Receptors Positive Advanced Breast Cancer
[Articolo su rivista]
Isca, Chrystel; Omarini, Claudia; Cortesi, Giulia; Moscetti, Luca; Barbolini, Monica; Dominici, Massimo; Piacentini, Federico
abstract
Background: CDK4/6 inhibitors are the new standard of care in hormonal receptors positive (HR+) advanced
breast cancer (ABC). Phase III trials demonstrated an improvement in survival outcomes in patients with combined
endocrine approach compared to endocrine therapy (ET) alone. The aim of this retrospective study was to assess
prognostic factors for clinical response to CDK4/6 inhibitors.
Methods: All patients receiving CDK4/6 inhibitors from September 2016 to July 2019 were registered in a database.
Data on tumor and patient’s characteristics as well as concomitant medications were collected. Survival data were
analyzed by Kaplan Meier curves and log rank test. Treatment toxicities were graded according to CTCAE v5. A
drug-drug interactions analysis among CDK 4/6 inhibitors and co-administered medications was performed too.
Results: 121 patients were included in the study: 49% of patients treated in 1st -line, 25% in 2nd -line and 26%
in 3rd –or further lines. 1st-line objective response rate (ORR) and clinical benefit rate (CBR) was 56% and 68%,
compared to 40% and 50% in 2nd-line and 31% and 47% in heavily pre-treated patients, respectively. Median PFS
according to line setting was: not reached in 1st-line, 17 months (95% CI 13-21) in 2nd-line and 7 months (95% CI
4-12) in 3rd or further lines. Negative prognostic factors in term of PFS were: previous chemotherapy for metastatic
disease (p=0.0001), visceral metastatic sites (p=0.002) and endocrine sensitivity (p=0.001). No association among
concomitant drugs administered and survival outcome was found. 94% of patients experienced neutropenia (G3-G4
60%) with 3% of febrile neutropenia. 71% of patients treated with Abemaciclib had diarrhea. Management of AE
included 63% of treatment delay, 44% of 1st dose reduction and 15% of 2nd dose reduction, all due to neutropenia.
No treatment discontinuation due to any toxicity was observed.
Conclusion: Data on efficacy and safety profile of CDK 4/6 inhibitors administered outside the context of a clinical
trial are consistent with those reported in Phase III trials. Previous chemotherapy for metastatic disease, visceral
metastatic site as well as previous endocrine sensitivity negatively affect CDK 4/6 inhibitors efficacy. Concomitant
medications did not affect survival outcome or safety profile.
2020
- Combined endocrine approaches vs endocrine therapy alone as first line treatment in elderly patients with hormone receptor-positive, HER2 negative, advanced breast cancer: To prescribe for the patient or the physician? A meta-analysis of phase II and III randomized clinical trials
[Articolo su rivista]
Omarini, C.; Piacentini, F.; Sperduti, I.; Barbolini, M.; Isca, C.; Toss, A.; Cortesi, L.; Barbieri, E.; Dominici, M.; Moscetti, L.
abstract
Background: Elderly patients are underrepresented in clinical study where combined endocrine strategies were compared to endocrine therapy (ET) in hormone receptors positive, HER2 negative, metastatic breast cancer. The role of the new endocrine approaches in elderly women is still unclear. Methods: We performed a meta-analysis of first line phase II/III randomized trials on ET versus combined strategies considering clinical benefit and safety profile. Trials with hazard ratio (HR) for PFS in elderly patients were included. Results: Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. For patients on CDK 4/6 inhibitors and ET, HR was 0.57 (p < 0.0001), with low heterogeneity [I2 0.0001%, p 0.96]. Hematological adverse events, as well as diarrhea with Abemaciclib, were significantly higher in elderly population. Conclusions: The magnitude of PFS benefit due to the combined strategies in elderly patients is similar to those reported in the overall clinical trial population. Adding CDK4/6 inhibitors to ET significantly prolongs PFS, even if toxicity profile have to be carefully considered. Future trials should be designed taking into account patients' age, geriatric assessment and comorbidity.
2020
- Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting
[Articolo su rivista]
Pizzuti, L; Krasniqi, E; Barchiesi, G; Della Giulia, M; Izzo, F; Sanguineti, G; Marchetti, P; Mazzotta, M; Giusti, R; Botticelli, A; Gamucci, T; Natoli, C; Grassadonia, A; Tinari, N; Iezzi, L; Tomao, S; Tomao, F; Tonini, G; Santini, D; Astone, A; Michelotti, A; De Angelis, C; Mentuccia, L; Vaccaro, A; Magnolfi, E; Gelibter, A; Magri, V; Cortesi, E; D'Onofrio, L; Cassano, A; Rossi, E; Cazzaniga, M; Moscetti, L; Omarini, C; Piacentini, F; Fabbri, Ma; Scinto, Af; Corsi, D; Carbognin, L; Bria, E; La Verde, N; Samaritani, R; Garufi, C; Barni, S; Mirabelli, R; Sarmiento, R; Veltri, E; D'Auria, G; Paris, I; Giotta, F; Lorusso, V; Cardillo, F; Landucci, E; Mauri, M; Ficorella, C; Roselli, M; Adamo, V; Ricciardi, Grr; Russo, A; Berardi, R; Pistelli, M; Fiorio, E; Cannita, K; Sini, V; D'Ostilio, N; Foglietta, J; Greco, F; Zamagni, C; Garrone, O; Di Cocco, B; Baldini, E; Livi, L; Desideri, I; Meattini, I; Sarobba, G; Del Medico, P; De Tursi, M; Generali, D; De Maria, R; Risi, E; Ciliberto, G; Sperduti, I; Villa, A; Barba, M; Di Leo, A; Vici, P.
abstract
We analyzed data from 738 HER2‐positive metastatic breast cancer (mbc) patients treated with pertuzumab‐based regimens and/or T‐DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression free survival at first‐line (mPFS1) was 12 months. Pertuzumab as first‐line conferred longer mPFS1 compared to other first‐line treatments (16 vs 9 months, p=0.0001), regardless of IHC subtype. Median PFS in second‐line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T‐DM1 compared to other agents (7 vs 6 months, p=0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs) (p=0.17), while a trend emerged for tumors with one HR (p=0.05). Conversely, PFS2 gain was significant in HRs‐negative tumors (p=0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T‐DM1 in second‐line following pertuzumab were significantly lower compared to pertuzumab‐naïve patients(p=0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p=0.02 and p=0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment‐related outcomes of HER2‐positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor (ER) pathways in HER2‐positive (mbc) patients.
2020
- Interstitial Lung Disease in Abemaciclib-treated Patients during SARS-CoV-2 Pandemic: A Case Series.
[Articolo su rivista]
Barbolini, Monica; Omarini, Claudia; Toss, Angela; Cortesi, Giulia; Fiorani, Claudia; Piombino, Claudia; Dominici, Massimo; Piacentini, Federico
abstract
Abemaciclib is a cyclin-dependent 4/6 inhibitor approved by FDA in 2017 and by EMA in 2018 for
treatment of hormone receptors positive, HER2 negative metastatic breast cancer in association
with endocrine therapy. In 2019 FDA warned for a rare but severe lung inflammation possibly
related to CDK 4/6 inhibitors. At the end of 2019 the world comes to know to a new corona virus
causing potential fatal lung injury. Here we report three different cases of interstitial lung disease in
patients treated with Abemaciclib during SARS-CoV-2 pandemic at Modena Cancer Center.
2020
- LETTER TO THE EDITOR: Henoch-schönlein Purpura (HSP) in a Patient on Abemaciclib
[Articolo su rivista]
Omarini, Caudia; Molinaro, Eleonora; Barbolini, Monica; Dominici, Massimo; Piacentini, Federico
abstract
No abstract available.
2020
- Modulation of Mutational Landscape in HER2-Positive Breast Cancer after Neoadjuvant Chemotherapy
[Articolo su rivista]
Omarini, Claudia; Bettelli, Stefania Raffaella; Manfredini, Samantha; Barbolini, Monica; Isca, Chrystel; Cortesi, Giulia; Maiorana, Antonino; Tazzioli, Giovanni; Dominici, Massimo; Piacentini, Federico
abstract
2020
- PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2þ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype.
[Articolo su rivista]
Guarneri, Valentina; Dieci, Maria Vittoria; Bisagni, Giancarlo; Brandes, Alba A.; Frassoldati, Antonio; Cavanna, Luigi; Musolino7, Antonino; 8, ; Giotta9, Francesco; Rimanti10, Anita; Garrone11, Ornella; Bertone, Elena; Cagossi, Katia; Nanni, Oriana; Piacentini, Federico; Orvieto, Enrico; Griguolo, Gaia; Curtarello, Matteo; Urso, Loredana; Pare, Laia; Chic, Nuria; D'Amico, Roberto; Prat and Pierfranco Conte, Aleix
abstract
Purpose: We explored the prognostic effect of PIK3CA mutation
in HER2þ patients enrolled in the ShortHER trial.
Patients and Methods: The ShortHER trial randomized 1,253
patients with HER2þ breast cancer to 9 weeks or 1 year of adjuvant
trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression
of 60 genes, including PAM50 genes was measured using the
nCounter platform.
Results: A mutation of the PIK3CA gene was detected in
21.7% of the 803 genotyped tumors. At a median follow-up of
7.7 years, 5-year disease-free survival (DFS) rates were 90.6%
for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors
[HR, 0.84; 95% confidence interval (CI), 0.56–1.27; P ¼ 0.417].
PIK3CA mutation showed a favorable prognostic impact in
the PAM50 HER2-enriched subtype (n ¼ 232): 5-year DFS
91.8% versus 76.1% (log-rank P ¼ 0.049; HR, 0.46; 95% CI,
0.21–1.02). HER2-enriched/PIK3CA mutated versus wild-type
tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related
genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well
as the upregulation of PDCD1 and MYBL2 were associated with
a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68–0.99; P ¼ 0.039 for 10% TILs
increment; HR, 0.81; 95% CI, 0.65–0.99; P ¼ 0.049 for PDCD1
expression; HR, 0.72; 95% CI, 0.53–0.99; P ¼ 0.042 for MYBL2
expression).
Conclusions: PIK3CA mutation showed no prognostic impact in
the ShortHER trial. Within the HER2-enriched molecular subtype,
patients with PIK3CA mutated tumors showed better DFS versus
PIK3CA wild-type, which may be partly explained by upregulation
of immune-related genes.
2020
- PIK3CA MUTATIONS IN HER2-POSITIVE BREAST CANCER PATIENTS ENROLLED IN THE ADJUVANT RANDOMIZED SHORT-HER STUDY.
[Poster]
Guarneri, Valentina; Dieci, Maria Vittoria; Bisagni, Giancarlo; Brandes, Alba A.; Frassoldati, Antonio; Cavanna, Luigi; Musolino, Antonino; Giotta, Francesco; Rimanti, Anita; Garrone, Ornella; Elenabertone, ; Cagossi, Katia; Nanni, Oriana; Piacentini, Federico; Orvieto, Enrico; Curtarello, Matteo; Chic, Nuria; D'Amico, Roberto; Prat, Aleix; Conte, Pierfranco
abstract
2020
- Predictors of HER2 gene amplification in immunohistochemistry score 2+ Early Breast Cancer according to 2018 ASCO/CAP guidelines: a single institution analysis.
[Poster]
Barbolini, M.; Omarini, C.; Bettelli, S.; Manfredini, S.; Dominici, M.; Piacentini, F.
abstract
Background: HER2 overexpression occurs in approximately
15-20% of invasive breast cancers (BC). From a
pathological point of view HER2 positivity is defined by
intense circumferential membrane complete staining in
more than 10% of tumour cells in immunohistochemistry
(IHC score 3+). When complete circumferential staining
is weak to moderate (IHC score 2+) double probe in situ
ibridation (ISH) is mandatory to define HER2 status. In
2018 ASCO/CAP guidelines were updated to provide
additional guidance in HER2 equivocal cases to allow a
greater discrimination between positive and negative
cases. Our aim is to find predictors of HER2 positivity
among IHC score 2+ early breast cancer specimens analysed
according to 2018 ASCO/CAP guidelines.
Patients and methods: 253 cases of early BC diagnosed
at Modena Cancer Center between November 2013 and
August 2017 were identified. Stage, ISH result, hormonal
receptor status (HR), proliferation index (MIB1), and histological
grade were captured; menopausal status was available too. All IHC score 2+ cases were reclassified
according to 2018 ASCO/CAP guidelines. The association
between pathological tumour features, clinical characteristics
and ISH positivity was assessed using Fisher test.
Results: Overall, 25.7% IHC score 2+ BC resulted HER2
amplified in double probe ISH. High tumour grade (G3 vs
G1-2) and MIB1 > 20% significantly predict HER2 ISH
amplification (p=0,0001). No correlation was found according
to HR, stage, or menopausal status. The majority (185;
98.4%) of HER2-ve BC were reclassified as group 5 (HER2/
CEP17 ratio <2 and HER2 copy number <4 signals/cell)
except for 3 specimens classified as group 4 (HER2/CEP17
RATIO <2 and HER2 copy number ³4 but <6 signals/cell).
In HER2+ve group the majority (62; 95.3%) specimens
were group 1 (HER2/CEP17 RATIO >2 and HER2 copy
number =4 signals/cell), no specimen was group 2, and only
3 cases were classified as group 3 (HER2/CEP17 RATIO
<2 and HER2 copy number >6 signals/cell).
Conclusions: In this IHC score 2+ BC series, reclassification
according to 2018 ASCO/CAP guidelines identified
only 4.6% group 3 and 1.6% group 4 cases. The routinely
assessment of grading and proliferation index could help
to predict HER2 amplification in IHC score 2+ samples
even if it must not substitute ISH assay in determining eligibility
for HER2 targeted therapies.
2020
- Primary treatment strategy in elderly patients with hormone receptor positive early breast cancer: is breast cancer surgery.
[Poster]
Nasso, C.; Barbolini, M.; Isca, C.; D'Onofrio, R.; Cortesi, G.; Dominici, M.; Piacentini, F.; Omarini, C.
abstract
Background: Older age, ECOG performance status,
major comorbidities and concomitant medications influence
the primary treatment strategy of hormone receptor
positive (HR+) early breast cancer (EBC) patients. In case
of frail patients, oncologist may choose primary endocrine
therapy (ET) instead of breast cancer surgery (BCS) even
if its clinical impact is still unknown.
Methods: We performed a retrospective study on women
aged 75 years and older with HR+ EBC diagnosed at the
Modena Cancer Center from 2010 to 2016. According to
primary treatment strategy patients were divided into two
groups: patients who underwent BCS (BCS group) versus patients treated with only ET (ET group). Patients’ clinical
data and tumor characteristics were collected. Disease Free
Survival (DFS) and Breast cancer-specific survival (BCSS)
were estimated by long rank test and Kaplan-Meier curves.
Results: 143 patients were involved in the study: 105 in
BCS group and 38 in ET one. Patients who underwent surgery
had significantly better ECOG (p=0.000001), low
tumour grade (p=0.04) and early clinical stage (p=0.0001)
compared to those in the ET group. In patients with negative
lymph-nodes at the diagnosis, tumor stage I-II and low
ki67 (<20%), BCS did not improve 5-years DFS in univariate
and multivariate analysis (p = 0.099, 95%CI
0.152-1.175). No differences were found in terms of
5-years BCSS between the two groups (p = 0.195).
Conclusions: Stage I-II at the diagnosis, negative axillary
lymph nodes and low ki67 identified a subgroup of HR+
EBC patients aged > 75 with low risk of disease progression
who may not benefit from primary BCS. In elderly
frail patients, primary ET instead of BCS could be a valid
treatment strategy that should be considered on a case-bycase
basis.
2020
- PROGNOSIS AND RESPONSE TO
NEOADJUVANT CHEMOTHERAPY
ACCORDING TO HER2 EXPRESSION IN
EARLY BREAST CANCER: a retrospective
single institution analysis
[Poster]
D'Onofrio, R.; Omarini, C.; Barbolini, M.; Nasso, C.; Isca, C.; Dominici, M.; Piacentini, F.
abstract
Background: The assessment of HER2 status plays a key
role in the treatment decision making process of early
breast cancer (BC).HER2 status is routinely assessed by
immunohistochemistry and/or in situ hybridization (ISH),
according to ASCO/CAP 2018 guidelines. The dichotomous
definition of HER2+ versus HER2- disease does
not reflect the spectrum of variable levels of HER2 protein
expression. We have analyzed the clinical outcomes
of a cohort of BC patients treated with neoadjuvant chemotherapy
(NACT) according to HER2 score.
Patients and methods: We performed a retrospective
analysis of 483 women with early BC treated with NACT
from March 2002 to November 2018 at Modena Cancer
Center. Clinical and pathological characteristics of patients
and disease were collected and compared to HER2 score
by Pearson’s chi square test. The impact of HER2 status on
pathological complete response (pCR) was set according
to logistic regression model.
Results: According to HER2 score, patients were divided
in 5 groups: 79 (16,3%) of them in HER2 score0 group,
153 (31,7%) in HER2 score1+, 53 (11%) HER2 score2+/
ISH-, 43 (9%) score2+/ISH+ and 155 (32%) score3+. Of
note, 59% of women had hormone receptor positive BC.
Overall, the HER2 status significant correlated to histotype
(p=0,003), grading (p=0,026) and pCR (p=0,0001).
The pCR was achieved in 132 (27%) patients: 46 (9,5%) in
HER2 score0/1+ group, 9 (1,9%) in HER2 score2+/ISH-,
8 (1,7%) in HER2 score2+/ISH+ and 69 (14,3%) in
HER2 score3+. The pCR rate was not statistically different
when both HER2 score0/1+ and HER2 score2+/ISHgroups
were compared to HER2 score2+/ISH+ one.
Considering HER2+ BCs, the pCR rate was significantly
higher in HER2 score3+ compared to HER2 score2+/
ISH+ (p=0,002). No statistically significant differences in
terms of RFS and OS inter-subgroups were observed.
Conclusions: The HER2 protein expression levels better
correlated to pCR compare to HER2 gene amplification. In
particular, the lack of difference in pCR rate between HER2 score2+/ISH+ and HER2 score2+/ISH– groups
may suggests a paradigm shift in the current classification
of HER2 status, consistently with emerging data on “HER2
low” BC landscape.
2020
- Survival analysis of the prospective randomized Cher-Lob study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer
[Relazione in Atti di Convegno]
Guarneri, V.; Dieci, M. V.; Bisagni, G.; Generali, D. G.; Cagossi, K.; Sarti, S.; Frassoldati, A.; Gianni, L.; Cavanna, L.; Pinotti, G.; Musolino, A.; Piacentini, F.; Michelotti, A.; Cinieri, S.; Griguolo, G.; Miglietta, F.; De Salvo, G. L.; Conte, P.
abstract
Background: The CHER-LOB randomized phase II study
showed that the combination of lapatinib and trastuzumab
plus chemotherapy increases the pathologic complete
response (pCR) rate compared with chemotherapy plus
either trastuzumab or lapatinib. Here we report the results
of survival analysis according to treatment arm and pCR.
Methods: The CherLOB study randomized 121 HER2-
positive, stage II-IIIA breast cancer patients to anthracyclines/
taxane-based chemotherapy plus trastuzumab,
lapatinib, or both. Patients received adjuvant trastuzumab
for up to 1 year. The primary end point of the study was
met, with a relative increase of 80% in the pCR rate
achieved with chemotherapy plus trastuzumab and lapatinib
compared with chemotherapy plus either trastuzumab
or lapatinib (Guarneri, J Clin Oncol 2012).
Relapse-free survival (RFS) was calculated from randomization
to breast cancer recurrence (locoregional or
distant) or death from any cause, whichever first. Overall
survival (OS) was calculated from randomization to
death from any cause.
Results: At a median follow up of 8.8 years, RFS rates at
5 years were: 85.8% in the trastuzumab + lapatinib arm,
77.8% in the trastuzumab arm, 78.1% in the lapatinib arm
(log-rank p=0.160). Patients treated with dual HER2
blockade (trastuzumab + lapatinib arm) experienced
numerically better RFS as compared to patients treated
with single HER2 blockade (trastuzumab arm and lapatinib
arm combined): 5-yr RFS 85.8% vs 78.0%, log-rank
p=0.087; HR=0.51, 95% CI 0.23-1.12, p=0.093. The
achievement of pCR was a strong prognostic factor. 5-yr
RFS rate was 97.3% for pCR patients vs 72.9% for nonpCR
patients (log-rank p<0.001, HR=0.12, 95% CI 0.03-
0.49, p=0.003); similar significant results were observed
in both the estrogen receptor-negative and estrogen-receptor
positive subgroups. OS was also improved in pCR
patients: 8-yr OS rates were 97.2% vs 80.0% (log-rank
p=0.028, HR=0.14, 95% CI 0.02-1.08, p=0.060).
Conclusions: In the Cher-LOB study, there was a not statistically
significant signal for a better RFS for patients
who received dual HER2 blockade with trastuzumab and
lapatinib plus neoadjuvant chemotherapy experienced
improved RFS as compared to patients treated with single
anti-HER2 agent (trastuzumab or lapatinib) plus chemotherapy.
Patients achieving a pCR had longer RFS and OS
as compared to non-pCR patients.
2020
- Survival analysis of the prospective randomized Cher-Lob study evaluating the dual anti-HER2 treatment with trastuzumab and lapatinib plus chemotherapy as neoadjuvant therapy for HER2-positive breast cancer (BC).
[Poster]
Guarneri, Valentina; Dieci, Maria Vittoria; Bisagni, Giancarlo; Giulio Generali, Daniele; Cagossi, Katia; Sarti, Samanta; Frassoldati, Antonio; Gianni, Lorenzo; Cavanna, Luigi; Pinotti, Graziella; Musolino, Antonino; Piacentini, Federico; Michelotti, Andrea; Cinieri, Saverio; Griguolo, Gaia; Miglietta, Federica; Luca De Salvo, Gian; Franco Conte, Pier
abstract
Background:
The CHER-LOB randomized phase II study showed that the combination of lapatinib and trastuzumab plus chemotherapy increases the pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here we report the results of survival analysis according to treatment arm and pCR.
Methods:
The CherLOB study randomized 121 HER2-positive, stage II-IIIA breast cancer patients to anthracyclines/taxane-based chemotherapy plus trastuzumab, lapatinib, or both. After surgery, patients received adjuvant trastuzumab for up to 1 year. The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared with chemotherapy plus either trastuzumab or lapatinib (Guarneri, J Clin Oncol 2012). Relapse-free survival (RFS) was calculated from randomization to breast cancer recurrence (locoregional or distant) or death from any cause, whichever first. Overall survival (OS) was calculated from randomization to death from any cause.
Results:
At a median follow up of 8.8 years, RFS rates at 5 years were: 85.8% in the trastuzumab + lapatinib arm, 77.8% in the trastuzumab arm, 78.1% in the lapatinib arm (log-rank p = 0.160). Patients treated with dual HER2 blockade (trastuzumab + lapatinib arm) experienced numerically better RFS as compared to patients treated with single HER2 blockade (trastuzumab arm and lapatinib arm combined): 5-yr RFS 85.8% vs 78.0%, log-rank p = 0.087; HR = 0.51, 95% CI 0.23-1.12, p = 0.093. The achievement of pCR was a strong prognostic factor. 5-yr RFS rate was 97.3% for pCR patients vs 72.9% for non-pCR patients (log-rank p < 0.001, HR = 0.12, 95% CI 0.03-0.49, p = 0.003); similar significant results were observed in both the estrogen receptor-negative and estrogen-receptor positive subgroups. OS was also improved in pCR patients: 8-yr OS rates were 97.2% vs 80.0% for non pCR patients (log-rank p = 0.028, HR = 0.14, 95% CI 0.02-1.08, p = 0.060).
Conclusions:
In the Cher-LOB study, there was a not statistically significant signal for a better RFS for patients who received dual HER2 blockade with trastuzumab and lapatinib plus chemotherapy as compared to patients treated with single anti-HER2 agent (trastuzumab or lapatinib) plus chemotherapy. Patients achieving a pCR had longer RFS and OS as compared to non-pCR patients.
2019
- Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.
[Articolo su rivista]
Dieci, Mv; Conte, P; Bisagni, G; Brandes, Aa; Frassoldati, A; Cavanna, L; Musolino, A; Giotta, F; Rimanti, A; Garrone, O; Bertone, E; Cagossi, K; Sarti, S; Ferro, A; Piacentini, F; Maiorana, A; Orvieto, E; Sanders, M; Miglietta, F; Balduzzi, S; D'Amico, R; Guarneri, V.
abstract
BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.
2019
- Axillary Ectopic Carcinoma of the Breast. Report of Two Cases with Different Clinical Presentation and Review of the Literature.
[Altro]
D'Onofrio, Raffaella; Piacentini, Federico; Combi, Francesca; Omarini, Claudia; Luca, Moscetti; Antonella, Drago; Andreotti, Alessia; Rovesti, Giulia; Enza, Palma; Anna, Gambini; Papi, Simona; Tazzioli, Giovanni
abstract
Aims: Primary ectopic breast cancer (PEBC) is a rare and often misdiagnosed condition. Through the discussion of two clinical
cases, we want to focus on clinical presentation, outcomes and treatment of PEBC, to lead clinicians to awareness and optimal
management.
Methods: We present the case of a 47-year-old patient, with a 30 mm axillary mass, that was diagnosed as a PEBC (infiltrating
lobular carcinoma, triple negative). The patient underwent systemic staging: diffuse metastatic bone lesions and leptomeningeal
metastasis were found.
The second patient is a 73-year-old woman with personal history of right breast tumor. She came to our attention for a 9 mm left
axillary mass, suspicious for a metastatic lymph node. A fine-needle cytology revealed the absence of lymphoid cells but the presence of atypical epithelial cells, as in a primary breast carcinoma. She was treated with local excision and sentinel node biopsy.
Results: The first patient presented with metastatic disease at the time of diagnosis and she deceased after three months from the
diagnosis, despite systemic chemotherapy. The diagnosis was performed at an early stage in the second patient. She underwent
surgery, complementary endocrine therapy and radiotherapy. She has no evident disease after two years from surgery.
Conclusion: Primary ectopic breast cancer is a rare clinical entity, often misdiagnosed or diagnosed with a long delay. The treatment of PEBC is analogous to that of orthotopic breast cancer, but we strongly recommend to approach the patient with a multidisciplinary team to provide the best staging workout and therapies
2019
- Breast cancer follow-up: a national survey of current clinical practice by the centers of Italian Oncological Group of Clinical Research (GOIRC).
[Poster]
Omarini, Claudia; Piacentini, Federico; Frassoldati, Antonio; Musolino, Antonino; Dominici, Massimo; Moscetti on behalf of GOIRC, Luca
abstract
Background: The number of breast cancer (BC) survivors is increasing due to the aging of the population and the improvement of survival rates. Survivors have health care needs including detection of early recurrences, treatment of therapy-related complications and psychological support. No randomized data exist to support any individual follow-up (FU) sequence or protocol. Pphysicians’ adherence to international guidelines is unknown. The aim of this study is to investigate the survivorship care plan in Cancer Centers affiliated to Italian Oncological Group of Clinical Research (GOIRC).
Methods: A questionnaire survey with 12 questions was e-mailed to the members of GOIRC in March 2019. Respondents were asked how they follow-up BC survivors. We have collected the survey data and compared them to national/international guidelines.
Results: 20 out of 30 GOIRC centers completed the survey. The majority of the oncologists (75%) reported to follow AIOM guideline in FU management. Although, 14 respondents (70%) are used to perform routinely tumor markers and imaging tests (chest X-ray and liver ultrasound) as screening tools for early detection of recurrence. Advanced imaging studies (bone scan, CT scan, PET/FDG CT) are routinely recommended in high-risk patients by 4 interviewed. Considering patients on aromatase inhibitors, all the respondents recommend lipid profile and bone density evaluation every two years. Moreover, nutritional counselling is offered in 7 centers (35%). Frequency of checkup is scheduled according with BC risk of relapse in 11 centers (55%), while visits are conducted six-monthly in the other 9 cases. Duration of FU is variable: 60% of interviewed monitor the patients until the end of the adjuvant endocrine therapy while in the other cases checkup is carried on over 10 years. At the end of oncology FU, all the interviewed recommended yearly mammography, in four cases annual tumor markers check is suggested too.
Conclusion
A majority of respondents in Italian Cancer Centers perform more intensive follow-up compared to guidelines recommendations. FU of BC survivors is still an unmet clinical need. Randomized national trial on survivorship care plan should be considered.
2019
- Clinical-Pathological Characteristics of HER2+ Breast Cancers patients among BRCA1/2+ carriers tested in Modena Cancer Center.
[Poster]
Barbolini, M; Omarini, C; Viola, L; Isca, C; Marchi, I; Caggia, F; Barbieri, E; Toss, A; Cortesi, L; Dominici, M; Piacentini, F.
abstract
Background and Objectives
Prevalence of HER2 positive breast cancer (BC) in BRCA1/2 carriers is still underestimated. Clinical behaviour of HER2+/BRCA+ BC could be in some ways different from sporadic HER2+ disease. The aim of this research is to describe clinical-pathological characteristics of this rare entity in patients treated at Modena Cancer Center.
Methods
Between January 2005 and July 2019, 2911 BC patients have been tested for BRCA1/2. 231 (7.9%) and 173 (5.9%) were found positive for BRCA1 and BRCA2 pathogenetic mutations respectively. We considered the HER2+ subgroup (14 patients), focusing on hormone receptor status, IGF-1R expression (semi-quantitative expression by immunohistochemistry with Anti-IGF-1R rabbit monoclonal), PI3K mutation (NGS Sequenom analysis) and clinical characteristics.
Results
All but one patients received trastuzumab as part of their treatment. Six patients were treated with neoadjuvant chemotherapy (NACT), comprehensive of trastuzumab +/- pertuzumab, achieving a pathological complete response in 33% of cases.
Two patients experienced disease recurrence after NACT (median EFS = 5.7 years).
From a pathological point of view, the majority of cancers were ductal infiltrating, grading 3 and hormone receptor positive.
3 cases a PI3K mutation was found: in one of them a double mutation (p.R38H + p.E545K) was detected.
IGF-1R showed high expression in 2 cases (IHC score 3+), intermediate expression in 2 cases (score 2+), low or absent expression in 3 cases.
Interestingly one HER2+/BRCA1 mutated patient shows both PI3K mutation and IGF-1R overexpression, achieving a partial response after NACT and still NED.
Conclusions
Here we report a low frequency of HER2+ BC in BRCA1/2 germline carriers. This rate is higher in patients with BRCA2 mutation, accordingly with previous literature. It is not clear, in this peculiar population that displays different possible pathogenetic drivers, which could be the main druggable
2019
- Differential molecular pathways expression in HER2 positive early breast cancer according to hormone receptor status.
[Articolo su rivista]
Omarini, C; Bettelli, S; Caprera, C; Manfredini, S; Barbolini, M; Moscetti, L; Isca, C; Toss, A; Barbieri, E; Cortesi, L; Kaleci, S; Maiorana, A; Tazzioli, G; Cascinu, S; Piacentini, F
abstract
PURPOSE:
Hormone receptors (HR) status in HER2 + breast cancer (BC) is a recognized stratification factor with relevant clinical implication. According to HR expression, HER2 + BC show different clinical characteristics, treatment sensitivity and prognosis. The interaction between HR and HER2 pathways remains incompletely understood.
METHODS:
Thirty-four HER2 + BC were included: 18 tumors with HER2+/HR + and 16 with HER2+/HR-. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer Pathway panel performed on FFPE BC biopsies.
RESULTS:
Gene expression analysis identified 127 genes with significantly different expression between the two cohorts. 83% of these genes were overexpressed in HER2+/HR- cohort. Globally, 23% of them belonged to PI3K pathway (41 genes), 15% to Trascriptional regulation (26 genes) and 12% to MAPK (22 genes). Regarding pathway expression, PI3K, MAPK and NOTCH were significantly differently expressed between the two groups (p = 0.003, p = 0.0018 and p = 0.02, respectively), all of them were overexpressed in HER2+/HR- tumors.
CONCLUSIONS:
According to HR status, HER2 + tumors express different pathways profiles: the overexpression of PI3K, MAPK and NOTCH pathways in HER2+/HR- group could justify different survival outcomes and treatment sensitivity. The identification of tumor driver pathways may be a useful instrument for individualized pathway-directed therapies. Further clinical implications are warranted.
2019
- Efficacy and safety of neoadjuvant chemotherapy plus trastuzumab and pertuzumab in non-metastatic HER2-positive breast cancer in real life: NEOPEARL study.
[Poster]
A Fabbri, M; Botticelli, A; Omarini, C; Cretella, E; Fabi, A; Alesini, D; Pizzuti, L; Piesco, G; Vaccaro, A; Atzori, F; Piacentini, F; Moscetti, L; Orlandi, A; Sini, V; Mercanti, A; L Framarino, M; Persano, M; Ceccherini, R; M Ruggeri, E
abstract
Background
In HER2+ breast cancer (BC) patients (pts) the pathological complete response (pCR) is associated with improved survival. With regimens based on the combination of trastuzumab (T), pertuzumab (P) and chemotherapy, pCR rates are slightly over 48%. We conducted a retrospective analysis on HER2+ BC pts to describe the outcomes of neoadjuvant combination of P+T and chemotherapy in the real-life setting.
Methods
Our cohort included 64 pts treated between Sept 2015 and Mar 2018 in 15 Italian Cancer Centers. Treatment outcomes were analyzed in terms of pCR (defined as ypT0/Tis, ypN0i-) and toxicities, recorded according to National Cancer Institute Common Toxicity Criteria. Statistical analysis was performed with T di Student test and χ2 test.
Results
Overall, in the 55 evaluable pts median age was 50 (range 28-77) and 29 pts (53%) were pre-menopausal. 24 pts (45%) were ER-/PgR-, 12 (21%) ER+/PgR-, 16 (29%) ER+/PgR+, median ki67 was 40. 9% of pts were cT1, 73% cT2, 13% cT3 and 5% cT4; 42 pts (76%) were cN+. All pts received 4 cycles of T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) and P (loading dose 840 mg, followed by 420 mg every 3 weeks). In 42 pts T+P were administered with docetaxel (75 mg/mq every 3 weeks), in 8 pts with paclitaxel (80 mg/mq) and 5 pts received docetaxel and carboplatin (AUC5). In 13 pts also 3 cycles of anthracyclines, according to the FEC scheme, were administered. A pCR was achieved in 29 pts (53%). No significant associations were found between pCR and baseline characteristics or treatments schedule. Seven out of 55 (13%) pts reported G3-G4 toxicities (5 pts neutropenia G3-G4, 1 pt vomiting G3, 1 pt diarrhoea G3, 1 pt anemia G3). Three out of 4 pts treated with docetaxel, carboplatin and P+T reported G3/G4 toxicities. A significant association was found between chemotherapy schedule and toxicities (p = 0.004).
Conclusions
The association of P+T+chemotherapy improved pCR rate in HER2+ BC pts treated in the real-life setting. Our results showed that the selection of chemotherapy that will be associated with the dual blockade of HER2 is of paramount importance in order to avoid severe toxicities and increase the compliance with treatment.
2019
- Endocrine therapy alone versus targeted combination strategy as first line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trial
[Abstract in Atti di Convegno]
Omarini, C; Sperduti, I; Barbolini, M; Isca, C; Bocconi, Alessandro; Toss, A; Cortesi, L; Barbieri, E; Piacentini, F; Cascinu, S; Moscetti, L
abstract
Background
Combined endocrine/targeted approaches have been investigated as first-line treatment in hormone receptors positive metastatic breast cancer (BC). Randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged >65 years) are under represented in most of the trials. Due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in elderly women.
Methods
This meta-analysis included first line phase II/III randomized published trials comparing ET to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged > 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Prospero registration number: CRD42019120215.
Results
8 studies were included: 4 (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found.
Conclusions
The novel experimental strategies showed an improvement in PFS in elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone, the magnitude of PFS benefit is age-independent. To define the role of novel agents, future trials should be designed taking in account not only the age, but also adequate geriatric assessment and comorbidity status.
2019
- Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.
[Abstract in Atti di Convegno]
Omarini, Claudia; Piacentini, Federico; Sperduti, Isabella; Barbolini, Monica; Isca, Chrystel; Nasso, Cecilia; Toss, Angela; D'Onofrio, Raffaella; Cortesi, Laura; Barbieri, Elena; Cascinu, Stefano; Moscetti, Luca
abstract
Background: Combined endocrine approaches have been widely investigated as 1st-line treatment in hormone receptors
positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclindependent
kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥
65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity
associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present metaanalysis
aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This metaanalysis
included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no
data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥ 65 years were excluded. The heterogeneity of the
data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials
(Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and
FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of
ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS
advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005].
The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No
significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population
subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in
the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The
magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent.
2019
- First-Line Treatment for Endocrine-Sensitive Bone-Only Metastatic Breast Cancer: Systematic Review and Meta-analysis
[Articolo su rivista]
Toss, A.; Venturelli, M.; Sperduti, I.; Molinaro, E.; Isca, C.; Barbieri, E.; Piacentini, F.; Omarini, C.; Cortesi, L.; Cascinu, S.; Moscetti, L.
abstract
In the last decade, several clinical trials have investigated novel endocrine combinations for the first-line treatment of hormone receptor-positive metastatic breast cancer. Nevertheless, the use of combinations for the first-line treatment of bone-only disease is widely discussed as a result of its indolent natural history. We performed a comprehensive search of phase 3 randomized clinical trials published in the literature through September 2018. Our aim was to explore the role of the new endocrine approaches in bone-only metastatic breast cancer, suggesting a possible strategy for their selection. In particular, we evaluated the comparative risk of adverse event occurrence during these treatments. A total of 6 studies were deemed suitable for meta-analysis: the Monaleesa-2, Monaleesa-7, Monarch-3, Paloma-2, SWOG, and Alliance trials. Overall, the novel strategies were shown to improve progression-free survival in bone-only disease (hazard ratio = 0.65; 95% confidence interval, 0.49-0.86; P = .003). Combinations with cyclin-dependent kinase inhibitors improved progression-free survival (hazard ratio = 0.54; 95% confidence interval, 0.39-0.75; P < .001) with an acceptable toxicity profile. Abemaciclib was associated with increased anemia and gastrointestinal toxicity (especially diarrhea), whereas palbociclib was associated with increased leukopenia (but not neutropenia) compared to the other compounds. Increased aspartate aminotransferase levels were reported for both ribociclib and abemaciclib. The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy represents an effective and well-tolerated approach for first-line treatment in bone-only disease settings. Because no direct comparison between the 3 cyclin-dependent kinase 4/6 inhibitors is available, the selection of the most appropriate treatment should be based on toxicity profile as well as patient preference and copathologies.
2019
- Immune infiltrate composition across intrinsic subtypes in hormone receptor (HR)+/HER2- early breast cancer (BC) enrolled in the prospective LETLOB trial.
[Poster]
Griguolo, G; V Dieci, M; Paré, L; Miglietta, F; G Generali, D; Frassoldati, A; Bisagni, G; Piacentini, F; Tagliafico, E; Cagossi, K; Ficarra, G; Prat, A; F Conte, P; Guarneri, V
abstract
Background
In HR+/HER2- early BC, high tumour infiltrating lymphocytes (TIL) levels predict higher pathological complete response to neoadjuvant chemotherapy, but are associated with shorter overall survival (Denkert, Lancet Oncol 2018). HR+/HER2- BC is a biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes, with different clinical behaviour (Cejalvo, CTR 2018). Little is known concerning the distribution of TIL levels and immune infiltrate composition across intrinsic subtypes in HR+/HER2- BC.
Methods
Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 postmenopausal patients with HR+/HER2- early BC from the LETLOB trial (neoadjuvant letrozole+/-lapatinib) (Guarneri, JCO 2014). Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. Relative leukocyte fractions were calculated using CIBERSORT (Newman, Nature Methods 2015), a deconvolution method based on RNA gene-expression signatures. Pre-treatment stromal TILs were assessed on centralized HES slides according to recommendations (Salgado, Ann Oncol 2015).
Results
Intrinsic subtype distribution was as follows: basal 18% (N = 12), HER2-enriched 8% (N = 5), Luminal A 39% (N = 25), Luminal B 36% (N = 24). Non-luminal subtypes (HER2-enriched and Basal) had significantly higher baseline TIL levels than luminal subtypes (median (range): 7 (0-100) and 2 (0-35), respectively; p = 0.038). Non-luminal subtypes also presented higher fractions of CD4 memory activated T-cells (p = 0.018), γδ T-cells (p = 0.010) and M1 macrophages (p = 0.001) and lower fractions of T-regulatory cells (p = 0.002) than luminal subtypes.
Conclusions
In HR+/HER2- early BC, non-luminal subtypes show higher TIL levels and a more pro-inflammatory anti-tumour immune infiltrate composition. This immune heterogeneity across intrinsic subtypes should be considered when analysing the complex prognostic role of TILs in HR+/HER2- early BC.
2019
- Impact of body composition parameters on tumor response to neoadjuvant chemotherapy in operable breast cancer patients.
[Poster]
Palumbo, Patrizia; Draisci, Stefano; Barbolini, Monica; Nasso, Cecilia; Isca, Chrystel; Bocconi, Alessandro; Balduzzi, Sara; Pecchi, Annarita; Galetti, Silvia; Torricelli, Pietro; Piacentini, Federico; Moscetti, Luca; Cascinu, Stefano; Omarini, Claudia
abstract
Fat tissue promotes cancer progression by increasing cell proliferation, cell survival and metastatic processes. Adipose tissue determines a dysregulation of several metabolic pathways by a continuous crosstalk between fat tissue and cancer cells. Moreover, influence of adipose tissue on cancer development depend on the type of fat too
BMI cannot account for differences in fat distribution and cannot distinguish between adipose tissue and muscles
Computed tomography (CT) imaging can be a useful tool for a directly measure of body fat distribution distinguishing among visceral, subcutaneous, internal fat tissue (mostly in the liver) and skeletal muscles mass.
Patients treated with neoadjuvant chemotherapy for early BC at the Modena Cancer Center from 2005 to 2017 we collected.
According to BMI score, patients were categorized in two main classes: normal weight (BMI < 25) and overweight (BMI ≥ 25) (Table 1)
Using Advance workstation (General Electric), software ADW server 3.2 or 4.7. we calculated body composition parameters (BCPs) from pre-treated CT scan images. BCPs considered are: subcutaneous fat area (SFA, cm2), visceral fat area (VFA, cm2), lumbar muscle cross-sectional area (LMCA, m2) and liver steatosis (L/S ratio)
BMI score and BCPs value were correlated with pathological complete response (pCR) and survival outcomes. All analyses were performed using STATA 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP).
pre-treatment CT scan imagine available for BCPs analysis
55% of the women had BMI < 25 versus 45% with BMI >25
Overweight was significantly associated with postmenopausal status, older age and hormonal receptor positive BC (Table 1)
Menopausal status was associated with higher VFA, presence of fatty liver disease and obesity disease compared to pre-menopausal one (Table 2).
No association between BMI classes and pCR was detected. High VFA and liver steatosis were negative predictive factors for pCR (pCR rate: 35% normal VFA vs 20% high VFA, no steatosis 32% vs steatosis 13%; p<0.05) ( Figure 1)
Neither BMI classes nor BCPs significantly influenced overall survival and relapse free survival.
The evaluation of BCPs is the best way to assess the real body composition
Menopausal status is associated with higher VFA, presence of fatty liver disease and obesity disease
Visceral adiposity as well as liver steatosis were negative predictive factors for pCR in BC patients treated with neoadijuvant chemotherapy .
2019
- Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.
[Articolo su rivista]
Pietri, E; Massa, I; Bravaccini, S; Ravaioli, S; Tumedei, Mm; Petracci, E; Donati, C; Schirone, A; Piacentini, F; Gianni, L; Nicolini, M; Campadelli, E; Gennari, A; Saba, A; Campi, B; Valmorri, L; Andreis, D; Fabbri, F; Amadori, D; Rocca, A.
abstract
LESSONS LEARNED:
The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity.
BACKGROUND:
Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC).
METHODS:
A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early.
RESULTS:
Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites.
CONCLUSION:
DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.
2019
- Post-surgical pyoderma gangrenosum of the breast: needs for early diagnosis and right therapy.
[Articolo su rivista]
Guaitoli, G; Piacentini, F; Omarini, C; Andreotti, A; Palma, E; Papi, S; De Pietri, Chiara; Conti, A; Cascinu, S; Tazzioli, G.
abstract
Post-surgical pyoderma gangrenosum (PSPG) of the breast is a rare dermatosis that worsens surgical manipulation, with a chronical relapsing course. Diagnosis is mostly clinical and made by exclusion after the failure of antibiotic therapies and surgical debridement, while the mainstay of therapy is corticosteroid-based. Here we report a case of PSPG of the breast in a young woman with breast cancer, to emphasize the needs of an early and accurate diagnosis, to guarantee the most efficacious treatment and to avoid life-threatening complications.
2019
- Predictive Role Of Body Composition Parameters In Operable Breast Cancer Patients Treated With Neoadjuvant Chemotherapy.
[Articolo su rivista]
Omarini, C; Palumbo, P; Pecchi, A; Draisci, S; Balduzzi, S; Nasso, C; Barbolini, M; Isca, C; Bocconi, A; Moscetti, L; Galetti, S; Tazzioli, G; Torricelli, P; Cascinu, S; Piacentini, F.
abstract
BACKGROUND:
Fat tissue is strongly involved in BC tumorigenesis inducing insulin resistance, chronic inflammation and hormonal changes. Computed tomography (CT) imaging instead of body mass index (BMI) gives a reliable measure of skeletal muscle mass and body fat distribution. The impact of body composition parameters (BCPs) on chemosensitivity is still debated. We examined the associations between BCPs and tumor response to neoadjuvant chemotherapy (NC) in patients treated for operable breast cancer (BC).
METHODS:
A retrospective review of BC patients treated with NC in Modena Cancer Center between 2005 and 2017 was performed. BCPs, such as subcutaneous fat area (SFA), visceral fat area (VFA), lumbar skeletal muscle index (LSMI) and liver-to-spleen (L/S) ratio were calculated by Advance workstation (General Electric), software ADW server 3.2 or 4.7. BMI and BCPs were correlated with pathological complete response (pCR) and survival outcomes.
RESULTS:
407 patients were included in the study: 55% with BMI < 25 and 45% with BMI ≥ 25. 137 of them had pre-treatment CT scan imagines. Overweight was significantly associated with postmenopausal status and older age. Hormonal receptor positive BC was more frequent in overweight patients (p<0.05). Postmenopausal women had higher VFA, fatty liver disease and obesity compared to premenopausal patients. No association between BMI classes and tumor response was detected. High VFA and liver steatosis were negative predictive factors for pCR (pCR rate: 36% normal VFA vs 20% high VFA, p= 0.048; no steatosis 32% vs steatosis 13%, p=0.056). Neither BMI classes nor BCPs significantly influenced overall survival and relapse-free survival.
CONCLUSION:
Visceral adiposity as well as steatosis were closely involved in chemosensitivity in BC patients treated with NC. Their measures from clinically acquired CT scans provide significant predictive information that outperform BMI value. More research is required to evaluate the relationship among adiposity site and survival outcomes.
2019
- Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial .
[Articolo su rivista]
Dieci, Mv; Bisagni, G; Brandes, Aa; Frassoldati, A; Cavanna, L; Giotta, F; Aieta, M; Gebbia, V; Musolino, A; Garrone, O; Donadio, M; Rimanti, A; Beano, A; Zamagni, C; Soto Parra, H; Piacentini, F; Danese, S; Ferro, A; Cagossi, K; Sarti, S; Gambaro, Ar; Romito, S; Bazan, V; Amaducci, L; Moretti, G; Foschini, Mp; Balduzzi, S; Vicini, R; D'Amico, R; Griguolo, G; Guarneri, V; Conte, Pf.
abstract
BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment.
2018
- Breast Location for De Novo Extramedullary Myeloid Sarcoma
[Articolo su rivista]
Tazzioli, Giovanni; Palma, Enza; Anna, Gambini; Messerotti, Andrea; Potenza, Leonardo; Luppi, Mario; Drago, Antonella; Grazia Amorico, Maria; Barbolini, Monica; Ficarra, Guido; Piacentini, Federico
abstract
Background: Myeloid Sarcoma (MS) is a rare hematologic cancer, which can occur as a breast mass
to be distinguished from other non-hematopoietic tumors.
Case Presentation: This report describe the unusual clinical history of a young woman diagnosed
with MS. Radiotherapy/surgery alone may be inadequate, while chemotherapy and hematopoietic
stem cell transplantation demonstrated to improve the prognosis for the isolated extramedullary
localization.
Conclusion: Performing a needle biopsy in order to exclude the diagnosis of a primitive breast
disease is irreplaceable.
2018
- Cancer Treatment Induced Bone Loss (CTIBL) in breast cancer women: a multidisciplinary approach at the Modena Cancer Center screening over 600 patients.
[Abstract in Rivista]
Pozzi, S.; Belletti, L.; Cortesi, L.; Moscetti, L.; Omarini, C.; Piacentini, F.; Toss, A.; Caputo, Francesco; Greco, S.; Isca, C.; Napolitano, M.; Tarantino, V.; Malinverni, C.; Checchi, Eleonora; Mascia, Maria Teresa; Cascinu, S
abstract
Background: CTIBL in breast cancer (BC) women is well
know. It is commonly, but not exclusively, related to aromatase
inhibitors. The “Nota 79” by AIFA contemplates
the primary prevention of fracture risk in BC women in
adjuvant hormonal treatment with bisphosphonates or denosumab,
at osteoporosis dosage. At the Modena Cancer
Center we started a collaboration with oncologists hematologists
and bone specialists in order to offer the
best tailored treatment in high risk fracture patients.
Patients and Methods: patients newly diagnosed with BC
in hormonal treatment fill-out a form, in order to evaluate
the risk factors for osteoporosis, and based on the results
and the bone density they are referred to the osteoncology
unit along with serological and urinary markers of bone
turn-over.
Results: in over 18 months of activity, more than 600
patients have been screened by self-completed questionnaire.
From the analysis of the first 400 questionnaires
emerged that 61% had one or more risk factors, 20%
received supplement of vitamin D, and approximately 5%
were on bisphosphonates. At baseline, the measurement of
the height, the evaluation of the spine at the chest X ray or
by morphometry highlighted asymptomatic vertebral fractures
in few patients. Several patients presented with secondary
hyperparathyroidism, that required correction
before to start any treatment with antiresorptive agents.
Cases with hypercalciuria were also corrected along with
antiresorptive therapy. Few cases demonstrated high bone
turn-over with CTX levels above the limits. The treatment
has been individualized based on the medical history and
comorbidities, oncological treatment and the bone turnover.
All the patients have been informed of the possible
risk of osteonecrosis of the jaw; dental medical history was
collected for each patient, but orthopanthomography and
odontoiatric evaluation was prescribed in selected patients.
Vitamin D level was corrected before any therapy and
improvement of the dietary habits and physical activity
was highly recommended. Data analysis is still ongoing.
Conclusions: all the patients receiving AIs require the prevention
of CTIBL, but the limited resources pushed us to
select, at this time, the patients with special needs to be
evaluated in multidisciplinary group. The complexity of the
bone health requires attentive evaluation by bone specialists
in selected cases before to start antiresorptive agents.
Supplemental data will be presented at the meeting.
2018
- Clinical and molecular predictors of long-term response in HER2 positive metastatic breast cancer patients.
[Articolo su rivista]
Omarini, C; Bettelli, S; Caprera, C; Manfredini, S; Caggia, F; Guaitoli, G; Moscetti, L; Toss, A; Cortesi, L; Kaleci, S; Maiorana, A; Cascinu, S; Conte, Pf; Piacentini, F
abstract
BACKGROUND:
HER2+ metastatic breast cancer (MBC) is a poor prognosis disease, unusually curable. To date, no predictive factors have been clearly correlated with long-term response to anti-HER2 agents.
METHODS:
54 HER2+ MBC patients treated with HER2 targeted therapy as first line treatment were analysed: 40 with a time to progression longer than 3 years in Long Responders (LR) group and 14 with a progression disease within one year of anti-HER2 therapy in a control group named Early Progressors (EP). The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on FFPE BC tissues.
RESULTS:
Considering baseline patients and tumor characteristics, EP women had more CNS spread and more metastatic burden of disease compared to LR (p > 0.05). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down regulated, all in EP group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways. MAPK pathway was differently expressed between LR and EP (p = 0.05). PI3K was the only pathway overexpressed in EP patients.
CONCLUSIONS:
Whole genome expression analysis comparing LR vs. EP identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathway could be a positive predictive factors. Further clinical implications are warranted.
ABBREVIATIONS:
BC: breast cancer; MBC: metastatic breast cancer; LR: long responder; EP: early progressor; FFPE: formalin-fixed paraffin-embedded; CNS: central nervous system; PFS: progression free survival; OS: overall survival.
2018
- Endocrine sensitive metastatic breast cancer and bone only disease: are the new treatments always better?
[Poster]
Toss, A.; Venturelli, M.; Sperduti, I.; Isca, C.; Barbieri, E.; Piacentini, F.; Omarini, C.; Cortesi, L; Cascinu, Stefano; Moscetti, L.
abstract
The standard first-line for endocrine sensitive metastatic
breast cancer (BC) is represented by endocrine therapy.
Several phase III clinical trials searched for more effective
strategies. The SWOG, FACT and FALCON trials analyzed
the role of Fulvestrant (Fv), producing contradictory results.
The Monaleesa2, Monaleesa7, Monarch3 and Paloma2 trials
showed that the addition of a CDK4/6 inhibitor to an
aromatase inhibitor (AI) increases the PFS. The use of the
combination for the first-line treatment of bone-only disease
(BoD) is widely discussed. Our meta-analysis aims to
explore the role of the new endocrine strategies in BoD.
The Prisma statement was used. A systematic review of
electronic databases identified the phase III clinical trials
comparing the standard AI to a novel experimental strategy.
The hazard ratios (HR) for PFS for the subgroup of BoD
were pooled in a meta-analysis. The heterogeneity of the
data was evaluated by Chi-square Q test and I2 statistic.
7 studies were included in the analyses. 4 trials explored
the role of CDK4/6 inhibitors (Monaleesa2 and 7, Monarch3
and Paloma2), 2 trials analyzed Fv + AI (SWOG and
FACT), while one trial studied Fv monotherapy (FALCON).
5 trials reported data regarding the BoD, while 2 trials
included the BoD in the non-visceral disease. Overall, the
meta-analyses showed a PFS advantage for the experimental
arms [HR 0.67 p 0.01], with a significant moderate/high
heterogeneity [I2 69.88% p 0.003]. Only the FALCON and
Paloma2 showed a significant improvement in PFS, respectively
for Fv and Palbociclib + Letrozole. Considering only
trials reporting data for BoD, the experimental arms significantly
improved the PFS [HR 0.60 p 0.001], with a low/
moderate non-significant heterogeneity [I2 37.73% p 0.17].
The meta-analyses of trials reporting data for BoD,
showed that the novel strategies are able to improve the
PFS. Nonetheless, only Palbociclib + Letrozole provided
statistically significant data of advantage in this setting. In
clinical trials, BoD is often included in the non-visceral disease
subgroup. Future clinical trials should take into account
the differences in natural history and better prognosis of
BoD, in order to define the best approach to these patients.
2018
- ERBB2 mutations in hormone receptor positive primary breast cancers samples and in their matched endocrine-resistant recurrences.
[Poster]
Venturelli, M.; Toss, A.; Piacentini, F.; Artuso, L.; Bernardis, I.; Parenti, S.; Tenedini, E.; Omarini, C.; Moscetti., 1; Cascinu, S.; Tagliafico, E.; Cortesi, L.
abstract
Previous preclinical studies showed that mutations in
ERBB2 might represent an alternative mechanism for
HER2 activation and the rate of mutations in BC is around
2%. They occur more frequently in HER2-negative
(HER2-) BC and are associated with poor survival. On
these bases, HER2- pts with mutation are potentially candidates
for HER2-targeted therapy, as already showed by
Neratinib. We evaluated the incidence of ERBB2 mutations
in 14 hormone receptor (HR) positive BC and in their
matched endocrine-resistant recurrences.
Using an NGS technology, we evaluated a panel of
genes including ERBB2, in FFPE tissues. We analysed 14
HR positive BCs and their matched recurrences. All the
relapses have been developed during an endocrine
treatment.
29% of pts were diagnosed with HER2+ BC, while
71% of pts developed HER2- BC. 3 pts were diagnosed at
stage I, 6 pts at stage II, 5 pts at stage III. We found 8 different
mutations in 9 samples: A356D, Q1206X, Q396X,
Q393X, P523L, I654V, G1220C, 135+3G>T. Only I654V
was previously described in literature. All but one
(135+3G>T) of these mutations are exonic variants. 5
mutations were in the extracellular domain, 1 in the tyrosine
kinase domain and 2 in the carboxy tail. 28.6% of pts
had ERBB2 mutations in the primary BCs and 35.7% in the
relapsed site. 66.6% of HER2+ primary BCs showed an
ERBB2 mutation, while only 21% of HER2- samples
brought a mutation. 2 patients acquired a new mutation in
the relapsed site, while 1 patient lost the mutation in the
relapsed tissue. The mDFS was 35.3 months. mDFS in
HER2+ and/or mutated pts was 46.4 months, while mDFS
in HER2- wild type pts was 28.5. The mOS was 104
months (6 pts still alive). mOS in HER2+ and/or mutated
pts was 115.6 months while mOS in HER2- wild type pts
was 97.5.
We found an overall detection rate of mutations higher
than that described in literature (ERBB2 mutations were
present in 32.1% of our samples), meaning that our pts
have been highly selected. In fact, only tumors relapsing
26 Tumori Journal 104(4S)
under an endocrine treatment, and thus with proved endocrine
resistance, have been included in our analyses. The
identification of an ERBB2 mutation in primary BCs might
justify a more targeted neo/adjuvant approach and, might
guide the subsequent treatment choices when the mutation
is identified in the relapsed tissue. Contrary to previous
literature, in our study the majority of mutations occurred
in HER2+ samples and HER2+ and/or mutated samples
did not show worse outcomes.
2018
- First-line treatment for endocrine sensitive bone-only metastatic breast cancer: Is more always better?
[Abstract in Atti di Convegno]
Toss, A.; Venturelli, Marta; Sperduti, I.; Isca, Chrystel; Barbieri, Elena; Piacentini, F.; Omarini, C.; Cortesi, L.; Cascinu, S.; Moscetti, L.
abstract
Background: The standard first-line for endocrine sensitive metastatic breast cancer
(BC) is represented by endocrine therapy. Several phase III clinical trials searched for
more effective strategies. The SWOG, FACT and FALCON trials analyzed the role of
Fulvestrant (Fv), producing contradictory results. The Monaleesa2, Monaleesa7,
Monarch3 and Paloma2 trials showed that the addition of a CDK4/6 inhibitor to an
aromatase inhibitor (AI) increases the PFS. The use of the combination for the first-line
treatment of bone-only disease (BoD) is widely discussed. Our meta-analysis aims to
explore the role of the new endocrine strategies in BoD.
Methods: The Prisma statement was used. A systematic review of electronic databases
identified the phase III clinical trials comparing the standard AI to a novel experimental
strategy. The hazard ratios (HR) for PFS for the subgroup of BoD were pooled in a
meta-analysis. The heterogeneity of the data was evaluated by Chi-square Q test and I2
statistic.
Results: 7 studies were included in the analyses. 4 trials explored the role of CDK4/6
inhibitors (Monaleesa2 and 7, Monarch3 and Paloma2), 2 trials analyzed Fv þAI
(SWOG and FACT), while one trial studied Fv monotherapy (FALCON). 5 trials
reported data regarding the BoD, while 2 trials included the BoD in the non-visceral
disease. Overall, the meta-analyses showed a PFS advantage for the experimental arms
[HR 0.67 p 0.01], with a significant moderate/high heterogeneity [I2 69.88% p 0.003].
Only the FALCONand Paloma2 showed a significant improvement in PFS, respectively
for Fv and Palbociclib þ Letrozole. Considering only trials reporting data for BoD, the
experimental arms significantly improved the PFS [HR 0.60 p 0.001], with a low/moderate
non-significant heterogeneity [I2 37.73% p 0.17].
Conclusions: The meta-analyses of trials reporting data for BoD, showed that the novel
strategies are able to improve the PFS. Nonetheless, only Palbociclib þ Letrozole provided
statistically significant data of advantage in this setting. In clinical trials, BoD is
often included in the non-visceral disease subgroup. Future clinical trials should take
into account the differences in natural history and better prognosis of BoD, in order to
define the best approach to these patients.
2018
- First-line treatment for endocrine sensitive bone-only metastatic breast cancer: Is more always better?
[Poster]
Toss, A; Venturelli, M; Sperduti, I; Isca, C; Molinaro, E; Barbieri, E; Piacentini, F; Omarini, C; Cortesi, L; Cascinu, S; Moscetti,
abstract
The standard first-line for endocrine sensitive metastatic breast cancer (BC) is represented by endocrine therapy. Several phase III clinical trials searched for more effective endocrine strategies. Nevertheless, the use of combinations for the first-line treatment of bone-only disease (BoD) is widely discussed, due to its indolent course. Our meta-analysis aims to explore the role of new endocrine strategies in BoD.
A systematic review of electronic databases was conducted to identify the phase III clinical trials comparing the standard AI to novel experimental strategies. The hazard ratios (HR) for PFS were pooled in a meta-analysis. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic.
8 studies were included in the analyses. 4 trials explored the role of CDK4/6 inhibitors (Monaleesa2 and 7, Monarch3 and Paloma2), 2 trials analyzed Fulvestrant + AI (SWOG and FACT), one trial studied Fulvestrant monotherapy (FALCON), while one trial evaluated the association between Bevacizumab and Letrozole (ALLIANCE). 6 trials reported data regarding the BoD, while 2 trials included the BoD in the non-visceral disease. Overall, the meta-analyses showed a PFS advantage for the experimental arms [HR 0.70 p 0.012], with a significant moderate/high heterogeneity [I2 66.48% p 0.004]. Only the FALCON and Paloma2 showed a significant improvement in PFS, respectively for Fulvestrant and Palbociclib + Letrozole. Considering only trials reporting data for BoD, the experimental arms significantly improved the PFS [HR 0.66 p 0.005], with a low/moderate non-significant heterogeneity [I2 44.95% p 0.106].
The novel strategies showed to be able to improve the PFS of BoD. Nonetheless, only Palbociclib + Letrozole provided statistically significant data of advantage in this setting. In clinical trials, BoD is often included in the non-visceral disease subgroup. Future clinical trials should take into account the differences in natural history and better prognosis of BoD, in order to define the best approach to these patients
2018
- Genomic alterations at the basis of treatment resistance in metastatic breast cancer: Clinical applications
[Articolo su rivista]
Toss, Angela; Piacentini, Federico; Cortesi, Laura; Artuso, Lucia; Bernardis, Isabella; Parenti, Sandra; Tenedini, Elena; Ficarra, Guido; Maiorana, Antonino; Iannone, Anna; Omarini, Claudia; Moscetti, Luca; Cristofanilli, Massimo; Federico, Massimo; Tagliafico, Enrico
abstract
The standard of care for breast cancer has gradually evolved from empirical treatments based on clinical-pathological characteristics to the use of targeted approaches based on the molecular profile of the tumor. Consequently, an increasing number of molecularly targeted drugs have been developed. These drugs target specific alterations, called driver mutations, which confer a survival advantage to cancer cells. To date, the main challenge remains the identification of predictive biomarkers for the selection of the optimal treatment. On this basis, we evaluated a panel of 25 genes involved in the mechanisms of targeted treatment resistance, in 16 primary breast cancers and their matched recurrences, developed during treatment. Overall, we found a detection rate of mutations higher than that described in the literature. In particular, the most frequently mutated genes were ERBB2 and those involved in the PI3K/AKT/mTOR and the MAPK signaling pathways. The study revealed substantial discordances between primary tumors and metastases, stressing the need for analysis of metastatic tissues at recurrence. We observed that 85.7% of patients with an early-stage or locally advanced primary tumor showed at least one mutation in the primary tumor. This finding could explain the subsequent relapse and might therefore justify more targeted adjuvant treatments. Finally, the mutations detected in 50% of relapsed tissues could have guided subsequent treatment choices in a different way. This study demonstrates that mutation events may be present at diagnosis or arise during cancer treatment. As a result, profiling primary and metastatic tumor tissues may be a major step in defining optimal treatments.
2018
- Immune characterization of breast cancer metastases: prognostic implications.
[Articolo su rivista]
Dieci, Mv; Tsvetkova, V; Orvieto, E; Piacentini, F; Ficarra, G; Griguolo, G; Miglietta, F; Giarratano, T; Omarini, C; Bonaguro, S; Cappellesso, R; Aliberti, C; Vernaci, G; Giorgi, Ca; Faggioni, G; Tasca, G; Conte, P; Guarneri, V.
abstract
BACKGROUND:
Tumor-infiltrating lymphocytes (TILs) evaluated in primary breast cancer (BC) convey prognostic information. Limited data in the metastatic setting are available.
METHODS:
Secondary lesions from 94 BC patients, 43 triple-negative (TN) and 51 HER2-positive, were evaluated for TILs and expression of CD8, FOXP3, and PD-L1 by immunohistochemistry.
RESULTS:
TILs levels on metastasis were generally low (median 5%) and did not differ between TN and HER2+ tumors. Younger patients showed significantly lower TILs (p = 0.002). In HER2+ patients, TILs were higher in lung metastases as compared to other sites (p = 0.038). TILs composition was different across metastatic sites: skin metastases presented higher FOXP3 (p = 0.002) and lower CD8/FOXP3 ratio (p = 0.032). Patients treated for metastatic BC prior to biopsy had lower CD8 (overall: p = 0.005, HER2+: p = 0.011, TN: p = 0.075). In TN patients, median overall survival (OS) was 11.8 and 62.9 months for patients with low and high TILs, respectively (HR 0.29, 95%CI 0.11-0.76, log-rank p = 0.008). CD8/FOXP3 ratio was also prognostic in TN patients (median OS 8.0, 13.2, and 54.0 months in 1st, 2nd and 3th tertile, log-rank p = 0.019). Both TILs and CD8/FOXP3 ratio were independent factors at multivariate analysis. Counterintuitively, in HER2+ BC, low TILs tumors showed better prognosis (median OS 53.7 vs 39.9 months in TILs low and TILs high, not statistically significant).
CONCLUSIONS:
Our findings indicate the relevance of TILs as prognostic biomarker for TNBC even in the advanced setting and provide novel hypothesis-generating data on potential sources of immune heterogeneity of metastatic BC.
2018
- Impact of anaemia on tumor response to neoadjuvant chemotherapy in breast cancer patients .
[Poster]
Omarini, Claudia; Guaitoli, Giorgia; Barbolini, Monica; Moscetti, Luca; Balduzzi, Sara; Caggia, Federica; Cascinu, Stefano; Piacentini, Federico
abstract
BACKGROUND - Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) in patients with breast cancer (BC) predicts long-term outcomes.
Anaemia is one of the most common side effects of cytotoxic drugs. Biologically, anaemia induces adaptive responses due to the low intra-tumoral oxygen levels that may be responsible for increase chemotherapy resistance. In literature, data regarding this issue are lacking.
AIM - To evaluate the influence of anaemia throughout treatment course on tumour shrinkage induced by NST. METHODS - Patients - 317 patients diagnosed with stage I-III BC treated with NST and with available blood tests were included. Patients and tumor characteristics and treatments information were collected. We focused on Haemoglobin (Hb) level (at baseline, at the end of NST, drop in Hb throughout treatment and duration of anaemia) and its correlation with pCR rate. Anaemia was defined as a drop of Hb under the local limit of normal in women (12 mg/dl).
Statistical analysis - Categorical variables were analyzed using chi-square test or Fisher's exact test, continuous variables using t test. Univariate and multivariate analyses were fit to determinate the association between anaemia and pCR rate. A p-value < 0.05 was considered statistically significant; hazard ratio was estimated with 95% of confidence limits. RESULTS- No difference in Hb levels was observed stratifying patients according to nuclear grade, tumor stage, cancer subtypes and chemotherapy regimens. Median baseline Hb was 13.3 g/dl while median Hb level at the end of NST was 10 g/dl. 31 patients had pre-treatment anaemia. 60% of patients developed anaemia during NST period. In the subgroup of anaemic patients, who had a decrease in Hb ≥ 2 g/dl from baseline or anaemia longer than two months, a lower rate of pCR was observed (16% vs 29%, p=0.03 and 16% vs 25%, p=0.01, respectively). Patients with both these characteristics had the lowest rate of pCR (10%, p=0.01). CONCLUSIONS - Anaemia is a negative predictive factor for tumor response in women treated with NST for BC. This evidence suggests that anaemia should be improved in order to improve response to NST.
2018
- Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus
[Articolo su rivista]
Omarini, Claudia; Filieri, Maria Elisabetta; Bettelli, Stefania Raffaella; Manfredini, Samantha; Kaleci, Shaniko; Caprera, Cecilia; Nasso, Cecilia; Barbolini, Monica; Guaitoli, Giorgia; Moscetti, Luca; Maiorana, Antonino; Conte, Pierfranco; Cascinu, Stefano; Piacentini, Federico
abstract
Background. Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. Patients and Methods. Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. Results. The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (, , and ). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. Conclusions. The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study.
2018
- Neoadjuvant treatments in triple-negative breast cancer patients: where we are now and where we are going
[Articolo su rivista]
Omarini, Claudia; Guaitoli, Giorgia; Pipitone, Stefania; Moscetti, Luca; Cortesi, Laura; Cascinu, Stefano; Piacentini, Federico
abstract
Abstract: Triple-negative breast cancer (TNBC) remains the poorest-prognosis breast cancer
(BC) subtype. Gene expression profiling has identified at least six different triple-negative
subtypes with different biology and sensitivity to therapies. The heterogeneous nature of TN
tumors may justify the difficulty in treating this BC subtype. Several targeted agents have been
investigated in clinical trials without demonstrating a clear survival benefit. Therefore, systemic
chemotherapy remains the cornerstone of current clinical practice. Improving the knowledge of
tumor biology is mandatory for patient management. In stages II and III, neoadjuvant systemic
treatment is an effective option of care. The achievement of a pathological complete response
represents an optimal surrogate for survival outcome as well as a test for tumor drug sensitivity.
In this review, we provide a brief description of the main predictive biomarkers for tumor
response to systemic treatment. Moreover, we review the treatment strategies investigated for
TNBCs in neoadjuvant settings focusing on experimental drugs such as immunotherapy and
poly [ADP-ribose] polymerase inhibitors that hold promise in the treatment of this aggressive
disease. Therefore, the management of TNBC represents an urgent, current, unmet need in daily
clinical practice. A key recommendation is to design biology-driven clinical trials wherein TNBC
patients may be treated on the basis of tumor molecular profile.
2018
- Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)
[Abstract in Atti di Convegno]
Musolino, A; Cavanna, L; Boggiani, D; Zamagni, C; Frassoldati, A; Caldara, A; Rocca, A; Gori, S; Piacentini, F; Berardi, R; Brandes, Aa; Foglietta, J; Villa, F; Pellegrino, B; Todeschini, R; Tognetto, M; Naldi, N; Bortesi, B; Boni, L; Montemurro, F; Ardizzoni, A
abstract
Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance.
Materials and Methods:This is an open-label, national multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC.The primary endpoint was the objective response rate (ORR) for evaluable patients (pts). The study was designed according to the Simon's two stage optimal design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A prospective, molecular correlative study has been being carried out on germinal DNA of study population to assess the role of BRCA mutations and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen.
Results: From July 2013 to September 2016, 83 evaluable pts (37 in the first stage, 46 in the second one) were enrolled. They received a median number of 6 cycles of treatment (range 1-24). The ORR (CR+PR) was 37.35% (90% CI: 28.47-46.93) and the clinical benefit rate (CR+PR+SD ≥ 24wks) was 48.78% (90% CI: 39.24%-58.39%). The most common grade 3-4 adverse events (> 10% of patients) were neutropenia and liver toxicity. With a median follow-up of 28.8 months, the median progression-free survival (PFS) and overall survival (OS) were 5.1 months (95% CI: 4.2-7.0) and 14.7 months (95% CI: 10.2-20.0), respectively. BRCA1/2 deleterious mutations were observed in 15 (22%) out of 68 genotyped pts. Women with BRCA1/2 mutations were associated with worse ORR, PFS and OS than those with BRCA1/2 wild-type. A panel of SNPs in genes of study drug metabolism pathways was evaluated. Among these, CYP3A4 392A >G and FGD4 2044236G>A SNPs were associated with greater liver toxicity by logistic regression analysis. Furthermore, CDA*2 79A>C, RRM1 2455 A>G, and CYP2C8 416G>A SNPs were associated with poorer overall survival by Cox proportional hazards model.
Conclusions:The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify pts with high probability of response with negligible toxicity.
2018
- Primary and secondary prevention to effectively reduce the risk of bisphosphonate-related osteonecrosis of the jaw in patients with bone metastases .
[Poster]
Piacentini, F; Omarini, C; Garuti, G; Badea, M; Moscetti, L; Cortesi, L; Toss, A; Barbieri, E; Barbolini, M; Guaitoli, G; Caputo, F; Cascinu, S
abstract
Background
Bone is one of the most frequent sites of metastasis in patients with advanced cancer. Nearly all patients with myeloma, 65–75%
of patients with prostate or breast cancer, and 30–40% of patients with lung cancer or other solid tumors, eventually develop bone
metastases. Bisphosphonates (BP), particularly zoledronic acid and denosumab, were demonstrated to effectively reduce skeletal
complications in patients with bone metastases. However, bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur
spontaneously, favored by dental extraction, dental implant surgery, or denture wearing. The purpose of this study was to
underline the role of dental prevention as an effective tool to reduce the risk of BRONJ.
Material and methods
BRONJ was identified with the standardized query “osteonecrosis” among all data from patients treated at Modena Cancer
Center from 2005 to 2016. For each case, demographic and medical information were analyzed, as well as data about notification
(year of occurrence, outcome), type and duration of BP exposure, and associated risk factors (dento-alveolar surgery,
chemotherapy, antiangiogenics). Data were differently analyzed taking into account the implementation of a Dental Prevention
Service in patients who are candidates for BP therapy.Results
Among 1663 patients treated with BP, 63 cases of BRONJ were identified (3.8%). 44 female and 19 men with a median age of 69
years (range 47-90 years), have been treated with BP for bone metastases from breast cancer (54%), hematologic malignancy
(21%), prostate cancer (13%), renal cancer (5%), lung cancer (2%) and other tumors (5%). 15 maxillae and 48 mandibles were
involved. The trigger event was a dental extraction in 29% of the cases, being spontaneously the other 71%. The median time to
BRONJ was 28 months (range 1-89.1 months) from the first dose of BP, and 25 was the mean number of BP doses administered
before BRONJ. Overall, a preliminary odontoiatric evaluation was performed in only 14 cases (22%). All but one of these
dentistry opinions were obtained after 2010 when the Dental Prevention Service was created, which is a drop out of the risk of
BRONJ from 4.1 to 1.9%.
Conclusions.
Prevention of the BRONJ is critical in in bone metastatic patients. The incidence of BRONJ over time can drop to 1.9% when
primary and secondary prevention measures are implemented in routine clinical practice.
2018
- 9 weeks versus 1 year adjuvant trastuzumab for HER2+ early breast cancer: Subgroup analysis of the ShortHER trial allows to identify patients for whom a shorter trastuzumab administration may have a favourable risk/benefit ratio
[Abstract in Rivista]
Conte, P. F.; Guarneri, V.; Bisagni, G.; Piacentini, F.; Brandes, A. A.; Cavanna, L.; Giotta, F.; Aieta, M.; Gebbia, V.; Frassoldati, A.; Musolino, A.; Garrone, O.; Taverniti, C.; Rimanti, A.; Sarti, S.; Rubino, D.; Bologna, A.; Vicini, R.; Balduzzi, S.; D'Amico, R.
abstract
2018
- 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.
[Articolo su rivista]
Conte, P; Frassoldati, A; Bisagni, G; Brandes, Aa; Donadio, M; Garrone, O; Piacentini, F; Cavanna, L; Giotta, F; Aieta, M; Gebbia, V; Molino, A; Musolino, A; Ferro, A; Maltoni, R; Danese, S; Zamagni, C; Rimanti, A; Cagossi, K; Russo, A; Pronzato, P; Giovanardi, F; Moretti, G; Lombardo, L; Schirone, A; Beano, A; Amaducci, L; Bajardi, Ea; Vicini, R; Balduzzi, Sara; D'Amico, R; Guarneri, Valentina
abstract
BACKGROUND:
Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment for HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The Short-HER study was aimed to assess the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab combined with chemotherapy.
PATIENTS AND METHODS:
HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT > 2cm, G3, lympho-vascular invasion, Ki-67>20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9-weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end-point. A DFS Hazard Ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary endpoints included 2-year failure rate and cardiac safety.
RESULTS:
1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR was 1.13 (90%CI 0.89;1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-yr OS is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90%CI0.74;1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95%CI0.22;0.50, p < 0.0001).
CONCLUSIONS:
This study failed to show the non-inferiority of a shorter trastuzumab administration. 1-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.
2017
- A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience.
[Articolo su rivista]
Vici, P; Pizzuti, L; Michelotti, A; Sperduti, I; Natoli, C; Mentuccia, L; Di Lauro, L; Sergi, D; Marchetti, P; Santini, D; Magnolfi, E; Iezzi, L; Moscetti, L; Fabbri, A; Cassano, A; Grassadonia, A; Omarini, Claudia; Piacentini, Federico; Botticelli, A; Bertolini, I; Scinto, Af; Zampa, G; Mauri, M; D'Onofrio, L; Sini, V; Barba, M; Maugeri Saccà, M; Rossi, E; Landucci, E; Tomao, S; Alberti, Am; Giotta, F; Ficorella, C; Adamo, V; Russo, A; Lorusso, V; Cannita, K; Barni, S; Laudadio, L; Greco, F; Garrone, O; Giulia, Md; Marolla, P; Sanguineti, G; Di Cocco, B; Ciliberto, G; De Maria, R; Gamucci, T.
abstract
We addressed trastuzumab emtansine (T-DM1) efficacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab-pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing significant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical benefit 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no differences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab-pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab-pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival benefit (p<0.0001), while overall survival was positively affected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical benefit (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to confirm and interpret our data on apparently lower T-DM1 efficacy when given as second-line treatment after pertuzumab, and on the optimal sequence order.
2017
- Differential gene expression patterns in HER2 positive metastatic breast cancer patients according to hormone receptor status
[Poster]
Omarini, Claudia; Kaleci, Shaniko; Guaitoli, Giorgia; Bettelli, Stefania Raffaella; Cecilia, Caprera; Manfredini, Samantha; Caggia, Federica; Baschieri, MARIA CRISTINA; Luca, Moscetti; Maiorana, Antonino; Cascinu, Stefano; Piacentini, Federico
abstract
Background: HER2 positive breast cancer (HER2+ BC) is a heterogeneous disease. Presenting features, patterns of recurrence and survival of HER2+ BC can differ according to hormone receptors (HR) status. The purpose of this study is to highlight different gene profiles and molecular pathways between HR+ and HR- metastatic HER2+ BCs. Material and Methods: 34 HER2+ metastatic BC patients were included: 18 patients with HR+/HER2+ and 14 with HR-/HER2+. Data regarding tumor characteristics, treatment information and clinical outcomes were collected. The expression of 770 genes and 13 molecular pathways were evaluated by means of Nanostring PanCancer pathway panel performed on BC formalin-fixed paraffin-embedded tissues from diagnostic core biopsy or surgical resection. Results: Gene expression analysis identified 118 genes with significantly different expression in the two cohorts. All but one of these genes were over-expressed; only the gene CACNG6 was down-regulated in HR+/HER2+ group. In particular, 93 genes were over-expressed in HR-/HER2+ while 24 were overexpressed in HR+/HER2+. Most of these genes encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. 62% of these genes were involved in PI3K, MAPK and RAS pathways (32, 22 and 18, respectively). PI3K, MAPK and NOTCH pathways were differently expressed between HR+/HER2+ and HR-/HER2+ (p=0.003, p=0.0018, p=0.02, respectively). All these three pathways were overexpressed in HR-/HER2+ BC. In particular, all the significantly different expression genes in NOTCH pathways were overexpressed in HR-/HER2+ group. Conclusions: This genome expression analysis identified a gene expression profile able to differentiate HR+ versus HR- HER2+ metastatic BC. The overexpression of PI3K, MAPK and NOTCH pathways in HR-/HER2+ BC could justify its more aggressive behaviour. The validation of this HER2+ BC profile needs further investigation. Keywords: metastatic breast cancer, gene expression profile, HER2 positive breast cancer, PanCancer
2017
- Differential gene expression patterns in HER2 positive metastatic breast cancer patients according to hormone receptor status.
[Abstract in Rivista]
Omarini, C; Kaleci, S; Guaitoli, G; Bettelli, S; Caprera, Cecilia; Manfredini, S; Caggia, F; Baschieri, Cristina; Moscetti, Luca; Maiorana, A; Cascinu, S; Piacentini, F
abstract
Background: HER2 positive breast cancer (HER2+ BC) is a heterogeneous disease. Presenting features, patterns of recurrence and survival of HER2+ BC can differ according to hormone receptors (HR) status. The purpose of this study is to highlight different gene profile and molecular pathways between HR+ and HR- metastatic HER2+ BCs.
Materials and methods: 34 HER2+ metastatic BC patients were included: 18 patients with HR+/HER2+ and 14 with HR-/HER2+. Data regarding tumor characteristics, treatment information and clinical outcomes were collected. The expression of 770 genes and 13 molecular pathways were evaluated by means of Nanostring PanCancer pathway panel performed on BC formalin-fixed paraffin-embedded tissues from diagnostic core biopsy or surgical resection specimen.
Results: Gene expression analysis identified 118 genes with significantly different expression in the two cohorts. All but one of these genes were over-expressed; only the gene CACNG6 was down-regulated in HR+/HER2+ group. In particular, 93 genes were over-expressed in HR-/HER2+ while 24 were overexpressed in HR+/HER2+. Most of these genes encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. 62% of these genes were involved in PI3K, MAPK and RAS pathways (32, 22 and 18, respectively). PI3K, MAPK and NOTCH pathways were differently expressed between HR+/HER2+ and HR-/HER2 + (p = 0.003, p = 0.0018, p = 0.02, respectively). All these three pathways were overexpressed in HR-/HER2+ BC. In particular, all the significantly different expression genes in NOTCH pathways were overexpressed in HR-/HER2+ group.
Conclusions: This genome expression analysis identified a gene expression profile able to differentiate HR+ versus HR- HER2+ metastatic BC. The overexpression of PI3K, MAPK and NOTCH pathways in HR-/HER2+ BC could justify its more aggressive behaviour. The validation of this HER2+ BC profile needs further investigation.
2017
- Erratum to: Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2− breast cancer: results from two prospective trials (Breast Cancer Research and Treatment, (2017), 163, 2, (295-302), 10.1007/s10549-017-4191-y)
[Articolo su rivista]
Dieci, M. V.; Frassoldati, A.; Generali, D.; Bisagni, G.; Piacentini, F.; Cavanna, L.; Cagossi, K.; Puglisi, F.; Michelotti, A.; Berardi, R.; Banna, G.; Goubar, A.; Ficarra, G.; Griguolo, G.; Conte, P.; Guarneri, V.
abstract
In the original publication of the article, the eighth and ninth co-author’s affiliations were published incorrectly. The correct affiliations of the co-authors are given in this erratum.
2017
- Everolimus Plus Exemestane in Advanced Breast Cancer: Safety Results of the BALLET Study on Patients Previously Treated Without and with Chemotherapy in the Metastatic Setting.
[Articolo su rivista]
Generali, D; Montemurro, F; Bordonaro, R; Mafodda, A; Romito, S; Michelotti, A; Piovano, P; Ionta, Mt; Bighin, C; Sartori, D; Frassoldati, A; Cazzaniga, Me; Riccardi, F; Testore, F; Vici, P; Barone, Ca; Schirone, A; Piacentini, Federico; Nolè, F; Molino, A; Latini, L; Simoncini, El; Roila, F; Cognetti, F; Nuzzo, F; Foglietta, J; Minisini, Am; Goffredo, F; Portera, G; Ascione, G; Mariani, G.
abstract
BACKGROUND:
The BALLET study was an open-label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor-positive metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%).
PATIENTS AND METHODS:
One thousand one hundred and fifty-one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%).
RESULTS:
One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus-related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus-related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting.
CONCLUSION:
Real-life data of the Italian patients BALLET-related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The Oncologist 2017;22:1-8Implications for Practice: With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from one line to another. Thus, it is important to assess even the potential of cumulative and additive toxic effects among the drugs. Previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The continuous monitoring of the safety signals of this drug combination from general clinical practice is important, in particular for stomatitis.
2017
- GD2 expression in breast cancer.
[Articolo su rivista]
Orsi, Giulia; Barbolini, Monica; Ficarra, G; Tazzioli, Giovanni; Manni, Paola; Petrachi, Tiziana; Mastrolia, Ilenia; Orvieto, E; Spano, Maria Carlotta; Prapa, Malvina; Kaleci, Shaniko; D'Amico, Roberto; Guarneri, V; Dieci, Mv; Cascinu, Stefano; Conte, P; Piacentini, Federico; Dominici, Massimo
abstract
Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features.Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system.Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis.We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants.
2017
- Impact of time to surgery after neoadjuvant chemotherapy in operable breast cancer patients
[Articolo su rivista]
Omarini, Claudia; Guaitoli, Giorgia; Noventa, Silvia; Andreotti, Alessia; Gambini, Anna; Palma, E; Papi, Simona; Tazzioli, Giovanni; Balduzzi, Sara; Dominici, Massimo; Cascinu, Stefano; Piacentini, Federico
abstract
The optimal time interval between the end of neoadjuvant systemic therapy (NST) and breast surgery is still unclear. It is not known if a delay in surgery might influence the benefit of primary chemotherapy. The aim of this study is to evaluate the relationship between time to surgery (TTS) and survival outcomes.
2017
- Metronomic Capecitabine Effectively Blocks Leptomeningeal Carcinomatosis From Breast Cancer: A Case Report and Literature Review.
[Articolo su rivista]
Maur, Michela; Omarini, Claudia; Piacentini, Federico; Fontana, Annalisa; Pettorelli, Elisa; Cascinu, Stefano
abstract
BACKGROUND Meningeal carcinomatosis is a rare complication in breast cancer patients. At present, there are no defined guidelines for its management. The efficacy of systemic treatment seems to depend on its ability to cross the blood-brain-barrier and its interaction with tumor vasculature. Metronomic chemotherapy is a known modality of drug administration able to inhibit tumor angiogenesis. CASE REPORT We present a case of symptomatic leptomeningeal carcinomatosis from breast cancer successfully treated with capecitabine. Based on the hypothesis that angiogenesis contributes to neoplastic meningitis, the patient was treated with a metronomic schedule that provided long-term clinical benefit with a very low toxicity profile. CONCLUSIONS To assess the real impact of metronomic chemotherapy in patients with meninges involvement, a phase II study will be starting soon in our institution. A review of the literature concerning the management of meningeal carcinomatosis is also presented.
2017
- Molecular Biomarkers for Prediction of Targeted Therapy Response in Metastatic Breast Cancer: Trick or Treat?
[Articolo su rivista]
Toss, Angela; Venturelli, Marta; Peterle, Chiara; Piacentini, Federico; Cascinu, Stefano; Cortesi, Laura
abstract
In recent years, the study of genomic alterations and protein expression involved in the pathways of breast cancer carcinogenesis has provided an increasing number of targets for drugs development in the setting of metastatic breast cancer (i.e., trastuzumab, everolimus, palbociclib, etc.) significantly improving the prognosis of this disease. These drugs target specific molecular abnormalities that confer a survival advantage to cancer cells. On these bases, emerging evidence from clinical trials provided increasing proof that the genetic landscape of any tumor may dictate its sensitivity or resistance profile to specific agents and some studies have already showed that tumors treated with therapies matched with their molecular alterations obtain higher objective response rates and longer survival. Predictive molecular biomarkers may optimize the selection of effective therapies, thus reducing treatment costs and side effects. This review offers an overview of the main molecular pathways involved in breast carcinogenesis, the targeted therapies developed to inhibit these pathways, the principal mechanisms of resistance and, finally, the molecular biomarkers that, to date, are demonstrated in clinical trials to predict response/resistance to targeted treatments in metastatic breast cancer.
2017
- Osteonecrosis of the Jaw in a Breast Cancer Patient Treated with Everolimus and a Single Dose of Zoledronic Acid.
[Articolo su rivista]
Omarini, Claudia; Filieri, Maria Elisabetta; Depenni, R; Grizzi, Giulia; Cascinu, Stefano; Piacentini, Federico
abstract
The first case of ONJ after the first infusion of zoledronic acid in a patient receiving everolimus and bisphosphonates for metastatic BC.
2017
- Oxford Manuale di Medicina Clinica
[Traduzione di Libro]
Ventura, Paolo; Cuoghi, Angela; De Ruvo, Nicola; Marcacci, Matteo; Piacentini, Federico
abstract
Traduzione della nona edizione del manuale tascabile di Medicina Clinica
2017
- Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer: ERIGE trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).
[Poster]
Musolino, Antonino; Porzio, Rosa; Rubino, Daniela; Frassoldati, Antonio; Caldara, Alessia; Schirone, Alessio; Gori, Stefania; Piacentini, Federico; Berardi, Rossana; Brandes, Alba Ariela; Cavazzini, Giovanna; Foglietta, Jennifer; Villa, Federica; Pellegrino, Benedetta; Camisa, Roberta; Todeschini, Renata; Tognetto, Michele; Naldi, Nadia; Baldari, Daniela; Montemurro, Filippo
abstract
Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Methods: We performed an open-label, national multicenter phase 2 study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC. The Simon's optimal two-stage design was used for estimating objective response rate (ORR) as study primary endpoint. A prospective, molecular correlative study was carried out on germinal DNA of study population to assess the role of germinal DNA polymorphisms and BRCA mutations in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016, 83 (37 in the first stage, 46 in the second one) assessable patients were enrolled. Median age at baseline was 56 years. Sixty-six and 17 patients were in first or second-line treatment, respectively. All patients were previously treated with an anthracycline and/or a taxane. With regard to the first stage of study enrolment, patients received a median number of 6 cycles of treatment. The ORR (CR+PR) was 43.24% (90% CI 29.3-58.0) and the clinical benefit rate (CR+PR+SD) was 64.9% (90% CI: 50.1%-77.8%). The most common grade 3/4 AEs ( > 10% of patients) were neutropenia without febrile neutropenia and liver toxicity. Grade 1/2 AEs were fatigue, anemia, thrombocytopenia, diarrhea, alopecia, peripheral neuropathy, and oral mucositis. Conclusions: The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. More mature toxicity and outcome data of the final study population and correlation with genome analysis will be presented at the meeting. Clinical trial information: 2012-003505-10.
2017
- Tumor-infiltrating lymphocytes and molecular response after neoadjuvant therapy for HR+/HER2- breast cancer: results from two prospective trials.
[Articolo su rivista]
Dieci, Mv; Frassoldati, A; Generali, D; Bisagni, G; Piacentini, Federico; Cavanna, L; Cagossi, K; Puglisi, F; Michelotti, A; Berardi, R; Banna, G; Goubar, A; Ficarra, G; Griguolo, G; Conte, P; Guarneri, V.
abstract
PURPOSE:
The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response.
METHODS:
Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed.
RESULTS:
StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the high vs low StrTIL group (64 vs. 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy.
CONCLUSIONS:
This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.
2017
- 3* Final analysis of the phase III multicentric Italian study Short-HER: 9 weeks vs 1 year adjuvant trastuzumab for HER2+ early breast cancer
[Abstract in Rivista]
Conte, P; Bisagni, G; Frassoldati, A; Brandes, A; Cavanna, L; Giotta, F; Aieta, M; Gebbia, V; Musolino, A; Garrone, O; Donadio, M; Cavazzini, G; Turletti, A; Zamagni, C; Danese, S; Ferro, A; Piacentini, F; Balduzzi, S; D'Amico, R; Guarneri, V
abstract
Introduction: chemotherapy plus 1 year trastuzumab is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab.
Methods: HER2+ breast cancer pts were randomized to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy and hormone therapy were started after the completion of chemotherapy. ShortHER is a non-inferiority trial with disease-free survival (DFS) as primary end-point. The sample size of 1250 pts has been estimated on the basis of an hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis was planned after 198 DFS events or a 5yr median follow up. Hazard ratio for DFS and OS (90% CI) are estimated according to the Cox model; data are also analyzed by the Bayesian approach.
Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are: median age 55 yrs (25-78); pts older than 60 yr 36%; stage I 40.6%, II 43.8%, stage III 15.2%; N0 53.5%, 1-3 positive nodes 30.7%, ≥ 4 15.2%. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms.
At the time of the analysis, 189 events have occurred and the median follow up of the study is 5.2 yrs. A total of 109 Grade ≥ 2 cardiac events have been reported, 82 in arm A (long) and 27 in arm B (short) (p < 0.0001); grade 3-4 cardiac events were 13 in arm A and 5 in arm B.
Conclusions: Shorter trastuzumab administration significantly reduces the rate of severe cardiac toxicity. Final DFS data will be reported at the time of the meeting.
EudraCT: 2007-004326-25.
2017
- 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER
[Abstract in Atti di Convegno]
Conte, Pier Franco; Bisagni, Giancarlo; Frassoldati, Antonio; Brandes, Alba Ariela; Anselmi, Elisa; Giotta, Francesco; Aieta, Michele; Gebbia, Vittorio; Musolino, Antonino; Garrone, Ornella; Taverniti, Cristiana; Cavazzini, Giovanna; Turletti, Anna; Rubino, Daniela; Picardo, Elisa; Ferro, Antonella; Piacentini, Federico; Balduzzi, Sara; D'Amico, Roberto; Guarneri, Valentina
abstract
Background: 1-year trastuzumab with chemotherapy is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The efficacy of less extended trastuzumab exposure is still under investigation. The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: This is a phase III, multicenter, Italian trial where pts with HER2+ breast cancer were randomly assigned to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy was administered after the completion of chemotherapy. Hormonal therapy started at the completion of chemotherapy for pts with hormone receptor positive tumors. This is a non-inferiority trial with disease-free survival (DFS) as primary end-point.Overall survival (OS) is evaluated as second primary analysis outcome. The sample size of 1250 pts has been estimated based on a hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis will take place after 198 DFS events. Secondary aims include 2-yrs failure rate, cardiac toxicity, correlative biomarkers analyses. Hazard ratio for DFS and OS (90% CI) will be estimated according to the Cox model. Data will also be analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are the following: median age 55 yrs (25-78), stage I 37.3%, IIA 40%, IIB 20.6%, III 2.1%. 30% of the pts had 1-3 positive nodes, 16% >=4. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of this writing, 95% of the planned DFS events have been reported. 105 Grade ≥2 cardiac events have been reported, 78 in arm A (long) and 27 in arm B (short). Grade 3-4 cardiac events were 20 in arm A and 11 in arm B. Conclusions: Shorter trastuzumab administration almost halves the rate of severe cardiac toxicity. Final DFS data will be available at the time of the meeting.
2016
- Clinical and molecular analysis of long-term HER2 positive metastatic breast cancer survivors.
[Poster]
Omarini, Claudia; Caprera, Cecilia; Manfredini, Samantha; Caggia, Federica; Guaitoli, Giorgia; Filieri, Maria Elisabetta; Moscetti, Luca; Bettelli, Stefania Raffaella; Kaleci, Shaniko; Cascinu, Stefano; Piacentini, Federico
abstract
ackground: Several multigene tests have been developed in Metastatic Breast Cancer (MBC) disease, in order to identify predictive factors correlated to clinical outcomes. The purpose of this study is to investigate the clinico-pathological and molecular characteristics that could differentiate long term responders from patients experiencing early progression during anti-HER2 treatments. Methods: A total of 34 HER2 positive MBC patients were included: 20 patients with a time to progression longer than 3 years in Long Responders group (LR) and 14 patients with a progression disease within one year of anti-HER2 therapy in Poor Responders group (PR). Tumor characteristics and treatment information were collected. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer pathway panel performed on BC formalin-fixed paraffin-embedded tissues from diagnostic core biopsy or surgical resection. Results: Baseline patients and tumor characteristics were similar between the two groups, although PR patients were more likely to have CNS spread and more metastatic burden of disease compared to LR (29% vs. 0, p = 0.02 and 57% vs. 20%, p = 0.04, respectively). Gene expression analysis identified 30 genes with significantly different expression in the two cohorts; five of these were driver genes (BRCA1, PDGFRA, AR, PHF6 and MSH2). The majority of these genes were over-expressed, mainly in LR patients, and encoded growth factors, pro- or anti-inflammatory interleukins and DNA repair factors. Only four genes were down-regulated, all in PR group (TNFSF10, CACNG1, IL20RB and BRCA1). Most of these genes were involved in MAPK and PI3K pathways (9 and 8, respectively). MAPK pathway was differently expressed between LR and PR (p = 0.05). Even if not statistically significant but clinically relevant, PI3K was the only pathway overexpressed in PR patients (median expression LR: 1441 ± 485 vs 1759 ± 762 in PR group; p= 0.1). Conclusions: Whole genome expression analysis comparing LR vs. PR identified a group of genes that may predict more favourable long-term outcomes. Up-regulation of MAPK and down-regulation of PI3K pathways could be a positive predictive factors. Further clinical implications are warranted.
2016
- Immunoglobulin G fragment C receptor polymorphisms and efficacy of preoperative chemotherapy plus trastuzumab and lapatinib in HER2-positive breast cancer
[Articolo su rivista]
Musolino, A; Naldi, N; Dieci, Maria Vittoria; Zanoni, Daniele; Rimanti, Anita; Boggiani, D; Sgargi, P; Generali, Dg; Piacentini, Federico; Ambroggi, M; Cagossi, K; Gianni, L; Sarti, S; Bisagni, G; Ardizzoni, Andrea; Conte, Pf; Guarneri, Valentina
abstract
Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.
2016
- Integrated evaluation of PAM50 subtypes and immune modulation of pCR in HER2-positive breast cancer patients treated with chemotherapy and HER2-targeted agents in the CherLOB trial
[Articolo su rivista]
Dieci, M. V; Prat, A; Tagliafico, Enrico; Paré, L; Ficarra, G; Bisagni, G; Piacentini, Federico; Generali, D. G; Conte, P; Guarneri, V.
abstract
In the CherLOB study, intrinsic subtypes, TILs and immune signatures all contribute to the chance of pCR after neoadjuvant chemotherapy plus anti-HER2 agents for HER2-positive breast cancer. However, immune gene signatures rather than TILs provide significant independent prediction of pCR beyond intrinsic subtypes.The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents.The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated.Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (chi(2) test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not.In this study, both tumor-related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes.
2016
- Molecular profile in primary and metastatic breast cancer treated with Exemestane and Everolimus.
[Abstract in Atti di Convegno]
Filieri, Maria Elisabetta; Bettelli, Stefania Raffaella; Maiorana, Antonio; Caprera, Cecilia; Manfredini, Samantha; Caggia, Federica; Iattoni, Elena; Cascinu, Stefano; Omarini, Claudia; Piacentini, Federico
abstract
Background. The PI3K/Akt/ mTOR pathway plays a significant role in endocrine resistance breast cancer (BC). Everolimus (EVE) has been approved after BOLERO-2 study, which showed a significant increase of PFS thanks to EVE plus Exemestane (EXE), compared to EXE alone. Hortobagyi et al. performed Next Generation Sequencing on 227 BOLERO-2 samples of primary BC to study the potential correlation between genetic alterations and EVE efficacy: a greater incidence of mutations in PI3KCA, PTEN, CCND1 and FGFR1 was detected, but treatment effect was independent from the genetic status. The aim of this study was to evaluate the molecular profile of both primary and secondary lesions in 25 metastatic BC patients treated with EVE+EXE in Modena University Hospital since 2014.
Materials and methods. Thirty-three DNA samples from 25 patients were examined, 13 from primary BC and 20 from metastatic lesions. In 8 patients both primary tumor and metachronous metastasis were evaluated. Genomic DNA samples from FFPE tissues was conducted using panel OncoCarta 2.0 on MassArray Sequenom platform that detect more than 150 single nucleotide variations from 18 genes (AKT1, BRAF, CTNNB1, FBX4, FBXW7, FGFR2/3, GNAQ, KIT, KRAS, MAP2K1/2, NRAS, PDGFR, PIK3CA, PTPN11, SOS1, TP53). Differences between mutational status of primary and metastatic BC have been evaluated using χ2 and Fisher tests.
Results. The median age was 54 years (range 50-67). 70% of patients had visceral involvement, 62% received more than 3 previous therapies, and for 8% of them an AI constituted the last treatment before EVE. Overall, 11 DNA samples were mutated (33%). 5 mutations were detected in the primary lesion with a frequency of 3% (PI3KCA, FBX4, KIT, MAP2K1, FBXW7) - 6 mutations in the metastasis (BRAF, KIT, TP53, FBXW7, CTNNB1, PI3KCA, AKT). Notably, mutations were found exclusively in primary lesion or in metastatic site, while only in one case both primary and secondary cancer were mutated, even if in two different genes. No significant correlation with treatment efficacy was evidenced.
Conclusions. The genes most frequently mutated in MBC were PI3KCA, AKT1 and FBXW7, even if the percentage of PIK3CA and AKT1 mutations was less than expected. No correlation between primary and metastatic mutational status was detected. Involving new patients maybe could be the way for more encouraging results.
2016
- Pre and post anti Her-2 therapy era: a mono-institutional analysis of the outcome in patients with residual disease after neoadjuvant therapy for Her-2 positive locally advanced breast cancer.
[Abstract in Atti di Convegno]
Iattoni, E.; Omarini, C.; Tamma, A. V.; Noventa, S.; Piacentini, F.; Moscetti, L.; Cascinu, S.
abstract
Background: Anti Her-2+ therapies (aH2Tx) have changed the outcome of women
with Her2 positive (Her2+) breast cancer and its activity showed a considerable impact
in the neoadjuvant setting in which a higher rate of pathologic complete response
(pCR) was observed. Of interest is the difference in outcome of patients who did not
achieved a pCR and the analysis of the residual disease (RD) represents a relevant issue
to explore to identify the subset of patients ( pts) with different outcome.
Methods: 67 consecutive Her-2+ pts with locally advanced breast cancer (LABC)
treated since 1993 to 2015 and who did not reached a pCR were evaluated. A minimum
of three years of follow up was requested for the outcome analysis. Overall survival
(OS) and disease free survival (DFS) has been explored in the two cohorts and the type
of RD after neoadjuvant aH2Tx was also examined. Immunochemistry expression for
estrogen and progesterone receptors (ER/PR) in the primary tumor for the
aH2Tx-not-receiving pts was: 8 pts was ER/PR negative, 10 were ER/PR positive, 6
were ER-/PR + , 1 ER + /PR-. In the aH2Tx-receiving group: 26 were ER/PR + , 6 were
ER + /PR-, 10 were ER/PR negative.
Results: 25 pts did not receive aH2Tx in the neoadjuvant and 19 did not in adjuvant
setting. 42 pts received aH2Tx in the neoadjuvant and 35 also in the adjuvant setting.
Eleven pts in the aH2Tx-non-receiving group had recurrent disease compared with five
recurrences in the aH2Tx-receiving group. The subtypes of RD in the aH2Tx
not-receiving group were as follow: 4 had Luminal A like disease, 2 Luminal B like, 1
was triple negative, 18 were Her2+. For the aH2Tx-receiving group: 4 were Luminal A
like, 5 Luminal B like, 30 were Her2+. The subtype of RD in the aH2Tx-not-receiving
group with recurrent disease it has changed in 2 out of 11 pts if compared to primary
tumor and in 2 out of 5 pts of the aH2Tx-receiving group.
Conclusion: Recurrent disease was observed more often in the non-receiving aH2Tx
pts, the analysis of impact of RD on outcome is still pending and will be presented at
the meeting. Optimizing the selection of aH2Tx by identifying subpopulations of
Her-2+ pts who need more or less therapy could be cost effective and would spare
some patients unnecessary exposure to ineffective treatments.
2016
- Predictive role of haemoglobin on disease response to neoadjuvant chemotherapy in breast cancer.
[Abstract in Atti di Convegno]
Omarini, Claudia; Iattoni, Elena; Filieri, Maria Elisabetta; Toss, Angela; Grizzi, Giulia; DEL GIOVANE, Cinzia; Valentina Tamma, Antonella; Cascinu, Stefano; Piacentini, Federico
abstract
Background: Tumour hypoxia has been shown to play an important role in the outcome of cancer patients. Data on the predictive role of haemoglobin (Hb) on disease response to primary therapies in breast cancer (BC) are lacking. The purpose of this study is to evaluate the influence of Hb level throughout treatment course in predicting the response to neoadjuvant chemotherapy. Methods: 252 patients diagnosed with stage I-III BC treated with anthracycline-taxane based primary chemotherapy were evaluated. Patient and tumor characteristics and treatment information were collected. Standard biological parameters (Ki67, nuclear grade, hormone receptors and HER2 status) were correlated with pathologic complete response (pCR). We focused on Hb (baseline and after therapy levels, drop in Hb throughout treatment) and its correlation to pCR rate. The Hb cut-off to discriminate anaemic vs non-anaemic patients was set at 12,0 g/dl. Results: Globally, pCR was achieved in 58 patients (23%), mainly in case of younger age ( < 50 years = 29%, ≥ 50 years = 17%; p = 0.01), high nuclear grade (Grade1-2 = 0%, grade 3 = 27%; p < 0.0001), high ki67 ( > 20% = 26%, < 20% = 12%; p = 0.02) and hormone receptor negative status (Luminal B/HER2 negative = 9%, Luminal B/HER2 positive = 32%, HER2 enriched = 46%, triple negative = 37%; p < 0.0001). Median baseline Hb was 13,3 g/dl while median Hb level after chemotherapy was 11.6 g/dl: pCR was not influenced by Hb level before and after primary chemotherapy. No difference in Hb levels were observed stratifying patients according to nuclear grade, tumour stage and cancer subtypes. Anaemia due to chemotherapy was reported in 56% of patients. The decrease in Hb levels from baseline was greater in patients with lower response rate. On univariate analysis, a decrease in Hb ≥ 2 g/dl was associated with a significantly lower rate of pCR (15% vs 43%; p = 0.047). This correlation was even more evident in the subgroup of anaemic patients (17% vs 32%; p = 0.037). Conclusions: A decrease in Hb ≥ 2 g/dl during neoadjuvant chemotherapy may negatively affect the rate of pCR in BC patients, thus suggesting that anaemia should be avoided in order to obtain the best response to primary treatments.
2016
- Prognostic Factors for Breast Cancer: an Immunomorphological Update
[Articolo su rivista]
Roncati, Luca; Barbolini, Giuseppe; Piacentini, Federico; Piscioli, Francesco; Pusiol, Teresa; Maiorana, Antonino
abstract
The prognostic variability recorded within homogeneous groups of patients for anatomo-clinical disease stages has led to a more detailed biological characterization of breast cancer. Recently, the attention of the scientific community has focused on the role of tumor-infiltrating lymphocytes (TILs). Therefore, the need of an in-depth immunomorphological characterization of TILs has been emerged. The presence of TILs has been retrospectively investigated in 113 female cases of ductal carcinoma. An immunohistochemical investigation with CD3, CD4, CD8, CD20, CD56, granulysin, perforin-1, granzyme-B and TIA-1 was performed according to the standard procedures on all 17 cases with TILs evidence. TILs consisted of T and B lymphocytes: the prevalent population showed a T immunoprofile with a CD8-immunopositive killer subpopulation (Tk), close-linked to carcinomatous cells, and a CD4-immunopositive helper subpopulation (Th), inside the tumor. A time sequence (firstly T, then B) has been disclosed. Granulysin, perforin, granzyme-B and TIA-1 were expressed by Tk cells. The activated Tk cells secrete these mediators as a result of the binding to the tumor target cell, causing its lytic planned death. The cytotoxicity supported by Tk cells appears an important favorable prognostic factor. Therefore, a graduation system for TILs in breast cancer has been here proposed (absent, non-brisk, brisk).
2016
- Safety and efficacy of T-DM1 in HER2 positive metastatic breast cancer patients: a real word
experience.
[Abstract in Atti di Convegno]
Omarini, Claudia; Medici, Gregorio; Guaitoli, Giorgia; Iattoni, Elena; Moscetti, Luca; Balduzzi, Sara; Cascinu, Stefano; Piacentini, Federico
abstract
Background: T-DM1 is an antibody–drug conjugate that combines the antitumor effects of trastuzumab with a cytotoxic antimicrotubule agent that is only released in HER-positive tumor cells. It has been approved for the treatment of patients with HER2 positive metastatic breast cancer (MBC) pre-treated with trastuzumab + taxanes or progressing while on adjuvant trastuzumab, after the pivotal phase III trial EMILIA. The aim of this study is to audit the real life experience with T-DM1 at the University Hospital of Modena.
Material and methods: All patients treated with T-DM1 in our Institution between May 2014 – February 2016 were retroprospectively collected. All patients registered at the time of analysis were evaluated for safety and efficacy. Treatment toxicities were graded according to CTCAE version 4.0. Efficacy was assessed as per clinical practice.
Results: Twenty-two patients have been treated with T-DM1. The median age was 58 years (range 38-77), 50% of them with ECOG 1-2. With regards to tumor characteristics, 72% were hormonal receptor positive BC and 82% of patients had visceral involvement at the beginning of T-DM1. All patients received previous trastuzumab and taxane, 50% received anthracycline-based therapy too. 27% of patients were pre-treated with at least three prior chemotherapy lines for MBC. Pertuzumab was previously administered to one patient, lapatinib to 8 patients. The median number of T-DM1 cycles was 9 (range 1-30), with 50% of patients receiving 5 or more courses. All patients were assessed for efficacy: 36% obtained PR and 18% SD as the best response. The clinical benefit rate (CR+PR+SD>6months) was 45%. The median PFS was 9.0 months (CI 2.8–20.8). Six patients (27%) out of 22 died. Mild grade transaminitis was the most common side effect observed in 50% of patients, followed by fatigue in 41% of patients, thrombocytopenia in 35% and diarrhea in 28%. No grade 3 adverse events were observed, although two hypersensitivity reactions were reported.
Conclusions: T-DM1 administered outside the context of a clinical trial is safe, well tolerated, and with reproducible efficacy, consistent with those published in the EMILIA and TH3RESA studies.
2016
- SOLUBLE TRAIL-ARMED HUMAN AD-MSC AS NOVEL CELL THERAPY APPROACH FOR PANCREATIC DUCTAL ADENOCARCINOMA
[Abstract in Atti di Convegno]
Candini, C. Spano. G. Grisendi. O.; Petrachi, G. Golinelli. T.; Rossignoli, F.; Prapa, M.; Orsi, G.; Barbolini, M.; Rovesti, G.; Maiorana, A.; Marmi, P.; Piacentini, F.; Conte, P.; Dominici, M.
abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive adult
tumors and its prognosis is still poor since the number of deaths almost equal
the number of new cases. New therapeutic approaches are therefore urgently
needed. In our model human adipose mesenchy.mal stromallstem cells (ADMSC)
have been armed with a novel soluble TRAIL variant that is constantly
released by modified progenitors (sTRAIL AD-MSC). The wild type TRAIL
form is known to act as a trimer stabilized by a zinc-binding site. In this srudy,
by gene engineering, we allow AD-MSC to secrete a trimeric zincindependent
soluble TRAIL variant. The molecule has been then challenged
in vitro and in vivo, either using sTRAIL AD-MSC supernatant or injecting
sTRAIL AD-MSC cells in a PDAC xenotransplant rnodel, We demonstrated
that sTRAIL was stable at 37°C far at least 24 hours and was able to induce
apoptosis in the PDAC lines BxPC-3 and MIA PaCa-2 and, more interestingly,
against primary PDAC cells. Moreover, sTRAIL released by AD-MSC was able to significantly counteract tumor growth with a reduction of the
cytokeratin-7 positive cells and by an anti-angiogenic effect. In parallel, a
retrospective study on PDAC specimens form patients (n = 19) has been
conducted in order to investigate TRAIL DR4, DR5 and OPG receptor
expression in "real" PDAC tissue and generate insights on the possible
clinical translation of our approach. Our results suggest that MSC can be
vehicles for novel TRAIL variants opening novel opportunities for PDAC
treatrnent by multiple mechanisms.
2016
- STRATEGIES TO PREDICT TREATMENT RESPONSE AND SELECT THERAPIES IN METASTATIC BREAST CANCER PATIENTS USING A NEXT GENERATION SEQUENCING MULTI-GENE PANEL
[Abstract in Atti di Convegno]
Toss, Angela; Cortesi, Laura; Artuso, Lucia; Tenedini, Elena; Bernardis, Isabella; Ficarra, G; Piacentini, Federico; Federico, Massimo; Tagliafico, Enrico
abstract
The standard of care for many
patients with advanced breast
cancer (BC )is gradually
evolving from empirical
treatment based on clinicalpathological
characteristics to
the use of targeted approaches
based on the molecular profile
of the tumor.
In the last decade, an
increasing number of
molecularly targeted drugs
have been developed for the
treatment of metastatic BC.
These drugs target specific
molecular abnormalities that
confer to cancer cells a survival
advantage. Interestingly,
the ability to perform multigene
testing for a range of
molecular alterations may
provide an opportunity to
clarify the mechanisms of
treatment response, to find the
strategies to overcome
treatment resistance and thus,
to identify patients who are
more likely to develop relapse
and who may be candidates for
matched targeted therapies.
The main aim of this study is to
find prognostic and predictive
molecular biomarkers for the
management of metastatic BC
patients in clinical practice.
2016
- STRATEGIES TO PREDICT TREATMENT RESPONSE AND SELECT THERAPIES IN METASTATIC BREAST CANCER PATIENTS USING A NEXT GENERATION SEQUENCING (NGS) MULTI-GENE PANEL
[Poster]
Toss, Angela; Cortesi, Laura; Artuso, Lucia; Tenedini, Elena; Bernardis, Isabella; Parenti, Sandra; Ficarra, Guido; Piacentini, Federico; Federico, Massimo; Tagliafico, Enrico
abstract
The standard of care for many
patients with advanced breast
cancer (BC )is gradually
evolving from empirical
treatment based on clinicalpathological
characteristics to
the use of targeted approaches
based on the molecular profile
of the tumor.
In the last decade, an
increasing number of
molecularly targeted drugs
have been developed for the
treatment of metastatic BC.
These drugs target specific
molecular abnormalities that
confer to cancer cells a survival
advantage [1]. Interestingly,
the ability to perform multigene
testing for a range of
molecular alterations may
provide an opportunity to
clarify the mechanisms of
treatment response, to find the
strategies to overcome
treatment resistance and thus,
to identify patients who are
more likely to develop relapse
and who may be candidates for
matched targeted therapies
[2-3].
The main aim of this study is to
find prognostic and predictive
molecular biomarkers for the
management of metastatic BC
patients in clinical practice. MATERIALS AND
METHODS
The amplicon-sequencing
analyses took advantage of the Ion
AmpliSeq™ technology (Thermo
Fisher, Waltham, MA, USA). A
custom panel was designed with
the help of the Designer online
tool (www.ampliseq.com),
which was employed to generate
optimized primers encompassing
the coding DNA sequences (with
100bp of exon padding and the
UTRs regions) of 25 genes in the
Human Reference Genome
(hg19); these genes were selected
searching and screening scientific
literature for treatments
resistance in BC and are reported
in Table 1. Primer pairs were
divided into two pools to
optimize multiplex PCR
conditions and the coverage, that
assessed to 89.02%. The
customized Ion AmpliSeq panel
was employed on samples from 7
primary BC samples and matched
metastatic sites (3 skin, 3 lymph
node and 1 lung metastases).
They were all processed using the
Ion AmpliSeq Library Kit 2.0,
starting from 15 nanograms of
FFPE extracted DNA/pool.
Samples were barcoded with the
Ion Express Kit to optimize
matched patients pooling on the
same 318 Chip v2 sequencing
chip. The template-positive Ion
Sphere Particles were sequenced
on a Personal Genome Machine
(Thermo Fisher, Waltham, MA,
USA). RESULTS The mutation profiles of paired primary and
secondary tumors of the seven patients enrolled in
this study are presented in Table 2. Ten different
genes (PTEN, PIK3CA, mTOR, ERBB2, ERBB3,
MET, INPP4B, MAP2K1, CDK6, KRAS) in 6
different patients showed possible damaging
variants as shown in Table 2.
• Four patients (number 1, 3, 5 and 6) showed no
additional or different mutations in secondary
tumors if compared to primary samples.
• In patient number 2, the metastatic site
presented new mutations if compared to the
primary tumor.
• Finally in patient number 4 and 7 we did not
detect in metastases some of the mutations
found in the primary tumor. DISCUSSION
In 5 patients (71,4%) the mutational status of primary tumor could explain treatment resistance and thus
predict relapse, in one patient the mutational status of the new subclones could be relevant for guiding
differently the subsequent treatment choices.
In 2 patients (28,5%) we were not able to detect in metastases some of the mutations found in the primary
tumor. This could be explained by considering the clonal evolution of metastases.
These preliminary data suggest that the multi-gene panel analysis of primary and secondary tumors may help
clinicians:
• in discriminating BC patients HR+ and/or HER2+ with mutations predicting an increased risk of adjuvant
treatment resistance and thus relapse
• in guiding treatment selection strategies in the metastatic setting.
The study is still open and we are currently recruiting other patients.
2016
- Tumor Stroma Manipulation By MSC
[Articolo su rivista]
Grisendi, Giulia; Spano, Carlotta; Rossignoli, Filippo; D. Souza, Naomi; Golinelli, Giulia; Fiori, Agnese; Horwitz, Edwin M; Guarneri, Valentina; Piacentini, Federico; Paolucci, Paolo; Dominici, Massimo
abstract
Tumor stroma (TS) plays relevant roles in all steps of cancer development. We here address several fundamental aspects related with the interaction between cancer cells and their stromal counterparts. Dissecting these players is of pivotal importance to understand oncogenesis, immunoescape and drug resistance. In addition, this better comprehension will allow the introduction of novel and more effective therapeutic approaches where manipulated stromal elements may become detrimental for tumor growth. Our group and others rely on the use of multipotent mesenchymal stromal/stem cells (MSC) as anti-cancer tools, since these putative TS cell precursors can deliver potent apoptosis-inducing agents. Multimodal-armed MSC can target a variety of cancers in vitro and, when injected in vivo, they localize into tumors mediating cell death without evident toxicities to normal tissues. While several aspects of these strategies shall require further investigations, these approaches collectively indicate how TS manipulation by MSC represents a tool to influence the fate of cancer cells, creating a new generation of anti-cancer strategies.
2015
- Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): A randomised, open-label, multicentre, phase 2 trial
[Articolo su rivista]
Piacentini, Federico
abstract
Background: Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. Methods: We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m2 once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596. Findings: Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator's choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefit was achieved in 12 (30·0%; 95% CI 16·6-46·5) patients given afatinib alone (difference vs investigator's choice: -11·9% [95% CI -32·9 to 9·7], p=0·37), 13 (34·2%; 19·6-51·4) given afatinib plus vinorelbine (difference vs investigator's choice: -7·6% [-28·9 to 14·2], p=0·63), and 18 (41·9%; 27·0-57·9) given investigator's choice. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in the investigator's choice group) and neutropenia (none vs 14 [38%] vs four [10%]). Interpretation: Patient benefit with afatinib-containing treatments was not different from that in patients given investigator's choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned. Funding: Boehringer Ingelheim.
2015
- Impact of time to surgery after neoadjuvant chemotherapy in patients with operable breast cancer.
[Abstract in Atti di Convegno]
Piacentini, F; Filieri, E; Grizzi, Giulia; Omarini, C; Maur, M; Guaitoli, G; Tazzioli, G; Madrigali, S; Caggia, F
abstract
Background: Some studies of adjuvant chemotherapy (CT) suggested that a shorter interval before the start of therapies may
improve survival outcomes in many groups of patients. Time to surgery (TTS) after neoadjuvant CT and survival outcomes have
not been established yet. The aim of this study is to evaluate the impact of TTS after neoadjuvant CT in terms of Overall Survival
(OS) and Disease Free Survival (DFS).
Patients and Methods: A retrospective analysis was conducted in 295 patients receiving neoadjuvant CT for stage I-IIIc breast
cancer between 1991 and 2013. 56 pts underwent surgery within 21 days (group A) from last CT cycle, 148 pts within 22-35 days
(group B) and 91 pts after 36 days (group C). The majority were infiltrating ductal carcinoma, stage IIA (37.6%) and IIB
(33.9%), with nodal involvement in 51.6% of the cases. LumA 18.3%, LumB/HER2- 28.2%, LumB/Her2+ 20.7%, HER2+ 9.8%,
TNBC 21%. All patients were treated with neoadjuvant CT: 70.5% with anthra-taxanes based regimen, 18% with anthra- alone,
10.9% with taxanes alone, 0.3% with CMF; plus Trastuzumab in 70% of HER2+ diseases.
Results: After a median follow up of 4.6 years, it was observed that patients in group A showed a significant better OS than
group B (HR 4.22; 95% CI, 1.27 – 14.00, p=0.018) and group C (HR 3.61; 95% CI, 1.01 – 12.86, p=0.048). Moreover group A
showed a significant better DFS than group B (HR 3.41; 95% CI 1.34 to 8.65, p=0.010) and group C (HR 3.77; 95% CI 1.42 to
9.95, p=0.007).
No correlations with OS were found in pts who achieved pCR (20.7%); pCR was predictive of better 5- and 10-years DFS
independently from TTS (95.4% in the pCR-group vs 75.4% of non-pCR group, HR 0.16; 95% CI 0.04 to 0.66, p=0.011). TTS
may influence DFS in non-pCR group: indeed 5-years DFS is 97.3% in group A, 72.7% in group B (HR 2.89; 95% CI 1.14 to
7.36, p=0.026), and 68.5% in group C (HR 3.44; 95% CI 1.3 to 9.1, p=0.013). No significant correlations with regard of stage at
diagnosis or molecular subtypes were found.
Conclusions: These results suggest that TTS after primary CT may influence patients' survival, regardless of stage at diagnosis
and tumor subtype, so that a shorter interval between that last cycle of neoadjuvant chemotherapy and breast surgery should be
addressed whenever possible .
2015
- Molecular Profile, as detected with Mass-Array
Spectrometry (Sequenom platform), in primary
and metastatic breast carcinoma treated with
Exemestane + Everolimus
[Abstract in Atti di Convegno]
Manfredini, S.; Bettelli, S.; Filieri, M. E.; Caprera, C.; Ficarra, G.; Piacentini, F.; Maiorana, A.
abstract
Background. PI3K/Akt/mTOR is one of the most important
pathways for the regulation of cell survival, proliferation and
apoptosis. Mutational events occurring in this pathway could lead to malignant transformation and endocrine resistance in
breast cancer. The mTOR inhibitor Everolimus (EVE) interferes
with cellular proliferation by binding FKB12 protein.
EVE has been definitely approved thanks to BOLERO-2
phase III study, which showed a significant prolongation of
Progression Free Survival (PFS) due to the addiction of EVE
to Exemestane therapy, compared to Exemestane alone, in
Hormonal Receptors-positive (RO+) and HER2-negative
(HER2-) metastatic breast cancer patients. Hortobagyi et al.
performed Next Generation Sequencing on 227 BOLERO-2
samples of primary breast carcinoma, to study the potential
correlation between genetic alterations and EVE efficacy. A
greater incidence of mutations in PIK3CA, PTEN, CCND1
and FGFR1/2 genes was detected and it was observed that
patients with no or only one genetic alteration in these genes
derive the most benefit from EVE therapy. To our knowledge,
no previous research has evaluated the mutational status both
in primary and metastatic breast cancers.
Materials and methods. Aim of this study was to evaluate the
molecular profile in primitive breast cancers (21 ductal carcinomas,
3 lobular carcinomas and 1 colloid carcinoma) and
visceral metastases (hepatic and pulmonary), in 25 patients
with advanced breast cancer (RO+ HER2-) treated with EVE
in combination with Exemestane. Thirty-three DNA samples
from 25 patients were examined, 13 from primary0 breast cancers
and 20 from metastatic lesions. In 8 patients, both the primary
tumor and the corresponding metachronous metastasis
were evaluated. Genomic DNA samples from FFPE tumoral
tissue were analized by using OncoCarta v2.0 panel on Mass
Array Sequenom platform. A preliminar Multiplex-PCR, followed
by SAP-dephosphorylating reaction and iPLEX-primer
specific extension, was performed to detect more than 150
single nucleotide variations in mutational hotspots from 18
implicated genes (AKT1, BRAF, CTNNB1, FBX4, FBXW7,
FGFR2, FGFR3, GNAQ, KIT, KRAS, MAP2K1, MAP2K2,
NRAS, PDGFRa, PIK3CA, PTPN11, SOS1, TP53). Differences
were evaluated using Chi-Square and Fisher Tests.
Survival analysis was conducted using Kaplan-Meyer curves.
Results. Overall, 11 DNA samples, out of the 33 examined,
were mutated (33%). Mutations were found in 10 ductal carcinomas
and in the colloid carcinoma. Five mutations were
detected in primary breast lesions and 6 in metastatic ones.
All mutations consisted of a single-nucleotide variation resulting
in aminoacidic substitution. Among primary lesions,
mutations were detected in the following genes: PIK3CA
(E545K), FBX4 (G30N), KIT (S709F), MAP2K1 (D67N),
FBXW7 (R465C). They occurred with a frequency of 3%,
respectively, namely in 1 out of 33 samples each. Only in
the AKT1 gene the same mutation (E17K) was found in 2
DNA primary lesion samples. In metastatic lesions, BRAF
(R444W), KIT (G565R), TP53 (R273H), FBXW7 (R479Q),
CTNNB1 (S45F), PIK3CA (E545K), AKT (E17K) were
mutated. Notably, mutations were found exclusively in primary
lesions or in metastatic ones, while only in one patient
both primary and secondary lesions were mutated; however,
these mutations occurred in two different genes: MAP2K1
(D67N) in breast, FBXW7 (R479Q) in metastasis. Of notice,
a reduction in PFS was observed in one patient which carried
3 different mutations (FBX4, PIK3CA, KIT) in the primary
tumor (3.4 month versus an average of 5 month) whereas a
significantly increased PFS (15.9 month) was detected in a
case with 2 mutations (PIK3CA, AKT1) in metastatic lesion.
Conclusion. Although the number of patients and samples is
quite limited, our findings in mutational status support literature
evidence, as genes most frequently mutated were PIK3CA, AKT1 and FBXW7, even if the percentage of
2015
- Preoperative Carboplatin–Paclitaxel–Bevacizumab in Triple-Negative Breast Cancer: Final Results of the Phase II Ca.Pa.Be Study
[Articolo su rivista]
Guarneri, Valentina; Dieci, Maria Vittoria; Bisagni, Giancarlo; Boni, Corrado; Cagossi, Katia; Puglisi, Fabio; Pecchi, Annarita; Piacentini, Federico; Conte, Pier Franco
abstract
Purpose: The phase II Ca.Pa.Be trial evaluated preoperative carboplatin–paclitaxel in combination with bevacizumab in triple-negative breast cancer patients with previously untreated stage II–III disease. The primary aim was the assessment of the rate of pathologic complete response (pCR). Secondary aims included safety, breast-conserving surgery rate, and early response assessment with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods: Patients with hormone receptor-negative, HER-2-negative stage II–III breast cancer were eligible. Treatment included paclitaxel 80 mg/mq + carboplatin area under the curve (AUC) 2 on days 1, 8, and 15, combined with bevacizumab 10 mg/kg on days 1 and 15 each 28 days, for 5 courses. At baseline, patients underwent breast DCE-MRI, followed by a single dose of bevacizumab 5 mg/kg (day −6). DCE-MRI was repeated before the initiation of chemotherapy. Results: Forty-four patients were enrolled. Forty-three patients underwent surgery, and 22 (50 %) received breast-conserving surgery (conversion rate from mastectomy indication at baseline, 34.4 %). A pCR in breast and axillary lymph nodes occurred in 22 patients (50 %). Bevacizumab-associated adverse events (AEs) were mild: G1–2 hypertension and bleeding occurred in 6 (13.6 %) and 12 (27 %) patients, respectively. No G4 nonhematologic AEs were recorded. More frequent G3 AEs were liver function test abnormalities (6.8 %), and diarrhea and fatigue (4.5 % each). The only G3–4 hematologic toxicity was neutropenia (G3, 25 %; G4, 9 %). Early assessed DCE-MRI response parameters failed to predict pCR. Conclusions: The neoadjuvant anthracycline-free combination of weekly paclitaxel and carboplatin plus bevacizumab is active and safe in triple-negative breast cancer, and the rate of pCR is comparable to that observed with more intensive carboplatin- and bevacizumab-containing regimens. Further investigation is warranted.
2014
- Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer
[Articolo su rivista]
Guarneri, Valentina; Generali, Daniele Giulio; Frassoldati, Antonio; Artioli, Fabrizio; Boni, Corrado; Cavanna, Luigi; Tagliafico, Enrico; Maiorana, Antonino; Bottini, Alberto; Cagossi, Katia; Bisagni, Giancarlo; Piacentini, Federico; Ficarra, Guido; Bettelli, Stefania Raffaella; Roncaglia, Enrica; Nuzzo, Simona; Swaby, Ramona; Ellis, Catherine; Holford, Clare; Conte, Pierfranco
abstract
Purpose
This is a randomized, double-blind, placebo-controlled study aimed to evaluate the clinical
and biologic effects of letrozole plus lapatinib or placebo as neoadjuvant therapy in hormone
receptor (HR) –positive/human epidermal growth factor receptor 2 (HER2) –negative operable
breast cancer.
Methods
Ninety-two postmenopausal women with stage II to IIIA primary breast cancer were randomly
assigned to preoperative therapy consisting of 6 months of letrozole 2.5 mg orally daily plus
lapatinib 1,500 mg orally daily or placebo. Surgery was performed within 2 weeks from the last
study medication. Clinical response was assessed by ultrasonography. Pre- and post-treatment
samples were evaluated for selected biomarkers. Fresh-frozen tissue samples were collected for
genomic analyses.
Results
Numerically similar clinical response rates (partial complete response) were observed (70% for
letrozole-lapatinib and 63% for letrozole-placebo). Toxicities were generally mild and manageable.
A significant decrease in Ki-67 and pAKT expression from baseline to surgery was observed in both
arms. Overall, 34 patients (37%) had a mutation in PIK3CA exon 9 or 20. In the letrozole-lapatinib
arm, the probability of achieving a clinical response was significantly higher in the presence of
PIK3CA mutation (objective response rate, 93% v 63% in PIK3CA wild type; P .040).
Conclusion
The combination of letrozole-lapatinib in early breast cancer was feasible, with expected and
manageable toxicities. In unselected estrogen receptor–positive/HER2-negative patients, letrozolelapatinib
and letrozole-placebo resulted in a similar overall clinical response rate and similar effect
on Ki-67 and pAKT. Our secondary end point findings of a significant correlation between PIK3CA
mutation and response to letrozole-lapatinib in HR-positive/HER2-negative early breast cancer
must now be independently confirmed.
2014
- Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of preoperative chemotherapy plus trastuzumab
and lapatinib in patients with HER2-positive operable breast cancer
[Abstract in Atti di Convegno]
Piacentini, Federico
abstract
Body: Introduction: In vitro studies have shown that lapatinib enhances the immune-mediated cytotoxicity (ADCC) of
trastuzumab. FcgR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in patients with
HER2-positive metastatic breast cancer. There are no data on the relationship between these polymorphisms and the
combination of trastuzumab plus lapatinib in the early stage setting. We performed a pharmacogenomics analysis of CHER-LOB,
a randomized phase II trial of preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B), or both (arm C) in
HER2-positive operable breast cancer.
Methods: FcgRIIa-H131R and FcgRIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Pathologic
complete response (pCR) of genotyped cases was evaluated by FcgR polymorphism and treatment arm.
Results: Genotyping was successfully performed in 73/121 (60%) patients. No deviation from the Hardy-Weinberg equilibrium
was observed. Similarly to the overall results of the CHER-LOB study, in the subset of patients genotyped in this analysis, a
significant improvement in pCR rate was observed in favor of the combination of lapatinib plus trastuzumab (arm C) compared to
arm A (OR=3.66, P=0.037), and B (OR=3.03, P=0.049). Such improvement was restricted to carriers of FcgRIIIa V allele (C vs. A,
OR=5.33, P=0.043; C vs. B, OR=6.50, P=0.012), while it was not observed in patients with FcgRIIIa F/F genotype (C vs. A,
OR=2.14, P=0.642; C vs. B, OR=0.71, P=0.737). Disease free survival (DFS) was not different by treatment arm in all genotyped
cases, but a trend toward significance for an interaction between FcgRIIIa V allele and better DFS with the combination of
lapatinib plus trastuzumab was detected (P=0.058). No significant associations were observed by FcgRIIa polymorphism.
Conclusions: Host-related immune signatures may mediate lapatinib enhanced trastuzumab-dependent ADCC. FcgRIIIa
genotypes may help predict different outcomes to lapatinib plus trastuzumab in HER2-Positive Early Breast Cancer.
2014
- La gestione del BTP oncologico integrata con il controllo del dolore di base.
[Capitolo/Saggio]
Piacentini, F.
abstract
raccolta di casi clinici
2014
- Quantitative expression of estrogen receptor on relapse biopsy for ER-positive breast cancer: prognostic impact
[Articolo su rivista]
Dieci, Maria Vittoria; Piacentini, Federico; Dominici, Massimo; Omarini, Claudia; Goubar, Aicha; Ficarra, Guido; Conte, Pierfranco; Guarneri, Valentina
abstract
BACKGROUND: The aim of this study was to evaluate the prognostic impact of quantitative estrogen receptor (ER) expression at relapse for ER-positive breast cancer with ER-positive recurrence.
PATIENTS AND METHODS: A total of 81 patients with ER-positive primary breast cancer and ER-positive paired recurrence were included. ER expression was evaluated as the percentage of tumor cells staining for ER under immunohistochemistry. Samples were defined as ER-high (ER>50%) or ER-low (ER≥10% and ≤50%).
RESULTS: Quantitative ER expression on relapse biopsy was an independent prognostic factor for overall survival in multivariate analysis, both as a continuous (hazard ratio=0.8; 95% confidence interval=0.7-0.92, p=0.001) and as a categorical (ER-high vs. ER-low; hazard ratio=0.26; 95% confidence interval=0.11-0.59, p=0.001) variable. Patients whose status changed from ER-high (primary BC) to ER-low (relapse) had the poorest outcome, with a 10-year overall survival rate of 14%.
CONCLUSION: Even in the case of maintenance of ER-positivity on primary and relapse of breast cancer, recurrence biopsy provides prognostic information.
2014
- Randomized phase II trial of afatinib alone or with vinorelbine versus investigator's choice of treatment in patients with HER2-positive breast cancer with progressive brain metastases after trastuzumab and/or lapatinib-based therapy: LUX-BREAST 3
[Poster]
Piacentini, Federico
abstract
Background Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The
metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a diffi cult therapeutic
challenge. We aimed to assess the effi cacy and safety of afatinib, an irreversible blocker of the ErbB protein family,
alone or combined with vinorelbine, compared with treatment of the investigator’s choice in women with
HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab,
lapatinib, or both.
Methods We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France,
Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confi rmed HER2-
overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in
Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We
randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus
intravenous vinorelbine 25 mg/m² once per week, or investigator’s choice of treatment in cycles of 3 weeks until
disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for
clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint,
assessed in the intention-to-treat population, was patient benefi t at 12 weeks, defi ned by an absence of CNS or extra-
CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in
corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed
trial is registered with ClinicalTrials.gov, number NCT01441596.
Findings Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and
randomly assigned to treatment: 40 to afatinib alone, 38 to afatinib plus vinorelbine, and 43 to investigator’s
choice. All patients discontinued study treatment before the data collection cutoff on Oct 16, 2014. Patient benefi t
was achieved in 12 (30·0%; 95% CI 16·6–46·5) patients given afatinib alone (diff erence vs investigator’s choice:
–11·9% [95% CI –32·9 to 9·7], p=0·37), 13 (34·2%; 19·6–51·4) given afatinib plus vinorelbine (diff erence vs
investigator’s choice: –7·6% [–28·9 to 14·2], p=0·63), and 18 (41·9%; 27·0–57·9) given investigator’s choice. The
most common treatment-related grade 3 or 4 adverse events were diarrhoea (seven [18%] of 40 patients in the
afatinib only group vs nine [24%] of 37 patients in the afatinib plus vinorelbine group vs two [5%] of 42 patients in
the investigator’s choice group) and neutropenia (none vs 14 [38%] vs four [10%]).
Interpretation Patient benefi t with afatinib-containing treatments was not diff erent from that in patients given
investigator’s choice of treatments; however, adverse events were frequent and afatinib-containing treatments seemed
to be less well tolerated. No further development of afatinib for HER2-positive breast cancer is currently planned.
2014
- Tumor infiltrating lymphocytes and correlation with pCR in ther CHERLOB study
[Poster]
Piacentini, Federico
abstract
Body: Background: Over one-third of patients (pts) with HER2-positive (+) advanced breast cancer (BC) develop brain
metastases (BM), which often leads to short survival. Afatinib (A), an irreversible ErbB family blocker, demonstrated activity in pts
with heavily pretreated, HER2+ metastatic BC (MBC) progressing after trastuzumab (T) therapy, with partial responses (PR) in
10% and clinical benefit in 46% of pts (Lin 2012a). We evaluated the activity of A alone or in combination with vinorelbine (V),
versus investigator’s choice of therapy for MBC (IC), in pts with HER2+ BC with BM after prior T and/or lapatinib (L) therapy.
Methods: Eligible pts had at least one measurable and progressive lesion in the central nervous system (CNS; ³10 mm on
magnetic resonance imaging) after prior systemic and/or radiation therapy. Pts were randomized to receive A (40 mg/day oral),
AV (40 mg/day oral + 25 mg/m2/week i.v.) or IC in 3-week cycles. Stratification factors were: ECOG performance status (PS, 0–1
vs 2), number of BM (£3 vs >3) and prior exposure to L (yes/no). The primary endpoint was pt benefit at 12 weeks (i.e. absence
of CNS and extra-CNS disease progression per RECIST 1.1, and no tumor-related worsening of neurological signs/symptoms or
increase in steroid dosage). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective
response rate (ORR) in CNS/extra-CNS lesions, and safety.
Results: 121 pts were randomized (2 were not treated): median age, 53 years; ECOG PS 0–1, 83%; >3 BM, 59%; prior L therapy,
78.5%. The IC treatment consisted of: T+ chemotherapy (CT) (22 pts); T+L+CT (3 pts); L+CT (10 pts); L alone (1 pt); or CT alone
(6 pts). In the treated set (n=119), the most frequent treatment-related adverse events (AEs) in the A and AV arms were diarrhea (90%
and 84%) and rash (38% and 54%); neutropenia (51%) was also common in the AV arm. Diarrhea (33%), neutropenia (21%) and
asthenia (21%) were the most frequent related AEs in the IC arm. Grade (G) 3/4 treatment-related AEs were observed in 50%/3% (A), 57%/24% (AV; G4 AEs were mainly neutropenias) and 14%/7% (IC) of pts; there were no treatment-related G5 events.
Conclusions: Approximately one third of pts with HER2+ MBC benefited from the assigned treatments and two thirds had CNS
lesions controlled per RECIST in each group. Objective response in CNS was infrequent (0 to 14%) with all treatments. Overall,
AEs were manageable in this heavily pretreated pt population.
2013
- Lapatinib and renal impairment: a case report
[Articolo su rivista]
Piacentini, Federico; Omarini, Claudia; Barbieri, Elena
abstract
This clinical report describes durable control of disease in a postmenopausal patient receiving hemodialysis and letrozole plus lapatinib since the diagnosis of HER2-positive, estrogen receptor-positive liver metastasis from breast cancer after anastrozole plus trastuzumab failure.
2013
- Loss of HER2 positivity and prognosis after neoadjuvant therapy in HER2-positive breast cancer patients
[Articolo su rivista]
Guarneri, Valentina; Dieci, Maria Vittoria; Barbieri, E; Piacentini, Federico; Omarini, Claudia; Ficarra, G; Bettelli, Stefania Raffaella; Conte, Pierfranco
abstract
Background: Emerging literature data are showing that a change in human epidermal growth factor receptor (HER2)
status adversely affects breast cancer patient’s prognosis. The aim of this study was to evaluate the prognostic impact of
HER2 loss in patients with HER2-positive disease treated with neoadjuvant therapy with or without anti-HER2 agents.
Methods: One hundred and seven consecutive HER2-positive patients were identified from a prospectively maintained
database. The first cohort includes 40 patients treated with chemotherapy (CT) alone. The second cohort includes 67
patients treated with neoadjuvant CT plus anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was
evaluated by immunihistochemistry or fluorescence in situ hybridization on pretreatment core biopsy and on surgical
specimen after therapy.
Results: The rates of pathologic complete response (pCR) and breast-conserving surgery were higher in the CT + anti-
HER2 cohort. A loss of HER2 expression was observed in 40% of the patients with residual disease after CT alone versus
14.7% of the patients after CT + anti-HER2 agents (P = 0.019). Patients not achieving a pCR have a significant increase in
the risk of relapse when compared with those achieving a pCR (hazard ratio [HR] 9.55, P = 0.028). Patients with HER2
loss tended to have a higher risk of relapse as comparing to patients with maintained HER2 positivity (HR 2.41,
P = 0.063).
Conclusion: The pCR is confirmed as a powerful predictor of long-term outcome. The rate of HER2 loss is higher in
patients receiving neoadjuvant CT without anti-HER2 agents. HER2 status on residual disease after preoperative therapy
can be helpful in selecting patients at different risk of relapse, to be included in prospective trial exploring further adjuvant
therapy.
2013
- Preoperative carboplatin-paclitaxel-bevacizumab in triple negative breast cancer: Final results of the phase II CA.Pa.Be study
[Abstract in Rivista]
Guarneri, Valentina; Boni, C; Puglisi, F; Cagossi, K; Piacentini, Federico; Bisagni, G; Dieci, Maria Vittoria; Barbieri, E; Vicini, Roberto; Conte, P.
abstract
Introduction: Management of triple negative breast cancer (TNBC) is still a major challenge: a significant proportion patients relapse despite adjuvant chemotherapy, and the median survival from relapse rarely exceeds 1 year. Angiogenesis activation as well as impairment in mechanisms of DNA repair are frequently described in sporadic TNBCs, but the role of angiogenesis inhibitors and platinum salts is still controversial. This is a phase II trial of preoperative carboplatin-paclitaxel in combination with bevacizumab in TNBC patients with previously untreated, stage II-III disease. The primary aim of the study is the pathologic complete response (pCR) rate. Among the secondary aims: safety, breast conserving surgery rate, early response assessment with dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI), biomarker analyses.
Methods: Patients with hormone receptor negative (ER and PgR <1%), HER2 negative stage II-III breast cancer are eligible. At baseline, patients undergo breast DCE-MRI, followed by a single dose of bevacizumab 5 mg/kg (day -7). DCE-MRI is repeated prior to start chemotherapy (CT). On day 1, patients start CT with paclitaxel 80 mg/sqm+carboplatin AUC2 on days 1,8, 15 q 28, combined with bevacizumab 10 mg/kg on days 1 and 15. Patients received 5 preoperative cycles and undergo surgery within 6 weeks from the last CT course. Bevacizumab is omitted on cycle 5, to minimize the risk of surgical complications. Tissue samples are centralized to evaluate treatment effect on several tissue markers, as well as to identify potential predictors of treatment benefit. The sample size is estimated with the two-stage Simon's design, on the basis of a 40% expected pCR rate. A total of 43 patients are required, with the combination deemed worthwhile in case of at least 13 pCRs.
Results: the accrual of the 44 planned patients is completed. Patients characteristics were as follows:
median age 46 yrs (29-74); clinical stage IIA: 38.2%, IIB: 35.3%, III: 26.5%; ductal histology: 89%; histologic grade 3: 95%. Notably, 59% of the patients had clinically involved axillary nodes. At present, 33 patients are assessable for toxicity. Bevacizumab-associated adverse events (AEs) were mild: grade 1-2 hypertension occurred in 3 patients (9%) and grade 1 bleeding in 9 patients (27%). No grade 4 non-hematologic AEs were recorded; Grade 3 AEs were: liver function tests abnormalities in 3 patients, diarrhea in 3 patients, and neuropathy in 1 patient. Thirty-one patients underwent surgery, 16 patients (51%) received breast conserving surgery. A pCR in breast and axillary lymph-nodes was achieved in 16 patients (51%); 25 patients (81%) had negative axillary nodes (yN0).
Conclusions: No unexpected toxicity was observed by combining bevacizumab to neoadjuvant platinum-taxane based CT. This combination is active in TNBCs, and the rate of pCR is in the expected range. Moreover, 80% of the patients have nodal negativity at surgery, and these results are of particular interest taking into account the high proportion of patients with clinically involved nodes at the time of diagnosis. The final results along with biomarkers data and early response assessment with DCE-MRI will be available at the time of the meeting.
2013
- Preoperative letrozole plus lapatinib/placebo for HR+/HER2 negative operable breast cancer: biomarker analyses of the randomized phase II LET-LOB study
[Poster]
Valentina, Guarneri; Antonio, Frassoldati; Daniele Giulio, Generali; Alberto, Bottini; Katia, Cagossi; Giancarlo, Bisagni; Corrado, Boni; Luigi, Cavanna; Piacentini, Federico; Bettelli, Stefania Raffaella; Guido, Ficarra; Maiorana, Antonino; Luca, Marini; Pier Franco, Conte
abstract
Background: This is a randomized, double-blind, placebo controlled study aimed to evaluate the clinical and biological effects of letrozole + lapatinib or placebo as neoadjuvant therapy in previously untreated hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal patients with stage II-IIIA breast cancer were randomly assigned to 6 months letrozole-lapatinib (Arm A, n=43) or letrozole-placebo (Arm B, n= 49). Clinical response was evaluated according to RECIST. The following biomarkers were centrally evaluated by IHC on diagnostic core biopsy and on surgical specimens: HER2, Ki-67, EGFR, pAKT, PTEN. PIK3CA mutations were evaluated by pyrosequencing. Results: 81 patients were evaluable by USG, 8 were assessed with mammography and/or palpation. Three patients who discontinued therapy and withdrew consent were counted as non-responders according to the ITT analysis. No differences in terms of objective response rate (partial+complete response) were observed between the two arms (70% vs 63%). The percentage of patients achieving disease progression, disease stabilization, partial response and complete response were 2%, 23%, 58%, 12% respectively in the letrozole-lapatinib arm, and 6%, 29%, 61%, 2% respectively in the letrozole-placebo arm. No patients achieved pCR. All the patients were centrally confirmed as having HER2 negative disease. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. A trend for a greater Ki67 suppression was observed in responding patients (mean Ki67 suppression -8.8 in responders vs -3.6 in non responders, p= 0.06). A mutation in PIK3CA exon 9 or 20 was observed in 37% of the patients. Overall, no differences in response were observed according to PIK3CA mutations, however, in the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the PIK3CA mutation subgroup (ORR 93% vs 63% in PIK3CA WT, Pearson’s chi2 p=0.040). Conclusions: This is the first trial showing a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in Hormone Receptor +/HER2- disease.
2013
- Prognostic impact of estrogen receptor (ER) level changes during progression for patients with both ER-positive (ER+) primary breast cancer and paired recurrence
[Poster]
Dieci, Maria Vittoria; Barbieri, Elena; Aicha, Goubar; Andre, Fabrice; Omarini, Claudia; Bettelli, Stefania Raffaella; Piacentini, Federico; Guido, Ficarra; Pier, Franco Conte; Guarneri, Valentina
abstract
Background: We have previously reported that ER+ breast cancer (BC) patients (pts) who become ER-negative at relapse have a poorer overall survival (OS) as compared to those still ER+ at relapse [Dieci et al., Ann Oncol 2013]. Our aim is to evaluate whether, among the group of patients with an ER+ status on both primary and recurrence, changes in the level of ER expression may be of prognostic value. Methods: A total of 81 pts with ER+ primary BC and ER+ paired recurrence who underwent relapse biopsy at Modena University Hospital were studied. ER status was assessed by IHC and the cutoff for ER-positivity was >=10%. Samples were defined as ER-high (>50%) and ER-low (>=10% and <=50%). HER2-status was defined according to IHC and/or FISH results. OS was calculated as the time interval between primary BC diagnosis and death or last follow up. Results: Biopsied recurrences were: distant (86%) and local relapses (14%). Fifteen percent of primary and 21% of recurrent tumors were HER2-positive. Sixty-two pts maintained the same ER level (i.e. high or low) on both primary and relapse (ER-level concordant), whereas 19 changed from ER-high to ER-low or viceversa (ER-level discordant). No difference in OS was observed between the ER-level concordant and the ER-level discordant groups (p=0.3). However, we identified those pts whose ER-high primary BC turned into ER-low as having a particularly poor outcome. Indeed, 10yrs-OS rates were 51% for the ER-level concordant group, 50% for pts changing from ER-low to ER-high and 14% for pts changing from ER-high to ER-low (p=0.0019). Finally, we focused on the subset of pts starting from an ER-high primary BC and showing an ER+/HER2-negative phenotype on both primary and relapse (n=51). The drop of ER-level expression below the 50% cut-off at relapse was confirmed as a poor prognostic factor, as compared to pts maintaining an ER-high level (10yrs-OS 53% vs 17%, p=0.0063). Conclusions: We demonstrated that, even in the case of maintenance of the same single-receptor status (ER+) and/or tumor phenotype (ER+/HER2-negative) between primary BC and recurrence, relapse biopsy may provide relevant prognostic information.
2012
- Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single Institution analysis
[Articolo su rivista]
Dieci, Maria Vittoria; Barbieri, Elena; Piacentini, Federico; Ficarra, G; Bettelli, Stefania Raffaella; Dominici, Massimo; Conte, Pierfranco; Guarneri, Valentina
abstract
Background: Tumor phenotype may change during breast cancer progression. This study evaluates the prognostic impact of receptor discordance between paired primaries and recurrences.Patients and Methods: 139 patients underwent histological sampling of suspected breast cancer recurrence. All the pathology assessments (ER, PgR and HER2) on both primaries and confirmed recurrences were performed at the same laboratory. Results: A breast cancer recurrence was confirmed in 119 cases. Rates of discordance were 13.4%, 39% and 11.8% for ER, PgR and HER2, respectively. Ninety-two patients maintained the same tumor phenotype (i.e., the same hormone receptors and HER2 status) whereas 27 (22.7%) changed during progression. The loss of hormone receptor-positivity and the loss of HER2-positivity resulted in a worse post-recurrence survival (p=0.01 and p=0.008, respectively) and overall survival (p=0.06 and p=0.0002, respectively), compared to the corresponding concordant-positive cases. Tumor phenotype discordance was associated with worse post-recurrence and overall survival (p=0.006 and p=0.002, respectively); those cases who turned into triple-negative experienced the poorest outcome, respect to the concordant group (p=0.001, overall survival).Conclusions: We demonstrated for the first time an impact on overall survival of phenotype discordance between primary breast cancer and relapse. Among discordant cases, receptor-loss resulted the main determinant of poorer outcome.
2012
- MANAGEMENT OF ADVANCED BREAST CANCER: HOW TO INTEGRATE SCIENTIFIC DATA AND CLINICAL JUDGMENT
[Abstract in Atti di Convegno]
Conte, P.; Dieci, M. V.; Piacentini, F.
abstract
Recent epidemiological data have shown a significant decline in breast cancer mortality over the past 15 years, as a result of screening programs, better education, and the introduction of more effective adjuvant treatments1. However, about 20-30% of the patients eventually relapse while approximately 5-7% of cases present with metastatic disease at diagnosis2. Metastatic breast cancer is still largely incurable: the median survival time is generally in the range of 2 to 4 years3.
In the metastatic setting, treatment goals can be quite different depending on patient and tumor characteristics. There are patients for whom the main objective is symptom control to improve or maintain quality of life, cases with life-threatening disease for whom a rapid tumor shrinkage is required, asymptomatic patients with slowly growing disease for whom a prolonged progression-free survival (PFS) duration is the desirable target; finally, some patients can obtain an important survival prolongation and a few of them might be cured4. The selection of treatment depends on several factors, including patient characteristics, aggressiveness of the disease, response to previous therapies, time since last exposure, agents used in the past and cumulative doses. Availability and
regulatory approval of various anticancer agents further diversify treatment patterns in different part of the world.
A rapidly growing pool of effective treatment options for advanced breast cancer has increased response rates and outcome. First, many new cytotoxic drugs are in development or have recently been approved in this setting, such as ixabepilone, eribulin and nab-paclitaxel. For instance, in the phase III trial EMBRACE, eribulin mesylate improved overall survival (median 13.1 months, 95% CI 11.8-14.3), compared to treatment of physician’s choice (median 10.6 months, CI 9.3-12.5; HR 0.81 95% CI 0.66-0.99, p=0.041), in patient who had received two to five prior chemotherapy regimens, including an anthracycline and a taxane for advanced breast cancer.5 In clinical studies, 3-weekly nab-paclitaxel has been shown to increase both the safety and the efficacy of 3-weekly paclitaxel in patients with advanced breast cancer (median time to progression 23 vs 16.9 weeks, hazard ratio 0.75, p=0.006).6 Weekly nab-paclitaxel produced meaningful results even in taxanes pre-treated patients (ORR 14% and 16% in the 100 and 125 mg/sqm cohorts, respectively; median PFS of 3 and 3.5 months, respectively).7 At the same time, research efforts are directed to implement the pool of targeted therapies, in order to offer more individualized options to breast cancer patients. In fact, the molecular breast cancer subtype is a fundamental determinant of treatment choice both in early and advanced setting. Breast cancer consists of at least three different diseases: hormone-sensitive breast cancer, the human epidermal growth factor receptor (HER2)-positive subtype, and triple-negative disease. Each molecular subtype
has distinct biological features and a distinct clinical course: hormone receptor–positive (HR+) disease is generally characterized by a more indolent course, with a long disease-free interval (DFI) and a tendency to relapse in the bone or soft tissues; amplification of the HER-2 gene confers a more aggressive clinical behavior to the HR+ subgroup, with a higher propensity for visceral relapses. Both triple-negative breast cancer and hormone receptor–negative (HR-)/HER-2+ breast cancer are aggressive subtypes, with early visceral or central nervous system metastases.
Each molecular subtype requires distinct therapeutic approaches.
In HR+ tumors, endocrine manipulation is the cornerstone of therapy. Treatment choice depends on many factors such as menopausal status and disease-free interval. For postmenopausal women many agents are available: non-steroidal and steroidal aromatase inhibitors (AI), tamoxifen and fulvestrant; however no
2012
- Predictors of human epidermal growth factor receptor 2 fluorescence in-situ hybridisation amplification in immunohistochemistry score 2+ infiltrating breast cancer: a single institution analysis.
[Articolo su rivista]
Dieci, Maria Vittoria; Barbieri, Elena; Bettelli, Stefania Raffaella; Piacentini, Federico; Omarini, Claudia; Ficarra, G; Balduzzi, Sara; Dominici, Massimo; Conte, Pierfranco; Guarneri, Valentina
abstract
Eligibility for anti-human epidermal growth factor receptor 2 (HER2) treatments in breast cancer requires a correct HER2 status assessment. Testing guidelines recommend fluorescence in-situ hybridisation (FISH) for samples scored as 2+ by immunohistochemistry. This study investigates the correlation between pathological features and FISH amplification in HER2 2+ breast cancer cases.Methods: 480 HER2 2+ breast cancer samples were included. The association between tumour grade, hormone receptor status, proliferation index (Ki67) and FISH amplification, using both US Food and Drug Administration (ratio ≥2) and American Society of Clinical Oncologists/College of American Pathologists cut-offs (ratio >2.2) was evaluated.Results: 90.2% of the samples were hormone receptor positive. The median Ki67 value was 23.5%; 311 (64.8%) samples showed a Ki67 value of 15% or greater. Tumour grade was evaluable in 421 cases (87.7%), 268 (55.8%) being grade 3. FISH amplification rates were 27.5% (ratio ≥2.0) and 20.8% (ratio >2.2). Grade 3 tumours were more frequently amplified than grades 1-2 tumours: 34% versus 18% (ratio ≥2.0, p<0.001) and 27% versus 9% (ratio >2.2, p<0.001). Samples with Ki67 of 15% or greater showed higher amplification ratesthan low Ki67 samples: 31% versus 21% (ratio ≥2.0, p=0.022) and 25% versus 12% (ratio >2.2, p=0.003). The OR for FISH amplification was significant in the case of grade 3 and high Ki67 with both cut-offs.Conclusions: In this study, high tumour grade and high Ki67 significantly predicted FISH amplification in 480 HER2 2+breast cancer samples.
2012
- Preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2 positive operable breast cancer: results of the randomized phase II CHER-LOB study
[Articolo su rivista]
Guarneri, Valentina; Frassoldati, A; Bottini, A; Cagossi, K; Bisagni, G; Sarti, S; Ravaioli, A; Cavanna, L; Giardina, G; Musolino, A; Untch, M; Orlando, L; Artioli, F; Boni, C; Generali, Dg; Serra, P; Bagnalasta, M; Marini, L; Piacentini, Federico; D'Amico, Roberto; Conte, Pierfranco
abstract
Purposes: This is a non-comparative randomized phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in HER2 positive, stage II-IIIA operable breast cancer patients. Primary aim was to estimate the percentage of pathological complete response (pCR; no invasive tumor in breast and axillary nodes).Methods: in the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/sqm) x 12 followed by FE75C x 4 courses q 3 weeks. The patients randomized to arm A received trastuzumab 4 mg loading dose followed by 2 mg weekly; in arm B patients received lapatinib 1500 mg p.o. daily; in arm C, patients received trastuzumab and lapatinib 1000 mg p.o. daily.Results: 121 patients have been randomized. Diarrhea, dermatologic, and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast conserving surgery were 66.7%, 57.9% and 68.9% in arm A, B and C, respectively. The pCR rates were 25% (90%CI 13.1 to 36.9) in arm A, 26.3% (90%CI 14.5 to 38.1) in arm B, 46.7% (90%CI 34.4 to 58.9) in arm C (exploratory p= 0.0187).Conclusions: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared to chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2 positive breast cancer.
2012
- Prognostic role of HER2 loss after neoadjuvant therapy in patients with HER2-positive operable breast cancer
[Abstract in Rivista]
Guarneri, Valentina; Barbieri, Elena; Piacentini, Federico; Dieci, Maria Vittoria; Omarini, Claudia; G., Ficarra; Bettelli, Stefania Raffaella; Conte, Pierfranco
abstract
Background: Emerging literature data are consistently showing that a change in HER2 status adversely affect the prognosis of breast cancer patients. Aim of the present analysis is to evaluate the prognostic impact of HER2 loss in breast cancer patients with HER2 positive disease treated with neoadjuvant therapy with or without anti-HER2 agents. Methods: A total of 94 HER2 positive patients were identified from a prospectively maintained database. The first cohort (A) includes 40 patients treated with chemotherapy alone (enrolled before 2005). The second cohort (B) includes 54 patients treated with neoadjuvant chemotherapy in combination with anti-HER2 agents (trastuzumab and/or lapatinib). HER2 expression was evaluated by IHC or FISH on pre-treatment core biopsy and on surgical specimen after neoadjuvant therapy. Patients were considered as having HER2 positive disease in case of IHC 3+ or FISH amplification. Results: No imbalance in terms of age, stage at diagnosis, tumor grade and expression of hormone receptor was observed in the two cohorts. In detail, 67% and 61% of the patients have a co-expression of HER2 and hormone receptor in cohort A and B, respectively. The rate of breast conservation was significantly higher in cohort B (chemotherapy+anti-HER2 agents) as compared to cohort A (chemotherapy alone) (59% vs 38%, p=0.048). Similarly, the rate of pathologic complete response (pCR) was significantly higher in cohort B (42.6% vs 7.5% in cohort A, p<0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 35% of the patients in cohort A vs 9% of the patients in cohort B (p=0.04). No patients achieving a pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (47% vs 15% in patients with no change, p=0.007). At 5 years, 53% of the patients with Her2 change and 75% of the patients without Her2 change were alive and free of recurrence (log rank test: p=0.03). Conclusions: The rate of HER2 loss was significantly higher in patients not receiving anti-HER2 agents as a part of the neoadjuvant therapy. In this series, the change in HER2 status has a negative prognostic impact.
2012
- Risposta rapida e duratura a fulvestrant in paziente con malattia metastatica e impegno viscerale
[Capitolo/Saggio]
Crivellari, D; Fanelli, F; Gravina, A; Palumbo, R; Piacentini, Federico
abstract
Caso clinico che descrive una paziente in post-menopausa con diagnosi di recidiva linfonodale, polmonare e scheletrica di carcinoma duttale infiltrante a recettori estrogenici positivi, diagnosticata in corso di ormonoterapia adiuvante con inibitore non steroideo dell’aromatasi (in esiti
di mastectomia sinistra e chemio-ormonoterapia adiuvante) e trattata con fulvestrant 500 mg.
2012
- Tumori ginecologici
[Capitolo/Saggio]
Conte, Pierfranco; Barbieri, Elena; Guarneri, Valentina; Piacentini, Federico; Dieci, Maria Vittoria
abstract
Introduzione: Le neoplasie ginecologiche, ovvero le neoplasie che insorgono nell’apparato riproduttivo femminile sono, con più di un milione di nuovi casi all’anno il secondo tipo di neoplasia più diffuso nel mondo dopo il carcinoma della mammella e la prima causa di morte con circa 500.000 decessi annui. In Italia, con 14.949 nuovi casi e 5.719 decessi all’anno rappresentano il terzo tipo di neoplasia più diffuso dopo il carcinoma della mammella e del colon-retto e la quarta causa di morte dopo il carcinoma della mammella, del colon-retto e del polmone (GLOBOCAN 2008).
I cinque tipi più frequenti di neoplasie ginecologiche sono il carcinoma della cervice uterina, il carcinoma del corpo dell’utero, il carcinoma dell’ovaio, il carcinoma della vulva ed il carcinoma della vagina. Sebbene spesso si tenda a raggruppare questo tipo di neoplasie con il termine di neoplasie ginecologiche, è opportuno ricordare che ognuna di queste neoplasie costituisce un’entità unica, che esordisce con segni e sintomi propri e che presenta prognosi e possibilità terapeutiche differenti.
Tutte le donne sono a rischio di sviluppare una neoplasia ginecologica, ma il rischio tende ad incrementare in rapporto all’età. Tra i fattori di rischio, l’unico agente con un rapporto etiopatogenetico certo è l’HPV per il carcinoma della cervice uterina e per alcuni carcinomi della vulva e della vagina.
I segni e sintomi più comuni di esordio delle neoplasie ginecologiche sono il sanguinamento vaginale anomalo, intermestruale o post-coitale, il dolore pelvico o addominale, il cambiamento dell’alvo, il bruciore in sede vulvo-vaginale.
Il trattamento delle neoplasie ginecologiche si basa sulla chirurgia, sulla chemioterapia e sulla radioterapia, le cui modalità di impiego e finalità sono stabiliti solo dopo un’accurata stadiazione di malattia.
2012
- 41. HER2+ EARLY BREAST CANCER: DO WE HAVE ALL THE NECESSARY ANSWERS?
[Abstract in Atti di Convegno]
Conte, P.; Verrusio, Manuela; Piacentini, F.
abstract
In the 1980s, HER2 overexpressing tumors were recognized as a distinct subset of breast cancer, with greater likelihood of nodal involvement, younger age of onset, higher grade pathology features (high proliferative rate, metastatic potential and neoangiogenesis), and poor survival (median about 3 years vs 6-7 years for HER2- negative tumors) . About 20-30% of breast cancer diagnosed at any stage shows HER2-receptor over-expression or gene amplification. Trastuzumab is a humanized monoclonal antibody against HER2 receptor that has change the biological history of the HER2-positive breast cancer subtype. The linkage of trastuzumab with the receptor blocks its activation, which in turn induces an arrest in the downstream intracellular transduction pathway and prevents the transcription of related genes. In vitro, trastuzumab demonstrated synergism with several cytotoxics (in particular anthracyclines and taxanes), with increased apoptosis and decreased cell proliferation. The cytotoxic synergism of combined trastuzumab and chemotherapy is also supported by clinical data in metastatic and neoadjuvant settings. In HER2+ advanced disease, the combination of trastuzumab and chemotherapy resulted in 25% survival increase (from 20 to 25 months median survival); the two pivotal studies with paclitaxel and docetaxel respectively have also demonstrated that patients with advanced disease receiving the trastuzumab and chemotherapy combination upfront had a better outcome than those who received trastuzumab delayed at disease progression . Similarly, in the neoadjuvant experience of MDACC, patients with HER2 positive operable breast cancer who received upfront chemotherapy (4 courses of paclitaxel followed by 4 courses of FEC) with concomitant trastuzumab achieved a significantly higher rate of pathological complete response (pCR = 66.7% with vs. 26.3% without trastuzumab respectively).
A large benefit in disease free and overall survival has been reported from 5 different randomized studies with trastuzumab in the adjuvant setting that have included more than 10,000 women with HER2 positive breast cancer. In these trials, one year of trastuzumab reduced by ~50% the risk of relapse (HR 0.52 in the combined analysis of the NSABP-B31 e NCCTG N9831 studies ; 0.76 in the HERA study ; 0.64 in the AC-TH arm and 0.75 in the TCH arm of the BCIRG006 trial ). Moreover, at an interim analysis of N9831 trial, an advantage for the combination of chemotherapy and trastuzumab over the sequence has been reported (HR 0.77; 99.9% CI, 0.53 to 1.1) even if the p value (0.02) didn’t cross the pre-specified O’Brien-Fleming boundary . In conclusion, both biological and clinical data strongly support the synergistic cytotoxic effects of trastuzumab and chemotherapy on HER2 positive breast cancer cells, while the sequential administration of trastuzumab after chemotherapy seems to induce mainly a cytostatic effect that might require longer treatment to achieve maximum clinical benefit. Unfortunately, the only study prospectively designed to test different durations of trastuzumab administration is the HERA trial; at present however, the results of the comparison of one versus two years of treatment are still pending. However, in a small adjuvant study from Finland, trastuzumab has been given upfront for 3 months in combination with docetaxel or vinorelbine followed by 3 FEC courses without trastuzumab: the risk of relapse revealed similar to that observed in a previous studies with 1 year of trastuzumab, suggesting that shorter treatment durations might produce comparable efficacy but with significant lower toxicities and costs. By now, one year of treatment with trastuzumab must be still considered the gold standard but the optimum adjuvant trastuzumab duration remains to be established.
With regard to cardiac toxicity, it is well known that trastuzumab by itself is not directly cardio-toxic but, by inhibiting t
2011
- Change in HER2 Status in HER2 Positive Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without Anti-HER2 Therapy: Analysis of Two Consecutive Cohorts
[Abstract in Rivista]
Barbieri, Elena; Piacentini, Federico; Dieci, Maria Vittoria; Ficarra, G; Bettelli, Stefania Raffaella; Conte, Pierfranco; Guarneri, Valentina
abstract
Introduction: emerging literature data have shown a change of HER2 expression from primary tumors to metastatic deposits. Tumor heterogeneity, genetic drift as well as selective pressure of adjuvant therapy have been suggested to explain this phenomenon.
Aim of the present analysis is to evaluate the change in HER2 expression after neoadjuvant chemotherapy with or without anti-HER2 agents.
Methods: two consecutive cohorts of HER2+ breast cancer patients treated with neoadjuvant therapy were identified from a prospectively maintained database including 310 patients. The first cohort (A) includes 38 patients enrolled before 2005, treated with chemotherapy alone. The second cohort (B) includes 48 patients treated with neoadjuvant chemotherapy in combination with antiHER2 agents (trastuzumab or lapatinib).
HER2 expression was evaluated by IHC on pre-treatment core biopsy (tru-cut with 14 gauge needle) and on surgical specimen after neoadjuvant therapy. FISH analysis was performed on IHC 2+ samples.
Results: The two cohorts were balanced in respect of tumor stage, patient age, and HR expression. In particular, a co-expression of HER2 and HR was observed in 60% of the patients in cohort A and in 70% of the patients in cohort B (p=0.2).
Patients in cohort B have a significantly higher rate of pathologic complete response (pCR) in comparison to cohort A (45% vs 11%, p=0.001). A change in HER2 expression from biopsy to post-therapy samples was observed in 39% of the patients in cohort A vs 12% of the patients in cohort B (p=0.02). No patients with pCR have recurred so far vs 25% of the patients with less than pCR (p=0.005). The rate of recurrence was significantly higher for patients experiencing a change in HER2 expression (50% vs 19%, p=0.018).
Conclusion: contrary to our expectations, patients not receiving anti-HER2 therapy as part of neoadjuvant therapy were more likely to have a change in HER2 status vs patients receiving anti-HER2 neoadjuvant therapy. The change in HER2 status has a negative prognostic impact.
2011
- Double-blind, placebo-controlled, multicentric randomized phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal HER2-negative, hormone receptor-positive operable breast cancer
[Abstract in Rivista]
Conte, Pierfranco; Guarneri, Valentina; D. G., Generali; A., Bottini; L., Bazzola; Piacentini, Federico; F., Artioli; K., Cagossi; G., Bisagni; M., Bagnalasta; Tagliafico, Enrico; Barbieri, Elena; L., Cavanna; A., Ravaioli; D'Amico, Roberto; Vicini, Roberto; A., Frassoldati
abstract
Background: The crosstalk between the ER pathway and erbB receptor family is emerging as a mechanism of resistance to hormonal therapy. The combination of lapatinib-letrozole might prevent or delay the development of endocrine resistance. On these premises we have designed a multicentric phase IIb randomized, double-blind, placebo controlled study to evaluate the clinical and biological effects of combined letrozole+lapatinib/placebo as neoadjuvant therapy in previously untreated ER+ve/HER2-ve breast cancer patients. Primary aim is the percentage of breast clinical response, as measured by ultrasonography (US). Secondary aims include pathologic response, percentage of breast conserving surgery, modulation of Ki67 and HER2/EGFR pathways, and gene expression analysis. Methods: After diagnostic core biopsy, patients were randomized to letrozole 2.5 mg continuous daily dosing (CDD) + lapatinib 1500mg CDD or to letrozole- placebo, given for 24 weeks before surgery. Results: As of October 2010, the planned accrual has been completed. Ninety-two postmenopausal women have been randomized. Patient characteristics were as follows: median age 68 yrs (range 48-89 yrs); stage at diagnosis: IIA 49%; IIB 41%, IIIA 10%. Median ER expression 95% (range 30-100%); median PgR expression 68% (range 0-100%). At diagnosis, mean US tumor size was 3 cm (range 1.2-8 cm). Seventy-one patients are evaluable so far. The ORR (PR + CR) by US at the completion of therapy was 61%; SD was observed in 27% of the patients. Four patients experienced PD. Five patients prematurely discontinued therapy due to toxicity (n=1), consent withdrawal (n=3) or lost to follow up (n=1). No change in mean LVEF was observed at the 3- and 6-month evaluations. The data will be unblinded by April 2011. Conclusions: Preliminary blinded results suggest that the combination of letrozole+lapatinib/placebo is associated with clear tumor downstaging. Final unblinded results per treatment arm, including pathologic response, clinical response by centralized review and biomarker analyses will be presented at the meeting.
2011
- Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial).
[Abstract in Rivista]
Guarneri, Valentina; A., Frassoldati; A., Bottini; D. G., Generali; K., Cagossi; F., Artioli; G., Bisagni; C., Boni; A., Ravaioli; D., Amadori; A., Musolino; L., Cavanna; M., Untch; L., Orlando; G., Giardina; Piacentini, Federico; Tagliafico, Enrico; M., Bagnalasta; D'Amico, Roberto; Conte, Pierfranco
abstract
Background: This is a randomized phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage pathological complete response (pCR), defined as complete disappearance of invasive tumor in breast and axillary nodes. Methods: chemotherapy (CT) consists of weekly paclitaxel x 12 followed by FE75C x 4. Pts randomized to arm A receive CT plus weekly trastuzumab; in arm B pts receive CT plus lapatinib 1250 mg po daily; in arm C pts receive CT plus weekly trastuzumab and lapatinib 750 mg po daily. The study sample size has been calculated according to the two-step Simon’s design. The overall planned accrual was 120 pts. P95HER2 expression will be measured by bioTheranostics, Inc (San Diego) to explore if there is a clinically relevant difference in the pCR rate according to p-95 status. Gene expression profile analysis to identify a predictive signature is ongoing. Results: 121 pts have been randomized as of November 2010. Pts characteristics are the following: median age 49 yrs (26-68 yrs); stage IIA 32%, IIB 50%; IIIA 18%; ER and or PgR positivity: 59%. Eighty pts have completed surgery and are evaluable for response: 50 pts (62.5%) received breast conservation (BCS). A conversion from mastectomy to BCS was observed in 23/44 pts initially candidate to mastectomy (conversion rate: 52%). The pCR rate is 36.2% (28% in arm A, 32% in arm B, and 48% in arm C). By using a 30% cutoff for p95 positivity, in a preliminary analysis on 48 cases, 57% resulted as p-95 positive. In this preliminary analysis, the pCR rate in 15 trastuzumab treated pts is 86% in p-95-negative and 13% in p-95-positive cases. Mean Left ventricular ejection fraction (range) at baseline was 62% (52%-77%), 61% (44%-78%) after 12-13 weeks, and 61% (44%-74%) at the end of therapy. No patient had symptomatic cardiac events. Conclusions: Preliminary activity data are promising, and cardiac safety data are reassuring. Final results per treatment arm, along with definitive biomarker correlations will be presented at the meeting.
2011
- Magnetic Resonance Imaging and Ultrasonography in Predicting Infiltrating Residual Disease after Preoperative Chemotherapy in Stage II-III Breast Cancer
[Articolo su rivista]
Guarneri, Valentina; Pecchi, A; Piacentini, Federico; Barbieri, Elena; Dieci, Mv; Ficarra, G; Tazzioli, Giovanni; Frassoldati, A; Battista, R; Canossi, Barbara; Mauri, C; D'Amico, Roberto; Conte, Pierfranco; Torricelli, Pietro
abstract
BACKGROUND: This study was designed to evaluate the accuracy of breast magnetic resonance imaging (MRI) and ultrasonography (US) in predicting the extent of breast residual disease after preoperative chemotherapy. METHODS: Patients withstage II-III invasive breast tumors who received preoperative chemotherapy and were imaged with post-treatment MRI were included. Histopathological verification was available for all patients. The longest diameter of residual tumor measuredwith MRI and US has been compared with the infiltrating residual tumor size at pathologic evaluation. RESULTS: A total of 108 patients were enrolled: 59 were imaged with both MRI and US (MRI group), and 49 were imaged with US only (non-MRI group). The non-MRI group was enrolled as an external control to avoid possible bias in the selection of patients. In the MRI group, the means of the deltas between MRI residual tumor size and pathologic size and between US and pathologic size were 0.16 cm and -0.06 cm respectively (P = not significant). Overall, a discrepancy limited in the interval from -0.5 cm to +0.5 cm compared with the pathologic size was observed in 54% and 51% of the patients with MRI and US, respectively (P = not significant). The linear correlation between the radiological measurement and pathologic tumor size was r = 0.53 for MRI and r = 0.66 for breast US. In the non-MRI group, the mean of the deltas between US residual tumor size and pathologic size was 0.06 cm, and the linear correlation was r = 0.79. CONCLUSIONS: In this series of patients, MRI and US do not show significant differences in predicting the breast residual infiltrating tumor after preoperative chemotherapy.
2011
- Primary pulmonary cancer colliding with metastatic breast carcinoma: hitherto unreported cases of cancer-to-cancer metastasis focusing on clinical implications
[Articolo su rivista]
Piacentini, Federico; Rossi, Giulio; Casali, Christian; Cadioli, Annamaria; Barbieri, Elena; Guarneri, Valentina
abstract
Lung is one of the main sites of metastatic tumors, but collision neoplasms consisting of a primary lung cancer and metastatic breast carcinoma have never been so far reported. We describe here 2 cases of primary non-small cell lung cancers (squamous cell and adenocarcinoma, respectively) colliding with metastatic breast carcinomas (ductal and lobular carcinomas, respectively). Clinico-pathologic features characterizing this challenging diagnosis and the important therapeutic implications are discussed.
2011
- TAILORED MANAGEMENT OF ADVANCED BREAST CANCER: IS IT WORTH TO TAKE A BIOPSY OF METASTATIC SITES?
[Abstract in Atti di Convegno]
Conte, P.; Piacentini, F.
abstract
Breast cancer is a clinically and molecularly heterogeneous disease. The molecular classification represents the foundation of treatment selection for early and advanced breast cancer: endocrine manipulation and/or HER2 targeted agents are administered on the basis of oestrogen and progesteron receptors and HER2 expression. In routine clinical practice, the assessment of these predictive parameters (ER, PR and HER2) is usually carried out in the primary tumor, and these results are also used to guide treatment choice in metastatic disease, even if it occurred many years after the primary diagnosis.
However, the appropriateness of this approach can now be questioned for some reasons. First of all, several reports have been published showing a lack of concordance in the expression of HER2 and hormonal receptors between primary tumors and disease recurrence, with range of discordance between 0% and 34% and between 18% and 54% respectively. According to the literature data, we have observed in a retrospective study of 75 patients an overall disagreement of 16% in the HER2 status (ten patients changed from negative to positive, two cases only from positive to negative) and of 21% in the expression of hormonal receptors (nine cases changed from positive to negative and seven cases from negative to positive) from primary tumors to disease recurrences. Noteworthy, it has recently been reported that also PI3KCA mutation occurs with high frequency but differently in primary and metastatic breast cancer (PIK3CA mutation was detected in 45% of the primary tumors and in 53% of paired metastases).
The increasing use in the adjuvant setting of targeted agents might exert selective pressure, possibly facilitating a modification in tumor phenotype: in fact, the change from a positive to negative hormonal receptor or HER2 status might reflect acquired resistance to hormonal or anti-HER2 therapy. But the finding that receptor status can change to both directions not support the hypothesis that during tumor progression, de-differentiation always occurs leading to a more aggressive phenotype. At the same time the conversion from a negative to positive phenotype can offer the patient the opportunity to receive a treatment that possibly could ameliorate the outcome: this issue has obviously direct relevance for treatment decision-making. Furthermore, new imaging and radiological techniques (e.g., ultrasound or computed tomography–guided biopsy) have improved our ability to easily and safely obtain tissue samples from metastatic sites.
The mechanisms underlying the change in the expression of hormonal receptors and HER2 have yet to be completely understood. According to intratumoral heterogeneity theory a clone with metastatic potential could not be detected in the primary lesion and could form metastatic deposits with different biologic properties. Another way is a possible genetic drift or a clonal selection which occurs during tumor progression or a selective pressure of prior therapies (as mentioned above).
Finally the technical reproducibility of the ER, PR and HER2 assay could in part justify the rates of discordance, because immunohistochemistry or FISH have less than 100% of accuracy and reproducibility. Several studies indicate that even when consecutive slides from the same tumor block are stained in different laboratories or interpreted by different pathologists, significant levels of discordance rates are found; differences in fixation methods, choice of antibody and threshold levels can also have a profound effect on immunohistochemistry results.
In summary, a substantial rate of discordance in pathology and molecular markers between primary breast cancer and asynchronous metastases is possible and can alter the patient management in up to 20% of them. Tissue confirmation should be considered standard of care in patients with clinical and/or radiological suspicion of metastatic
2011
- Timing for starting second line therapy in recurrent ovarian cancer.
[Articolo su rivista]
Guarneri, Valentina; Barbieri, Elena; Dieci, Maria Vittoria; Piacentini, Federico; Conte, Pierfranco
abstract
Ovarian cancer is the leading cause of gynecologic cancer-related death in Europe and the USA. The optimal treatment strategy for this malignancy includes accurate presurgical and surgical staging, optimal debulking surgery, and first-line therapy with platinum-based chemotherapy. Unfortunately, the majority of patients diagnosed with advanced ovarian cancer will eventually relapse and die. However, an appropriate management can have a major impact on survival: salvage chemotherapy can prolong survival in the majority of cases and, in selected patients, surgical cytoreduction of recurrent disease can be beneficial. The optimal timing for starting second-line therapy should be based on symptomatic or radiologic recurrence. In fact, even though cancer antigen 125 (CA 125) elevation significantly anticipates a clinical relapse, a randomized trial failed to show a survival advantage for starting second-line therapy on the basis of CA 125 elevation. This is the most solid evidence coming from a randomized trial; however, we must take into account some limitations: in this study the role of secondary cytoreduction was not considered and, at the time of study conduction, more active salvage drugs/regimens were not yet available. In the near future, a better knowledge of ovarian cancer biology, more sensitive diagnostic techniques, more accurate and less invasive surgical procedures along with the availability of new agents will further improve prognosis. In this scenario, the anticipation of salvage therapy will probably play a different role
2011
- Trans-CHER-Lob: A Biomarker Analysis of the Randomized Phase II Study of Neoadjuvant Chemotherapy Plus Trastuzumab, Lapatinib or Combined Trastuzumab and Lapatinib in HER2 Positive Operable Breast Cancer.
[Abstract in Rivista]
Guarneri, Valentina; Frassoldati, A; Ficarra, G; Maiorana, Antonino; Bettelli, Stefania Raffaella; Bottini, A; Cagossi, K; Bisagni, G; Ravaioli, A; Amadori, D; Musolino, A; Cavanna, L; Orlando, L; Giardina, G; Piacentini, Federico; Bagnalasta, M; Conte, Pierfranco
abstract
Introduction: The CHER-Lob study is a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or combined trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. A translational program to evaluate predictors of response as well as treatment effects on tissue biomarkers was pre-planned.
Methods: The CHER-Lob translational program includes the central evaluation of HER2, p95HER2, PTEN, pAKT, Ki67 on pre and post-therapy samples. All these biomarkers have been evaluated by immunohistochemistry. FISH analysis was performed in case of HER2 IHC 2+, and in all the discordant cases between central and local laboratories. Biomarkers change from baseline to surgery has been evaluated with the Wilcoxon signed-ranks matched-pair test.
Results: 121 patients have been randomized. The pathologic complete response rate (breast and axillary lymphnodes) was 26% in Arm A (chemotherapy + trastuzumab), 28% in arm B (chemotherapy + lapatinib) and 44% in arm C (chemotherapy + trastuzumab and lapatinib). The concordance between central and local HER2 assessment on pre-treatment biopsy was 97%.
The mean (min;max) PTEN expression pre- and post-therapy were 66% (0;100) and 68.4% (0;100) respectively.
The mean (min;max) pAKT expression pre- and post-therapy were 23.3% (0;100) and 8.8% (0;90) respectively. A significant decrease was observed in the overall samples (p=0.01). When analyzing the lapatinib alone arm, the difference was no longer significant (p=0.06), while it maintained significance when evaluating the two trastuzumab containing arms (p=0.0013). The mean (min;max) ki67 expression pre- and post-therapy were 29.5% (4;90) and 16.6% (1;50) respectively. A significant decrease was observed when looking at the whole population (p<0.0001). A significantly higher ki67 inhibition was observed in the dual vs single anti-Her2 therapy (p= 0.003).
Conclusions: The central HER2 retesting showed a high concordance with local laboratories. Treatment induced a suppression in pAKT expression, that was higher in patients receiving trastuzumab. The dual anti-HER2 blockade induced a higher KI67 inhibition as compared to single anti-Her2 blockade. The evaluation of the predictive and prognostic role of these biomarkers is ongoing. Supported by GlaxoSmithKline
2011
- TREATMENT OF EARLY HER2+ BREAST CANCER: ACHIEVEMENTS AND UNMET NEEDS
[Abstract in Atti di Convegno]
Conte, P.; Piacentini, F.
abstract
Among breast cancers diagnosed at any stage, 20%–30% are found to have HER2 gene amplification/receptor overexpression that is associated with aggressive behaviour (high proliferative activity, metastatic potential and neoangiogenesis) and poor outcome. Trastuzumab, the humanized monoclonal antibody against HER2 receptor, is an essential component of the treatment of patients with HER2-positive breast cancer that has change the biological history of the disease.
In the adjuvant setting, the results of six phase III randomized trials with more than 10,000 HER2-positive breast cancer patients have been presented so far; different chemotherapy regimens and different modalities of trastuzumab administration (in combination or sequentially after chemotherapy) have been explored. Five trials have demonstrated the superiority of adding trastuzumab to chemotherapy compared with chemotherapy alone (the DFS was 33%–52% greater independently from age, nodal status, hormonal status, or tumor size and the OS was 34%–41% greater), while only PACS04 trial has shown no benefit for adding trastuzumab at the completion of chemotherapy versus control. The majority of these trials have tested one year of trastuzumab therapy. But the HERA trial is the only one specifically designed to test prospectively different durations of trastuzumab administered with sequential approach (that is at the end of adjuvant chemotherapy), with positive results in terms of DFS and OS; up to now, the results of the comparison of 1 versus 2 years of treatment are still not yet available. Moreover, the cytotoxic synergism of combined trastuzumab and chemotherapy is supported not only by the previous mentioned trials, but also by clinical data in metastatic (25% survival increase) and neoadjuvant settings (26.3% of pCR without and 66.7% of pCR with trastuzumab respectively in the MDACC experience). Interestingly, a small Finnish study wherein trastuzumab was administered for a very short period (9 weekly administrations) concomitantly with chemotherapy suggested that a shorter treatment might produce comparable efficacy with significant lower toxicities. The cardiac safety of trastuzumab is in fact another relevant clinical issue, particularly when it is used as adjuvant therapy. In all the adjuvant trastuzumab trials, despite the selection of the optimal patient population, symptomatic congestive heart failure occurred in 1.5%-2.5% of the patients treated with sequential trastuzumab (HERA trial, PACS 04, and N9831 arm B) and in a percentage ranging from 0.4 (BCIRG006 arm C, without anthracyclines) to 3.6 of the patients in the trials in which trastuzumab was started concomitantly with chemotherapy (BCIRG 006 arm B, N9831 arm C, NSABP B-31); moreover, a significant proportion of patients never started trastuzumab because of LVEF decline (1.9-6.4%) or did not complete the planned trastuzumab therapy due to cardiac events (6-18%). To test the hypothesis that a shorter duration of adjuvant trastuzumab concomitant with chemotherapy might be effective but less toxic, we have designed a phase III multicentre, randomized trial in order to evaluate if short (9 weekly administrations) versus long (18 three-weekly administrations) adjuvant trastuzumab combined with chemotherapy is equally effective in terms of DFS, and less toxic from a cardiac viewpoint. Other European trials are addressing the same questions (PHARE trial, SOLD trial, PERSEPHONE trial), but in addition this trial will explore less intensive adjuvant trastuzumab regimens in the node negative pT1a,b HER2 positive breast cancer population so poorly represented in most clinical trials.
At the same time, Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) is a four-arm randomized trial designed to compare adjuvant trastuzumab and lapatinib in women with early-stage HER2-positive breast cancer: it examine which anti-HER2 agent is more effective an
2010
- Achievements and unmet needs in the management of advanced ovarian cancer
[Articolo su rivista]
Guarneri, Valentina; Piacentini, Federico; Barbieri, Elena; Conte, Pierfranco
abstract
Ovarian cancer is the second most common gynaecological malignancy, and represents the leading cause of gynecologic cancer-related death in Europe and United States. The majority of the cases are in fact diagnosed in advanced stage, with limited chance to be cured. Optimal management of advanced ovarian cancer includes histopathological diagnosis, accurate surgical staging, debulking surgery and platinum-based chemotherapy. The combination of carboplatin and paclitaxel is commonly recognised as the standard regimen because of tolerability and activity. Intraperitoneal chemotherapy provides superior efficacy results, but its use is still controversial because of poor tolerability and compliance. Unfortunately, despite its chemosensitivity, the majority of ovarian cancer patients, including those who achieve a complete response to first-line chemotherapy, will relapse and eventually die. Among the strategies to improve patient outcome, maintenance therapy has failed to show a consistent benefit across clinical trials. Salvage second-line therapy is generally based on rechallenge with platinum in patients with platinum sensitive disease. Patients with platinum resistant/refractory might benefit from liposomal doxorubicin or topotecan. Other active cytotoxics include docetaxel, gemcitabine, etoposide and vinorelbine as well as epothilone derivatives such as patupilone which is still in development. Among targeted agents, the antiangiogenic agent bevacizumab seems extremely promising and is actively investigated in combination with first-line chemotherapy. More recently, interesting results have been obtained with the inhibitors of poly-ADP-ribose polymerase (PARP) in patients with BRCA-mutated tumors.
2010
- ACHIEVEMENTS AND UNMET NEEDS IN THE MANAGEMENT OF EPITHELIAL OVARIAN CANCER
[Relazione in Atti di Convegno]
Conte, P.; Piacentini, F.; Barbieri, E.; Guarneri, V.
abstract
NA
2010
- Anti-HER2 neoadjuvant and adjuvant therapies in HER2 positive breast cancer
[Articolo su rivista]
Guarneri, Valentina; Barbieri, Elena; Dieci, Mv; Piacentini, Federico; Conte, Pierfranco
abstract
Since the introduction of anti-Her2 agents, the prognosis of HER2 positive breast cancer patients significantly improved. In the adjuvant setting, the monoclonal antibody trastuzumab has been evaluated in six randomized trials including more than 10,000 patients. Different modes of administration (concurrent versus sequential), durations (one year, two years or 9 weeks) and different chemotherapy regimens have been evaluated. To date, one year of trastuzumab in combination or after chemotherapy is the standard adjuvant therapy for patients with HER2 overexpressing tumors. Cardiac safety is still a major clinical issue, in particular in the treatment of early breast cancer. Several large randomized trials exploring shorter, and potentially less toxic, regimens are ongoing across several European countries. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy resulted in a significantly higher activity as compared to chemotherapy alone. Unfortunately, primary and secondary resistance to trastuzumab is observed both in early and advanced disease. Several mechanisms are described as possible determinants of trastuzumab failure, and several new antiHER2 strategies are in development. Lapatinib, the HER1-2 TK inhibitor is currently approved in advanced disease after trastuzumab failure. Lapatinib is under evaluation in a large adjuvant trial, and in several neoadjuvant studies. Other molecules such pertuzumab, which binds the HER2 dimerization domain, or the pan-erbB TK inhibitor neratinib are under evaluation in the (neo)-adjuvant setting.
2010
- KI67 AS A PREDICTOR OF RESPONSE AND LONG TERM SURVIVAL IN HORMONE RECEPTOR POSITIVE/HER2 NEGATIVE BREAST CANCER PATIENTS TREATED WITH PREOPERATIVE CHEMOTHERAPY
[Poster]
Barbieri, Elena; Piacentini, Federico; Dieci, Maria Vittoria; Ficarra, Guido; Conte, Pierfranco; Guarneri, Valentina
abstract
Purpose: Breast cancer is a heterogeneous disease, and newer technologies have identified different molecular classes with distinct behaviour. In particular, hormone receptor positive tumors can be classified as luminal A or luminal B subtypes. Luminal A is a true endocrine dependent disease, generally characterized by high hormone receptor expression, low proliferation and HER2 negativity. Luminal B tumors show a more aggressive phenotype, expressed as a higher proliferation and/or HER2 positivity. It is known that hormone receptor positive tumors are less likely to achieve a pathologic complete response (pCR) after preoperative chemotherapy. Aim of the present analysis was to discriminate, on the basis of tumor proliferation as measured by Ki67, patients with hormone receptor positive/HER2 negative tumors with different probability of obtaining a pCR, and with different long term outcome.
Patients and Methods: 274 consecutive stage II-III breast cancer patients treated with preoperative chemotherapy were evaluated. Patients were classified as having hormone receptor positive tumors in case of ER and/or PgR >/= 10%. On the basis of immunohistochemical characteristic, patients were classified as follows: Luminal A, in case of hormone receptor positivity, HER2 negativity, and Ki67<15% (16%); Ki67-Luminal B, in case of hormone receptor positivity, HER2 negativity and Ki67 >/= 15% (37%); HER2-Luminal B in case of hormone receptor positivity and HER2 positivity (19%); HER2, in case of hormone receptor negativity and HER2 positivity (8%); triple negative, in case of hormone receptor negativity and HER2 negativity (20%)
Results: Patients characteristics were as follows: median age 50 yrs (range: 27-76); clinical stage: IIA 35.7%, IIB 42.3%, III 22%. After a median of 4 courses of preoperative chemotherapy, 46% of the patients underwent conservative surgery. A pCR, as defined as absence of infiltrating tumor in both breast and axillary lymph-nodes, was observed in 28 patients (10.2%). All hormone receptor positive patients received adjuvant hormonal therapy for 5 years after surgery.
The probability of obtaining a pCR was significantly lower in patients with hormone receptor positive tumors: 6.8% vs 17.5% in hormone receptor negative, p=0.010. No pCR was observed in the 40 patients classified as having Luminal A tumor; two pCRs only were observed among the 89 patients classified as having Ki67-Luminal B tumors. Patients in the Ki67-Luminal B group had significantly shorter disease-free survival (DFS) as compared with Luminal A patients (5-yr DFS 63% vs 86%, p= 0.0061). The 5-yr overall survival in Ki67-Luminal B group was 88% versus 93% in the Luminal A group. However, with 14 events only, this difference was not statistically significant.
Conclusions: In this analysis, patients with Ki67-Luminal B have a worse DFS as compared to patients with Luminal A disease. Due to the limited number of events, no differences in the probability of obtaining a pCR were observed between Luminal A and Ki67-Luminal B tumors.
2010
- Ki67 as a Predictor of Response and Long Term Survival in Hormone Receptor Positive/HER2 Negative Breast Cancer Patients Treated with Preoperative Chemotherapy
[Abstract in Rivista]
Barbieri, Elena; Piacentini, Federico; Dieci, Maria Vittoria; Ficarra, G; Conte, Pierfranco; Guarneri, Valentina
abstract
Ki67 as a Predictor of Response and Long Term Purpose: Breast cancer is a heterogeneous disease, and newer technologies have identified different molecular classes with distinct behaviour. In particular, hormone receptor positive tumors can be classified as luminal A or luminal B subtypes. Luminal A is a true endocrine dependent disease, generally characterized by high hormone receptor expression, low proliferation and HER2 negativity. Luminal B tumors show a more aggressive phenotype, expressed as a higher proliferation and/or HER2 positivity. It is known that hormone receptor positive tumors are less likely to achieve a pathologic complete response (pCR) after preoperative chemotherapy. Aim of the present analysis was to discriminate, on the basis of tumor proliferation as measured by Ki67, patients with hormone receptor positive/HER2 negative tumors with different probability of obtaining a pCR, and with different long term outcome.
Patients and Methods: 274 consecutive stage II-III breast cancer patients treated with preoperative chemotherapy were evaluated. Patients were classified as having hormone receptor positive tumors in case of ER and/or PgR >/= 10%. On the basis of immunohistochemical characteristic, patients were classified as follows: Luminal A, in case of hormone receptor positivity, HER2 negativity, and Ki67<15% (16%); Ki67-Luminal B, in case of hormone receptor positivity, HER2 negativity and Ki67 >/= 15% (37%); HER2-Luminal B in case of hormone receptor positivity and HER2 positivity (19%); HER2, in case of hormone receptor negativity and HER2 positivity (8%); triple negative, in case of hormone receptor negativity and HER2 negativity (20%)
Results: Patients characteristics were as follows: median age 50 yrs (range: 27-76); clinical stage: IIA 35.7%, IIB 42.3%, III 22%. After a median of 4 courses of preoperative chemotherapy, 46% of the patients underwent conservative surgery. A pCR, as defined as absence of infiltrating tumor in both breast and axillary lymph-nodes, was observed in 28 patients (10.2%). All hormone receptor positive patients received adjuvant hormonal therapy for 5 years after surgery.
The probability of obtaining a pCR was significantly lower in patients with hormone receptor positive tumors: 6.8% vs 17.5% in hormone receptor negative, p=0.010. No pCR was observed in the 40 patients classified as having Luminal A tumor; two pCRs only were observed among the 89 patients classified as having Ki67-Luminal B tumors. Patients in the Ki67-Luminal B group had significantly shorter disease-free survival (DFS) as compared with Luminal A patients (5-yr DFS 63% vs 86%, p= 0.0061). The 5-yr overall survival in Ki67-Luminal B group was 88% versus 93% in the Luminal A group. However, with 14 events only, this difference was not statistically significant.
Conclusions: In this analysis, patients with Ki67-Luminal B have a worse DFS as compared to patients with Luminal A disease. Due to the limited number of events, no differences in the probability of obtaining a pCR were observed between Luminal A and Ki67-Luminal B tumors.
2010
- Predictive and prognostic role of p53 according to tumor phenotype in breast cancer patients treated with preoperative chemotherapy: a single-institution analysis
[Articolo su rivista]
Guarneri, Valentina; Barbieri, Elena; Piacentini, Federico; Giovannelli, Simona; Ficarra, G; Frassoldati, A; Maiorana, Antonino; D'Amico, Roberto; Conte, Pierfranco
abstract
Introduction and aims: The p53 protein is a mediator of the cellular response to DNA damage. The aim of this study was to evaluate the predictive and/or prognostic value of p53 expression in relation to the molecular subtypes of breast cancer in patients treated with preoperative chemotherapy. Patients and methods: Patients with stage II-III breast cancer were included in the study. The expression of p53 was evaluated by immunohistochemistry on the diagnostic core biopsy specimen. Patients received 4-6 courses of preoperative chemotherapy. Pathological complete response (pCR) was defined as complete disappearance of invasive tumor in the breast and axillary lymph nodes. Results: 154 patients were included in the study and the molecular subtypes of their tumors were classified as follows: triple negative 18.2%, hormone receptor positive 60.4%, and HER2 positive 21.4%. p53 was expressed in 43.5% of the patients. A significant association between p53 expression and breast cancer molecular subtypes, tumor differentiation, and proliferation was observed. pCR was achieved in 8 patients (5.2%). p53 expression, molecular subtype, and nuclear grading were significant predictors of pCR (odds ratio for pCR in patients with p53-expressing tumors 10.03, p=0.0077). In univariate analysis, the expression of p53 as well as high proliferation and lymph node involvement after preoperative chemotherapy were predictors of a worse disease-free survival. Patients with p53 positivity also had a worse overall survival. In multivariate analysis, both p53 expression and nodal status after preoperative chemotherapy were significantly associated with disease-free and overall survival: the hazard ratios for relapse and death in patients with p53-expressing versus non-p53-expressing tumors were 2.29 (p=0.015) and 7.74 (p=0.002), respectively. The hazard ratios for relapse and death in node-positive versus node-negative patients were 3.63 (p=0.003) and 3.64 (p=0.041), respectively. Conclusions: In this series of patients, p53 expression was significantly associated with markers of aggressive tumor biology, and with a higher likelihood of attaining pCR. p53 expression was a negative prognostic parameter for diseasefree and overall survival in univariate and multivariate analysis.
2010
- PREVALENCE OF NODE NEGATIVE AND SMALL SIZE TUMORS IN A NATIONAL, RANDOMISED, PHASE III ADJUVANT TRIAL IN HER2 + EARLY BREAST CANCER (SHORT-HER STUDY)
[Abstract in Atti di Convegno]
Conte, Pf.; Agostara, B.; Aieta, M.; Banna, G.; Barbieri, E.; Belfiglio, M.; Boni, C.; Boni, L.; Brandes, A.; Cascinu, S.; Cavanna, L.; Colucci, G.; D’Amico, R.; Donadio, M.; Fornari, G.; Frassoldati, A.; Galligioni, E.; Garrone, O.; Gebbia, V.; Grasso, F.; Grisolia, Immacolata Deborah; Guarneri, V.; Lelli, G.; Molino, A.; Musolino, A.; Nanni, Oriana; Piacentini, F.; Pronzato, P.; Vicini, R.; Zamagni, C.
abstract
Introduction: Several large randomized trials have shown the superiority of combining trastuzumab with chemotherapy versus chemotherapy alone as adjuvant treatment for HER2+ breast cancer patients. Unfortunately, only a minority of the patients enrolled in these trials were node negative, and virtually none had pT1a,bN0 disease, even though recent data have demonstrated a worse outcome for these small HER2+ tumors versus HER2- cases. It is therefore of interest to know the prevalence of N0 disease and of pT1a,b in patients with HER2+ early breast cancer. We are running a large phase III trial comparing two different trastuzumab durations (Short-HER study). We are reporting the characteristics of patients randomized as of April 2010.
Methods: The Short-HER study is phase III, multicentric, Italian trial where 2500 HER2+ breast cancer patients will be randomized to: Arm A (Long) 4 courses of anthracycline based chemotherapy (AC or EC) followed by 4 courses of docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab followed by FEC x3.
Results: 470 patients from 66 Italian centers have been randomized, 229 in arm A (long) and 241 in Arm B (Short). Mean age is 54 years (29 to 76); 68% of the cases have ER+ disease. Regarding stage distribution, among 400 evaluable patients, 34.7% have stage I, 37.3% have stage IIA, 10.5% have stage IIB, and 17.5% have stage III disease. In particular, 51% of the patients have node negative disease, and 6.7% have stage pT1a,bN0 disease.
Conclusions: In the largest Italian series of HER2+ patients enrolled in a phase III trial, more than 50% have node negative disease, and around 7% have pT1a,bN0 disease. Given the prevalence of low stage disease, these data reinforce the importance of exploring less intensive, and possibly less toxic, adjuvant trastuzumab regimens.
Supported by Agenzia Italiana del FArmaco (AIFA).
2010
- Primary systemic treatment of operable breast cancer with targeted agents
[Relazione in Atti di Convegno]
Conte, Pierfranco; Guarneri, Valentina; Piacentini, Federico
abstract
Primary systemic treatment (PST) is the standard therapy for inflammatory and locally advanced breast cancer but it is currently more and more used even in some subsets of patients with operable disease, instead of conventional adjuvant treatments. So far, this strategy has not yet produced a clear survival advantage, as compared to standard postoperative therapy.1 However, PST can allow for breast conservative surgery when up-front mastectomy would be recommended, or can offer a better cosmetic result in case of unfavourable breast-to-tumor size ratio, without jeopardizing survival2,3. Moreover, PST permits an in vivo evaluation of treatment efficacy according to therapy-induced changes of the nodule, and allows to identify subgroups of patients with different prognosis: the patients who achieve a pathological complete response (pCR) benefit most from the treatment and have an excellent prognosis while those with residual breast and/or nodal disease after PST have a worse prognosis.
To date, several tumor characteristics have been identified as predictors of the probability of pCR: poorly differentiated tumors, with high proliferation rate HT negative or HER2 positive are more likely to respond to chemotherapy.4-7 However, even if the pCR rate is different across the breast molecular subtypes, once a pCR is achieved, prognosis is good irrespectively of tumor phenotype.7
As pCR rate is now considered a powerful surrogate of long-term disease-free survival, several studies have been conducted to improve the rate of pCR and the more promising results have been obtained with sequential anthracyclines and taxanes.
In the ECTO trial, 1355 patients have been randomized to receive post-operative doxorubicin times four followed by CMF times four (A CMF) or post-operative doxorubicin plus paclitaxel times four followed by CMF times four (AP CMF) or four courses of pre-operative AP followed by four courses of CMF. The rate of breast conservative surgery was 65% in patients randomized in the preoperative arm as comparing to 34% in patients not treated upfront with chemotherapy (p>0.001); a pCR in breast and axillary nodes was observed in 20% of the cases.8 In the study conducted by the Aberdeen Breast Group, 162 patients received four courses of preoperative chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CVAP). Patients achieving a partial or a complete response were randomised to either four further cycles of CVAP or four courses of docetaxel, while non-responders received four cycles of docetaxel. In this relatively small trial, it was shown that both cCR (34% versus 62%) and pCR (18% versus 34%) were in favour of the docetaxel arm.9 In the GEPARTRIO study, 286 patients were evaluated after two courses of preoperative docetaxel, doxorubicin and cyclophosphamide (TAC): non responders were randomized to four cycles of TAC or four courses of capecitabine and navelbine, while responders received four additional courses of TAC. The pCR rate was 22.3% in responding patients receiving six courses of TAC, 7.3% in non responding patients receiving four additional courses of TAC and 3.1% only in those patients randomized to four courses of capecitabine-navelbine.10 In the NSABP-B27, 2411 patients were randomized to receive: four courses of AC followed by surgery; four courses of AC followed by four courses of docetaxel and then surgery; four courses of AC followed by surgery followed by four courses of post-operative docetaxel. It was shown that the addition of docetaxel almost doubled the pCR rate (26.1% versus 12.9% and 14.4% in the two pre-operative AC arms).11 Another interesting trial conducted at the M.D. Anderson Cancer Center has evaluated the sequential administration of weekly vs 3-weekly paclitaxel, followed by FAC: the administration of paclitaxel on a weekly schedule resulted in a significantly higher pCR rate (28.2% versus 15.7%, p=0.02).12 Furt
2010
- 35. PREDICTORS OF HER2 FISH POSITIVITY IN PRIMARY BREAST CANCER DIAGNOSIS SCORED 2+ WITH IHC: RESULTS OF A SINGLE INSTITUTION ANALYSIS
[Abstract in Atti di Convegno]
Barbieri, E.; Bettelli, S.; Piacentini, F.; Ficarra, G.; Conte, Pf.; Guarneri, V.
abstract
Background: HER-2 positivity in breast cancer is defined as a 3+ score in immunohistochemistry (IHC) assay (defined as uniform intense membrane staining of > 30% of invasive tumor cells) or FISH amplification (ratio of HER-2 to CEP17 of > 2.2 or average HER-2 gene copy number > six signals/nucleus for those test systems without an internal control probe). In case of 2+ staining at IHC, the test is considered equivocal, and FISH is mandatory to verify the HER-2 status. Up to 15% of breast cancer are IHC 2+. Aim of this study was to identify potential predictors of FISH positivity for those cases scored IHC 2+.
Methods: During 2009, a total of 200 samples were processed for FISH assay. Among them, 161 (80.5%) were primary breast diagnoses with HER2 IHC score2+. Twelve cases (7.5%) resulted not evaluable, leaving 149 cases eligible for this analysis. We have evaluated the correlation between FISH positivity and hormone receptor expression, nuclear grade and proliferation.
Results: Mean age of the patients was 64 years (range 25-97). Hormone receptors status was known in 125/149 patients (84%); 107 (86%) were ER +, 92 (74%) were PgR + , 110 (88%) were either ER or PgR +. MIB-1 was available in 121 cases (81%). The mean Ki67 value was 20% (range: 2 to 80). Nuclear grade was available in 108 cases (72.5%), 50 cases were G1 or G2 (46%) and 58 were G3 (54%). FISH resulted amplified in 41 pts. (27.5%). None of the evaluated factors was significantly associated with the probability of FISH positivity: the odds ratios for FISH positivity were 1.005 for age <50 vs >50 yrs. (p= 0.704), 1.001 for proliferation (p=0.927), 1.497 for grade 3 vs. 1-2 (p=0.269), 0.96 for hormone receptor negative vs. positive (0.960).
Conclusions: In this study, hormone receptor status, nuclear grade and proliferation were not significantly associated with the probability of FISH positivity. The percentage of hormone receptor positivity in this population was surprisingly high, and we are evaluating the prevalence of hormone receptor positivity in patients with HER2 IHC 0/1+ and 3+ diagnosed during the same year . The study is ongoing to include cases diagnosed between 2000-2008
2009
- A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy.
[Articolo su rivista]
Guarneri, Valentina; Piacentini, Federico; Ficarra, G; Frassoldati, A; D'Amico, Roberto; Giovannelli, Simona; Maiorana, Antonino; Jovic, Gordana; Conte, Pierfranco
abstract
BACKGROUND: Preoperative chemotherapy (PCT) allows for in vivo testing of treatment effects on tumor and its microenvironment. Aim of this analysis was to evaluate the effect of PCT on tumor biomarker expression and to evaluate the prognostic role of treatment-induced variation of these biomarkers (molecular response). METHODS: Two hundred and twenty-one stage II-III breast cancer patients were included. The following parameters were evaluated at baseline and on surgical specimens after PCT: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67, p53, human epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and apoptosis. RESULTS: A pathological complete response was observed in 8.8% of the patients. PCT induced a significant reduction in the expression of ER, PgR, Ki-67, and apoptosis. As by multivariable model, Ki-67 > or = 15% and nodal positivity after preoperative chemotherapy (PCT) were significant predictors of worse disease-free survival [hazard ratio (HR) 3.79, P < 0.0001 and HR 2.31, P = 0.037, respectively]. Ki-67 > or = 15% after PCT was also a significant predictor of overall survival (HR 3.75, P = 0.013). On the basis of these two parameters, patients were classified into three groups: (i) low risk (negative nodes and Ki-67 <15%), (ii) intermediate risk (nodal positivity or Ki-67 > or = 15%), and (iii) high risk (nodal positivity and Ki-67 > or = 15%). As compared with the low-risk group, the HRs for recurrence were 3.1 and 9.3 for the intermediate- and high-risk group, respectively (P = 0.0001); the HRs for death were 2.4 and 6.5 for the intermediate- and high-risk group, respectively (P = 0.042). CONCLUSIONS: Ki-67 and nodal status have been used to generate a simple and easily reproducible prognostic model, able to discriminate patients with worse prognosis among the heterogeneous group of women with residual disease after PCT.
2009
- PREDICTIVE AND PROGNOSTIC ROLE OF P53 EXPRESSION IN STAGE II-III BREAST CANCER PATIENTS TREATED WITH PREOPERATIVE CHEMOTHERAPY: A SINGLE INSTITUTION ANALYSIS
[Abstract in Atti di Convegno]
Guarneri, V.; Piacentini, F.; Barbieri, E.; Ficarra, G.; Conte, Pf.
abstract
NA
2009
- Preplanned first-step analysis of LET-LOB neoadjuvant study: A double-blind randomized phase IIb trial of letrozole (L) plus lapatinib (Lp) or placebo (P) in postmenopausal HER2-ve, HR+ve operable breast cancer.
[Abstract in Rivista]
A., Frassoldati; Guarneri, Valentina; A., Bottini; K., Cagossi; L., Cavanna; G., Bisagni; D'Amico, Roberto; Piacentini, Federico; C., Oliva; Conte, Pierfranco
abstract
Background: In HR+ve BC, the simultaneous blockade of ER and HER-related pathways could prevent the hormone-resistance due to activation of EGFR-family signalling, as shows the high activity of the combination of letrozole and lapatinib in HR+ve/HER2+ve advanced BC. The LET-LOB trial evaluates the clinical and biological effects of the combined inhibitory strategy with letrozole + lapatinib in untreated ER+ve/HER2-ve BC patients suitable for hormonal neoadjuvant therapy. Methods: Postmenopausal women with stage II-IIIa, HR+ve/HER2-ve BC are randomized to L (2.5 mg/d) + Lp (1500 mg/d) or L + P, given continuously for 24 weeks before surgery. Primary end point is the clinical RR (with ultrasonography, US); secondary endpoints are the pathological RR, the safety, and HR/EGFR-related biomarker evaluation. According to the "two step Simon's design" of the study, at least 20 cORs (8 in L+P and 12 in L+Lp) must be observed in the first 43 patients; then, additional 48 patients will be recruited to demonstrate a 40% increase in cOR with L+Lp, assuming a cOR of 50% with L+P. Results: Since April 2007, 39/55 randomized patients completed the preoperative treatment. Median age was 68 yrs. At diagnosis, mean US tumor size was 3 cm. All patients were HER2-ve, and either ER+ve or PR+ve (both +ve: 76%). After 3 and 6 months of therapy, a 29% and 41% reduction from baseline mean US longest tumor diameter was observed. No change in mean LVEF has been reported at the 3- and 6-month evaluations. 5 episodes of G3 toxicity have occured (skin rash, 1; liver function parameters, 4). So far 31 women underwent surgery (conservative in 65 %). The efficacy results according to the first step Simon's analysis will be performed by the IDMC on march 2009, and will be presented at the meeting along with updated clinical and safety data. Conclusions: Preliminary blinded results suggest that the combination of L+Lp in ER+ve/HER2-ve operable BC is feasible, without early cardiac events or other severe toxicities, and associated with clear tumor downstaging. Biological correlative studies will clarify the relationship between the double inhibition strategy and the clinical response. Supported by GlaxoSmithKline.
2009
- P53 EXPRESSION IS A SIGNIFICANT PREDICTOR OF RESPONSE AND PROGNOSIS IN STAGE II-III BREAST CANCER PATIENTS TREATED WITH PREOPERATIVE CHEMOTHERAPY
[Abstract in Atti di Convegno]
Guarneri, V.; Piacentini, F.; Barbieri, E.; Frassoldati, A.; Ficarra, G.; D’Amico, R.; Conte, Pf.
abstract
Introduction and Aims: p53 protein is a mediator of the cellular response to DNA damage. Mutation in p53 genes has been reported in breast cancer (BC) , and has been suggested as potential marker of chemoresistance. Aim of this study is to evaluate the predictive and/or prognostic role of p53 expression in a consecutive series of BC patients (pts) treated with preoperative chemotherapy (PCT).
Patients and Methods: pts with stage II-III BC were included. The expression of p53 was evaluated by IHC on the diagnostic core biopsy, (Cellmar D07Ab, cut off: staining in ³ 10% of cells). Pts received 4-6 courses of PCT before surgery. Pathologic complete response (pCR) was defined as complete disappearance of invasive tumor in breast and axillary nodes. The association between biomarkers and pCR was assessed by Pearson chi square test. Survival was estimated with the Kaplan-Meier method.
Results: 155 BC pts were included. Median age was 52 yrs (range: 29-76). Clinical stage at diagnosis: II A-B in 80% of the pts, IIIA-B in 20% of the pts. The majority of the pts (72%) had ER+ tumors; 22% of the pts were HER2 +. 68 pts (44%) showed p53 overexpression (mean expression 24%: range 0-99%). p53 overexpressing tumors were significantly less ER +(63% vs 79%, p=0.02). p53 expression was also positively correlated with higher levels of ki67 (87 vs 70%, p=0.012). PCT consisted of anthracycline-based regimens in 40 pts; anthra/taxanes combinations in 110 pts; a taxane regimen in 4 cases. After PCT, 43% of the pts underwent conservative surgery. A pCR was observed in 5.3% of the pts. The probability of pCR was significantly higher in case of p53 overexpression (10.8% vs 1%, p=0.009), ER negativity (11.6% vs 2.8%, p=0.028), HER2 positivity (12 vs 3.4%, p=0.04), and nuclear grade 3 (9% vs 0, p=0.02). The overall 5-yr DFS and OS were 70% and 85%. The 5-yr DFS in case of p53 <10% was 82% vs 55% in p53 >/= 10% (p=0.0038). The 5-yr OS in case of p53 <10% was 99% vs 67% in p53 >/= 10% (p<0.0001).
Conclusions: the expression of p53 is significantly associated with a higher probability of achieving a pCR to PCT including anthracyclines +/- taxanes. However, inspite of the greater chemosensitivity, in our study p53 overexpression is a negative prognostic parameter. The role of p53 in patients receiving PCT warrants further studies.
Supported in part by a Ministry of Health Research grant (Progetti Integrati Oncologia # 04/07)
2009
- Safety and Activity Report of a Randomized Phase II Trial of Preoperative Anthracycline-Based Chemotherapy Plus Lapatinib, Trastuzumab or Both in HER2 Positive Breast Cancer: CHERLOB Trial.
[Abstract in Rivista]
Guarneri, Valentina; Frassoldati, A; Bottini, A; Cagossi, K; Piacentini, Federico; Ravaioli, A; Cavanna, L; Amadori, D; Bisagni, G; Giardina, G; Conte, Pierfranco
abstract
Introduction: We have designed a randomized phase II trial of preoperative sequential taxanes-anthracyclines in combination with trastuzumab, lapatinib, or both trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage of pathological complete response (pCR) as defined as complete disappearance of invasive tumor in both breast and axillary nodes.
Methods: chemotherapy (CT) consists of paclitaxel 80 mg/m2 weekly x 12 weeks followed by FE75C x 4 cycles administered every 3 weeks. Patients randomized to arm A receive CT plus weekly trastuzumab; in arm B patients receive CT plus lapatinib 1500 mg po daily; in arm C patients receive CT plus weekly trastuzumab and lapatinib 1000 mg po daily. Trastuzumab and lapatinib are administered throughout the entire CT plan. The study sample size has been calculated according to the two steps Simon's design. The overall planned accrual is 120 patients. Following the second safety report from the Independent Data Monitoring Committee on the first 30 evaluable patients, due to the occurrence of grade 3 diarrhea in 20% and in 41% of the patients randomized to arm B and C respectively, lapatinib doses have been reduced to 1250 mg in arm B and 750 mg in arm C.
Results: 66 patients have been randomized: 20 in arm A, 20 in arm B, and 26 in arm C. Median age is 50 years (range 27-66). The overall non hematologic toxicity of grade (G) >1, as reported as maximum toxicity per patient, is as follows: diarrhea G2 29%, G3 22%; skin rash G2 29%, G3 7%; hepatobiliary events G2 10%, G3 5%, G4 3%.
Left ventricular ejection fraction (LVEF) has been evaluated at baseline, after 12-13 weeks, and at the end of therapy. Mean LVEF% (range) was 62% (52%-77%), 61% (44%-78%) and 61% (53%-74%) respectively. No patient had symptomatic cardiac events. Forty-five patients underwent surgery, and are evaluable for response: 67% of the patients received breast conserving surgery. A pCR in breast and axillary nodes has been observed in 39% of the cases.
Conclusions: The study accrual is ongoing. The safety of patients randomized following the amendment reducing lapatinib dosage will be presented at the Meeting. Supported by GlaxoSmithKline
2009
- ShortHER: TRATTAMENTO ADIUVANTE CON HERCEPTIN PER 3 MESI VERSO 12 MESI, IN ASSOCIAZIONE CON DUE DIFFERENTI REGIMI DI CHEMIOTERAPIA, NELLE PAZIENTI CON CARCINOMA MAMMARIO HER2 POSITIVE: ANALISI PRELIMINARE DELLE TOSSICITA’
[Relazione in Atti di Convegno]
Ferrari, A.; Grisolia, D.; Piacentini, F.; Barbieri, E.; Guarneri, V.; Frassoldati, A.; Giovannelli, S.; Sabbatini, R.; Pagano, M.; Vicini, R.; Conte, Pf.
abstract
NA
2009
- ShortHER: TRATTAMENTO ADIUVANTE CON HERCEPTIN PER 3 MESI VERSO 12 MESI, IN ASSOCIAZIONE CON DUE DIFFERENTI REGIMI DI CHEMIOTERAPIA, NELLE PAZIENTI CON CARCINOMA MAMMARIO HER2 POSITIVO
[Abstract in Atti di Convegno]
Piacentini, F.; Ferrari, A.; Barbieri, E.; Guarneri, V.; Frassoldati, A.; Giovannelli, S.; Sabbatini, R.; Pagano, M.; Grisolia, D.; Vicini, R.; Conte, Pf
abstract
Introduzione – Almeno cinque studi randomizzati hanno dimostrato che la somministrazione di Trastuzumab (Herceptin -H) in associazione alla chemioterapia adiuvante migliora significativamente la prognosi delle pazienti con tumore mammario HER2 positivo. La durata ottimale del trattamento rimane tuttavia argomento dibattuto. Il trial clinico ShortHer è uno studio multicentrico, randomizzato e di fase III, coordinato dal Dipartimento di Oncologia del Policlinico Universitario di Modena e sponsorizzato dall’AIFA; si propone di valutare su un campione di 2500 donne se un trattamento di breve durata con H associato a chemioterapia (Braccio Short: 3xDocetaxel100 g.1, q21 + H settimanale per 9 dosi totali→3xFE60C) risulti almeno non inferiore, in termini di sopravvivenza libera da malattia e globale, rispetto al trattamento standard per un anno (Braccio Long: 4xEC/AC g.1, q21→4xPaclitaxel175/Docetaxel100 g.1, q21 + H trisettimanale per 1 anno).
Pazienti – Lo studio è stato attivato nel dicembre 2007 ed attualmente coinvolge circa 126 centri italiani (54 già attivi). Sono elegibili al trattamento donne con carcinoma mammario HER2 positivo operato, con linfonodi positivi o con linfonodi negativi ad alto rischio (almeno uno tra i seguenti: T >2 cm, G3, invasione vascolare/linfatica, elevata proliferazione (Ki67 >20%), età <35 anni, recettori ormonali (RE e RPg) negativi (<10%); oppure T >1cm associato ad uno o più dei parametri soprariportati), candidate a chemioterapia adiuvante.
Risultati – Al 15 settembre 2009 sono state randomizzate 292 pazienti:
- 143 pazienti nel braccio Short, con le seguenti caratteristiche: età mediana, 52 anni (range 31-74); stato postmenopausale, 50%; LVEF basale 63% (range 52-82); RE positivi, 70% con espressione media dei RE del 68,6% (range 10-100); RPg positivi, 55% con espressione media dei RPg del 55,1% (range 10-100).
- 149 pazienti nel braccio Long con le seguenti caratteristiche: età mediana, 54 anni (range 29-76); stato postmenopausale, 53%; LVEF basale 63% (range 50-81); RE positivi, 72% con espressione media dei RE del 67,6% (range 10-100); RPg positivi, 59% con espressione media dei RPg del 47,4% (range 10-100).
Inoltre, in 11(8%) casi del braccio Short e in 15(10%) casi del braccio Long i tumori presentano dimensioni inferiori al centimetro (pT1a e pT1b) e stato linfonodale negativo (pN0 e pN0i+).
Conclusioni – Questa casisitica fornirà indicazioni per stabilire la durata ottimale della terapia adiuvante con Trastuzumab; permetterà inoltre di confermare il ruolo di Trastuzumab anche nel sottogruppo di pazienti con piccoli tumori HER2 positivi per le quali al momento non esistono condivise linee guida di trattamento.
2008
- A prognostic model based on nodal status and Ki 67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy
[Abstract in Rivista]
Guarneri, Valentina; Piacentini, Federico; A., Frassoldati; G., Ficarra; D'Amico, Roberto; Giovannelli, Simona; Conte, Pierfranco
abstract
Introduction and Aims: The achievement of a pathologic complete response (pCR) after preoperative chemotherapy (PCT) is a validated surrogate end point for long term outcome. On the other side, patients with residual disease in the breast and/or axilla are an heterogeneous group with very different prognosis, including both patients with truly chemo-resistant disease as well as patients with an important tumor downstaging even if not in pCR. Aim of this analysis is to identify, in patients with residual disease, potential markers able to discriminate patients at higher risk of relapse.
Patients and Methods:. The following parameters were evaluated on the surgical specimen in patients with less than pCR following PCT: residual breast disease, number of involved nodes, proliferation (Ki 67), hormone receptor, HER2, p53, EGFR, VEGFR2. Survival curves were estimated with the Kaplan-Meier method and the log rank test was used to test for differences between groups. Hazard Ratios and their confidence intervals were estimated by using Cox model.
Results: 195 breast cancer patients were included. Median age 51 yrs (range: 27-73); 71% of the patients had ER+ tumors at diagnosis, 20% were HER2+. After PCT, 55% of the patients received mastectomy, 45% underwent conservative surgery. 57% of the patients had residual breast disease < 2 cm; 38% between 2-5 cm; 35% had no involved nodes, 30% 1-3 nodes, 19% 4-9 nodes, and 16% > 10 nodes; 50% of the patients had Ki 67 >/= 15%. Among the examined parameters, nodal positivity and Ki 67>/=15% were significantly related with a higher risk of relapse (HR 2.5 , p=0.014 and HR 3.4, p <0.0001 respectively). Ki 67 >/=15% was also predictive of a higher risk of death (HR 4.1, p=0.007). On the basis of these two parameters, patients were classified in three groups: 1) low risk (negative nodes and Ki 67<15%): 14.4% of the patients ; 2) intermediate risk (nodal positivity or Ki67 >/= 15%): 54.4% of the patients; 3) high risk (nodal positivity and Ki 67>/= 15%): 31.2% of the patients. Five-year DFS rates were 90%, 72%, and 43% respectively (log rank test p<0.0001); as compared with the low risk group, the HRs for recurrence were 3.1 and 9.3 for the intermediate and high risk group respectively (p=0.0001). Five-year OS rates were 86%, 88%, and 64% respectively (log rank test p=0.035); as compared with the low risk group, the HRs for death were 2.4 and 6.5 for the intermediate and high risk group respectively (p=0.042). Conclusions: In this series of patients, Ki 67 and nodal status have been used to generate a simple and easily reproducible prognostic model, able to discriminate patients with worse prognosis among the heterogeneous group of women with residual disease after PCT. In the era of customized treatment strategies, patients at higher risk are the optimal candidates to study the efficacy of additional postoperative treatments.
2008
- ATTIVAZIONE DEL PERCORSO UNITARIO DI TRATTAMENTO ONCOLOGICO PER IL TUMORE DELL MAMMELLA (PUNTO) PRESSO L’AZIENDA OSPEDALIERO-UNIVERSITARIA POLICLINICO DI MODENA
[Abstract in Atti di Convegno]
Frassoldati, A.; Fontana, G.; Piacentini, F.
abstract
Introduzione: in linea con le indicazioni delle principali linee guida internazionali sulle “breast units”, il p.un.t.oamico (percorso unitario di trattamento oncologico) nasce dall’esigenza di garantire un approccio multidisciplinare al tumore mammario ed alla paziente che ne riceve diagnosi. Opera all’interno del Policlinico come gruppo di specialisti con interesse prevalente per la patologia mammaria (in Radiologia, Chirurgia, Chirurgia plastica, Anatomia patologica, Oncologia, Radioterapia, Servizio Psicosociale) che, incontrandosi settimanalmente presso il COM, discute sui percorsi diagnostico-terapeutici da adattare a ciascun nuovo caso e valuta possibili miglioramenti del processo clinico in generale. L’organizzazione di un percorso di diagnosi e trattamento per le neoplasie mammarie interpreta concretamente la volontà di offrire alla donna un punto di riferimento unitario, visibile e raggiungibile, che risponda ai principi di elevata qualità assistenziale, contenimento dei tempi negli standard internazionali e soddisfazione della paziente, ma che soprattutto faciliti i contatti con le strutture sanitarie in una fase della vita psicologicamente delicata. Tali obbiettivi sono perseguiti mediante la centralizzazione delle prenotazioni e la creazione di una segreteria unificata, l’adozione di protocolli di trattamento basati sulle evidenze scientifiche più aggiornate, la disponibilità al dialogo dei professionisti, il supporto delle associazioni di volontariato. Non meno importante lo sviluppo e l’implementazione di sistemi informatici di monitoraggio dell’andamento e dei tempi del percorso che consentano di adottare eventuali misure di miglioramento: in quest’ottica verranno valutati indicatori di processo (ad esempio, intervallo fra diagnosi definitiva ed intervento chirurgico), indicatori clinici (ad esempio, tasso di identificazione del linfonodo sentinella), indicatori di esito (ad esempio, sopravvivenza globale per stadio). E’ infine prevista una valutazione del livello di soddisfazione della paziente rispetto al percorso clinico assistenziale nel suo complesso e nei diversi aspetti di organizzazione, informazione e qualità percepita delle prestazioni.
Dal gennaio 2008 ad oggi si sono rivolte al p.un.t.oamico 285 donne, così suddivise:
PERCORSO 1: Diagnosi - CH - Terapia adiuvante – RT : 227 pazienti
PERCORSO 2: Diagnosi - Terapia primaria - CH - Terapia adiuvante - RT : 45 pazienti
PERCORSO 3: Diagnosi - CH – RT : 4 pazienti
PERCORSO 4: Diagnosi - Terapia primaria - RT : 6 pazienti
PERCORSO 5: RT - Terapia medica : 0 pazienti
PERCORSO 6: Terapia medica : 3 pazienti.
2008
- CHER LOB Trial: Preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2-positive operable breast cancer--Safety report as per Independent Data Monitoring Committee (IDMC) and preliminary activity data
[Abstract in Rivista]
Guarneri, Valentina; A., Frassoldati; K., Cagossi; A., Bottini; A., Michelotti; L., Cavanna; Jovic, Gordana; Piacentini, Federico; C., Oliva; Conte, Pierfranco
abstract
Background: We conducted a phase IIb randomized trial of preoperative chemotherapy (CT) plus trastuzumab (T), lapatinib (L), or the combination of T+L in HER2+ operable breast cancer > 2cm . Primary endpoint is the % of pathologic complete response (pCR) in breast and axillary nodes. Secondary endpoints: breast objective response, % of breast conservative surgery, safety, molecular responses, gene expression related to pCR. Methods: Patients with HER2+ stage II-IIIA breast cancer are randomized to Arm A: CT+T; Arm B: CT+L; Arm C: CT+T+L. CT consists of paclitaxel (P) 80 mg/m2 weekly for 12 weeks followed by 4 cycles of FE75C q3weeks. T is administered at 2 mg/kg weekly in arms A and C; L is administered at 1,500 mg po daily in arm B, and at 1,000 mg po daily in arm C. Both T and L are administered throughout the duration of CT. Left ventricular ejection fraction (LVEF) is evaluated at baseline, before the start of FEC, and at the completion of treatment. The planned sample size, calculated with the two steps Simon's design, includes 120 patients. Safety analyses by the IDMC are planned at the following time-points: 1) after the first 15 patients treated for >3 months; 2) after the first 30 patients treated for >3 months. If no safety concerns, further analyses are planned for every 30 patients until study closure. Results: 28 patients have been randomized: 8 in Arm A, 9 in Arm B, 11 in Arm C. A total of 187 doses of weekly P+T, L or T+L, and 46 courses of FEC+T, L or T+L are evaluable. Hematologic toxicity: grade (G) 3-4 neutropenia in 9.6% of weekly P and in 52% of FEC cycles. Nonhematologic toxicity (excluding nausea and vomiting) reported for >5% of cycles were: diarrhea (G1-2: 26%; G3: 4%), G1-2 skin toxicity (23%), and G1 neurotoxicity (10%) during weekly P; G1-2 diarrhea (20%), G1-2 skin toxicity (28%) and G1 neurotoxicity (20%) during FEC therapy. The mean LVEF was 64% (range 54-74%) at baseline, 63% (60-71%) after 12 weeks, and 61% (60-63%) at the end of therapy. Conclusions: The preliminary safety data on the combination of T and L with an anthracycline-containing regimen seem encouraging. The first 2 evaluations as per IDMC and preliminary activity data will be presented at the Meeting.
2008
- Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management
[Articolo su rivista]
Guarneri, Valentina; Giovannelli, Simona; Ficarra, G; Bettelli, Stefania Raffaella; Maiorana, Antonino; Piacentini, Federico; Barbieri, Elena; Dieci, Maria Vittoria; D'Amico, Roberto; Jovic, Gordana; Conte, Pierfranco
abstract
The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS: Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS: Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS: Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patients
2008
- COMPARISON OF HER-2 STATUS IN PRIMARY BREAST CANCER AND METASTATIC SITES: RESULTS FROM A SINGLE INSTITUTION ANALYSIS
[Relazione in Atti di Convegno]
Guarneri, V.; Giovannelli, S.; Ficarra, G.; Bettelli, S.; Piacentini, F.; Barbieri, E.; Dieci, Mv.; Jovic, G.; Conte, Pf.
abstract
Introduction:HER-2 overexpression occurs in 15-20% of breast cancer; the assessment of HER2 status is necessary to select patients who are candidate to receive anti-HER2 agents, such as trastuzumab. The evaluation of HER2 is generally carried out in primary tumor. However, it is controversial if it would be more appropriate to reassess HER2 status in the metastatic lesion. Aim of the present analysis is to compare the HER2 status in primary tumors versus metastatic sites in metastatic breast cancer patients.
Patients and Methods: The Archive of the Pathology Division was searched to identify all the biopsies performed since 2004 resulted positive for metastases from breast cancer. Among these patients, only those with available samples from primary tumor and followed at our department were considered for this analysis. Therefore, 68 out of the previously 89 identified patients are included in the present study.
HER-2 overexpression was evaluated by IHC and/or by FISH. Overall, samples were considered positive for HER2 in case of IHC 3+, or 2+ and FISH amplification, or FISH amplification. In case of discordance between IHC and FISH, HER 2 status was defined according to the FISH result.
Results: Median age at diagnosis was 53 years (range 27-74). Among the 49 patients evaluable by IHC, 40 (82%) were negative (0-1+); 3 (6%) were IHC 2+, and 6 (12%) were 3+.
Among the 38 patients evaluable by FISH, 32 (84%) were non-amplified, and 6 (16%) were amplified. Overall, at diagnosis, 15% of tumors were HER2 positive. Sites of biopsied metastases were: soft tissues (n=22), liver (n=20), chest wall (n=13), CNS (n=4), bronchus (n=4), bone (n=1), bone marrow (n=2), and other (n=2).
On paired metastases, HER2 status was found to be unchanged in 57 out of the 68 (84%) evaluable patients, while a change in HER2 status was observed in 11 cases (16%). All the discordant cases were assessed both by IHC and FISH whenever possible, or by using the same modality. Surprisingly, only 2 patients changed from HER2 positivity to HER2 negativity (without receiving anti HER2 therapy prior to metastatic site biopsies), while in 9 patients her2 was negative on primary tumors and overexpressed in paired metastases.
Conclusion. The unexpected discordance observed in our analysis, with particular regard to those tumors that convert from negative to positive HER2 status, warrants further studies with larger series. However, based on these data, when feasible with minimal invasiveness, a biopsy of metastatic disease might increase treatment options for a significant proportion of patients.
2008
- Development of hypogammaglobulinemia in patients treated with imatinib for chronic myeloid leukemia or gastrointestinal stromal tumor
[Articolo su rivista]
Santachiara, Rita; Maffei, Rossana; Martinelli, Silvia; Arcari, Annalisa; Piacentini, Federico; Trabacchi, Elena; Alfieri, Pierluigi; Ferrari, Angela; Leonardi, Giovanna; Luppi, Gabriele; Longo, Giuseppe; Vallisa, Daniele; Marasca, Roberto; Torelli, Giuseppe
abstract
Imatinib mesylate is a tyrosine kinase inhibitor used as first line treatment in chronic myeloid leukemia and gastrointestinal stromal tumor patients. Although several in vitro and animal studies demonstrated that imatinib affects immune response, few immune alterations are described in humans. We retrospectively studied hematologic and immunological parameters in 72 chronic myeloid leukemia and 15 gastrointestinal stromal tumor patients treated with imatinib at standard dosage and in 20 chronic myeloid leukemia patients treated before the introduction of imatinib in clinical practice. Both chronic myeloid leukemia and gastrointestinal stromal tumor patients developed a significant reduction of gammaglobulin and immunoglobulin serum levels. No significant hypogammaglobulinemia was observed in chronic myeloid leukemia patients in the pre-imatinib era. These data demonstrate that imatinib treatment induces hypogammaglobulinemia that can reach a severe entity in 10% of cases, both in chronic myeloid leukemia and in gastrointestinal stromal tumor patients. Prospective studies are needed to evaluate immune humoral alterations and to define the real incidence of infectious events, including viral reactivations.
2008
- Lapatinib or placebo plus letrozole as preoperative treatment of hormone receptor-positive HER2-negative operable breast cancer. Preliminary report of safety and activity of the double-blind randomized phase IIb LET-LOB study
[Abstract in Rivista]
A., Frassoldati; Guarneri, Valentina; A., Bottini; K., Cagossi; L., Cavanna; G., Bisagni; G., Jovic; Piacentini, Federico; C., Oliva; Conte, Pierfranco
abstract
Background: Crosstalk between hormone- and EGFR-family pathways is a possible cause of resistance to aromatase inhibitors (AI), as suggested by the increased expression of HER2, EGFR and MAPK in long-term estrogen-deprived breast cancer (BC) cells. Lapatinib (Lap) is an orally active small molecule inhibitor of EGFR and HER2 tyrosine-kinases. Combination of an AI and Lap in ER+/HER2- tumors could avoid the onset of resistance due to early stimulation of EGFR and HER2 pathways. To evaluate these effects, we designed an international multicenter phase IIb double-blind randomized trial in ER+/HER2- BC pts candidates for hormone neoadjuvant therapy. Methods: Postmenopausal pts with stage II-IIIa, HR+/HER2- BC are randomized to letrozole (Let; 2.5 mg/d) plus lapatinib (Lap; 1,500 mg/d) or placebo (P), given continuously for 24 weeks before surgery. Activity (with ultrasonographyc, US) and cardiac safety (with echocardiogram) assessment are performed after 12 and 24 weeks. Tissue biomarkers of hormone and EGFR-family related pathways are analyzed before and after treatment. An initial sample size of 42 pts will be enrolled assuming a 50% chance of cOR with Let+P and a 40% increase in cOR with the Let+Lap (equal to 70% absolute cOR). Additional 48 pts will be treated in case we observe 20 cOR in the first cohort (Simon's design). Results: 19 Italian and European centers are participating in the study. From April 2007, 28 pts have been randomized, and 15 pts were treated for at least 3 months (mo). Six pts completed the six mo treatment, and 4 underwent surgery. At diagnosis, mean US tumor size was 2.87 cm (range 2-6 cm). All pts were ER+ (73% ER+/PR+) and HER2-. No significant decrease in mean LVEF was observed at the 3-mo evaluation (60.9%-61.5%). No grade 3-4 toxicities were reported. A 34% absolute reduction in median longest US tumor diameter has been observed after 3 mo (15 pts) and 65% reduction has been obtained at 6 mo (6 pts). Updated blinded safety and activity results will be presented. Conclusions: The combination of Lap or P with Let in ER+/HER2-operable breast cancer was safe, without any early cardiac toxicity, and induced clear tumor shrinkage.
2008
- Letrozole Versus Letrozole Plus Lapatinib (GW572016) in Hormone-Sensitive, HER2-Negative Operable Breast Cancer: A Double-Blind, Randomized Phase II Study with Biomarker Evaluation (EGF109077-LAP107692/LETLOB)
[Articolo su rivista]
Frassoldati, A; Guarneri, Valentina; Piacentini, Federico; Jovic, Gordana; Giovannelli, Simona; Oliva, C; Conte, Pierfranco
abstract
Many hormone receptor-positive tumors show primary or acquired resistance, possibly because of a crosstalk with other growth factor-related transduction pathways (mainly epidermal growth factor receptor family related). The LETLOB study is a European multicenter, placebo-controlled, randomized phase II trial in postmenopausal patients with hormone-sensitive, HER2-negative, stage II-IIIA (T > 2 cm, N0-1, M0) breast cancer, in which letrozole or the combination of letrozole plus lapatinib will be administered for 6 months before surgery. Clinical endpoints (primary [ultrasonographic objective response], secondary [rate of pathologic complete response and of conservative surgery, safety, and time to treatment failure], and biologic [inhibition of intermediate and final biomarkers of the proliferative and apoptosis pathways and gene profile correlation with response]) will be evaluated
2008
- Magnetic resonance imaging and ultrasonography in predicting pathologic extent after preoperative chemotherapy in stage II-III breast cancer
[Abstract in Rivista]
Guarneri, Valentina; Pecchi, Annarita; Torricelli, Pietro; Piacentini, Federico; A., Frassoldati; C., Mauri; R., Battista; B., Canossi; D'Amico, Roberto; Conte, Pierfranco
abstract
Introduction and aims: the main advantage of preoperative chemotherapy (PCT) is tumor down-staging, that can allow either mastectomy in large, inoperable primaries, or breast conserving surgery (BCS) for patients initially candidate to mastectomy. Therefore, an accurate measurement of residual disease after PCT is critical in the optimal surgical planning. Aim of this study is to evaluate the accuracy of breast magnetic resonance imaging (MRI) and ultrasonography (USG) in predicting the extent of breast residual disease.
Patients and Methods: patients with stage II-III invasive breast tumor receiving PST and imaged with post-treatment MRI, USG or both were included; deltas were calculated as differences between the longest tumor diameter as measured by MRI and USG and the pathologic size of residual breast tumor. Differences between deltas were tested by using T test for paired data.
Results: 45 patients treated with PCT in our Institution were eligible. Patients characteristics were as follows: mean age 50 yrs (range 30-70 yrs); stage IIA 31%, IIB 49%, IIIA-B: 20%. Eighty-nine % of the cases had ductal histology, 69% had ER positivity, and 24% had HER2 over-expression. The mean T size at diagnosis was 3.8 cm (range 1.5-8 cm). PCT type was anthracycline-based (24%) or anthracycline-taxane combination (76%). Forty-four patients have been evaluated after PCT by MRI, 41 by USG, 40 patients by both MRI and USG. The mean T size (range) after PCT was 2 cm (0-6.5 cm) and 1.7cm (0-5cm) as measured by MRI and USG respectively. The mean interval between breast imaging and surgery was 20 days (range 1-63). Type of surgery was mastectomy in 45% and BCS in 55% of the cases; 6 patients (13%) achieved a pathologic complete response (pCR). The mean pathologic T size was 1.98 cm (range 0-6 cm). The mean of the deltas were 0.04 (SD 1.91) and -0.19 (SD 1.53) for MRI and USG respectively (p=0.22). A complete response by MRI was observed in 9 cases: 3 cases were confirmed as pCRs; 2 cases presented with scattered microscopic residual disease. An USG complete response was observed in 8 cases (4 confirmed pCRs).
Conclusion: in this series of patients, MRI and USG do not show significant differences in predicting the breast residual tumor after PCT. The major challenge for breast imaging after PCT is represented by scattered residual disease.
2008
- Phase II, randomized trial of preoperative epirubicin-paclitaxel +/- gefitinib with biomarker evaluation in operable breast cancer.
[Articolo su rivista]
Guarneri, Valentina; Frassoldati, A.; Ficarra, G.; Puglisi, F.; Andreetta, C.; Michelotti, A.; Cresti, N.; Boni, C.; Bisagni, G.; Berardi, R.; Battelli, N.; Santoro, A.; Banna, G.; Bottini, A.; DI BLASIO, B.; Maiorana, Antonino; Piacentini, Federico; Giovannelli, Simona; Jovic, Gordana; Conte, Pierfranco
abstract
PURPOSE: To evaluate the in vivo effect of adding gefitinib to preoperative chemotherapy on the EGFR-dependent p42/44 MAPK in operable breast cancer (BC) patients. Secondary aims: to evaluate EGFR, (p)-EGFR, Ki67, apoptotic index (TUNEL test) and VEGFR2 expression from baseline to surgery, percentage of pathologic complete response (pCR), and toxicity. PATIENTS AND METHODS: 90 patients with stage II-IIIA BC have been randomized to receive epirubicin 90 mg/sqm and paclitaxel 175 mg/sqm on day 1 plus: gefitinib 250 mg daily from day 5 to 16 (Arm A, intermittent), gefitinib 250 mg daily from day 1 to 21 (Arm B, continuous), or placebo (Arm C). Treatment plan: 4 courses every 3 weeks, followed by surgery. RESULTS: After preoperative therapy, 86/90 patients underwent surgery; 46 patients (51%) received breast conservative surgery. A pCR was observed in 4 patients. No significant differences in the expression of p42/44 MAPK, EGFR, (p)-EGFR, VEGFR2, proliferation index and apoptosis were observed comparing the combined Arms A + B vs C, and comparing Arm A vs B. Hematologic toxicities were not significantly different comparing Arms A + B vs Arm C, and comparing Arm A vs B. Significantly higher skin and mucosal toxicities were observed when comparing the two gefitinib Arms (A + B) vs Arm C (32% vs 9.6%, P = 0.018; 57% vs 29%, P = 0.009 respectively), while no significant differences were observed comparing Arm A vs B. CONCLUSION: Adding gefitinib to chemotherapy did not result in different effects on the EGFR-dependent pathway, proliferation, apoptosis and VEGFR2 expression as compared to placebo, while enhancing skin and mucosal toxicity. The two schedules of gefitinib (intermittent vs continuous) did not result in different biologic effects.
2008
- Preoperative chemotherapy plus lapatinib or trastuzumab or both in Her2 positive operable breast cancer. EGF109085-LAP106988/CHERLOB Trial.
[Articolo su rivista]
Guarneri, Valentina; Frassoldati, A; Piacentini, Federico; Jovic, Gordana; Giovannelli, Simona; Oliva, C; Conte, Pierfranco
abstract
Randomised phase II trial of chemotherapy plus trastuzumab, lapatinib or both in HER2 positive operable breast cancer. 120 patients will be randomised. Primary end point is pCR; secondary end points safety and biomarker expression before and after therapy.
2008
- Progress in the treatment of Early and Advanced Breast Cancer
[Capitolo/Saggio]
Guarneri, Valentina; Piacentini, Federico; Conte, Pierfranco
abstract
Breast cancer represents a major health problem with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade , in spite of increasing incidence, breast cancer mortality is declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments.
The better knowledge of breast cancer biology allows nowadays to spare the cosmetic, physical and psychological consequences of radical mastectomy to the majority of breast cancer patients. The sentinel node technique is rapidly expanding and will further reduce the extent and the consequences of surgery.
Several clinical and pathologic factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse and international guidelines have been established to help clinicians to choose the appropriate postoperative treatments. Nodal status, tumor size, tumor grade, age, HER2 expression are universally accepted as important factors to define risk categories. Newer factors such as uPA/PAI-1, cyclin-E and other proliferative indices and gene expression profile are promising and will allow a better discrimination between patients at different risk. Their generalized use is however not yet recommended because of lack of reproducibility, necessity of fresh tumor samples, limited data and follow up. Endocrine manipulation with tamoxifen, ovarian ablation or aromatase inhibitors is the preferred option in case of endocrine-responsive tumors. Tamoxifen administered for five years has been considered for may years the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen with a different safety profile. At present time aromatase inhibitors represents the preferred option for postmenopausal patients.
Chemotherapy is the treatment of choice in case of steroid receptor negative tumors. Polychemotherapy is superior to single agents and anthracycline containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four CMF are the recommended regimens.
New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. These agents are currently approved for adjuvant therapy in US and European Countries.
Chemotherapy followed by endocrine therapy represents the standard adjuvant treatment of high risk patients with endocrine responsive tumors. For Her2-neu overexpressing tumors, the addition of trastuzumab, a monoclonal antibody directed against the extra-membrane portion of the Her2 receptor, significantly reduced the risk of recurrence and death.
Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer. The upfront administration of chemotherapy significantly increases the rate of breast conserving surgery and allows an in vivo chemosensitivity testing. A proportion of patients achieve a pathologic complete response and these patients have significantly better long term outcomes.
Twenty-five to forty% of breast cancer patients eventually develop distant metastases. At this stage the disease is incurable, however treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In case of hormone receptor positivity and in the absence of visceral, life threatening disease endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure antiestrogens and progestins. Aromatase inhibitors are the most active agents, however the choice and the sequence of endocrine therapies is also dictated by prior adjuvant treatment. Chemotherapy
2008
- VALORE PROGNOSTICO E PREDITTIVO DI p53 NEL CARCINOMA MAMMARIO TRATTATO CON CHEMIOTERAPIA NEOADIUVANTE
[Abstract in Atti di Convegno]
Piacentini, F.; Guarneri, V.; Ficarra, G.; Frassoldati, A.; D’Amico, R.; Giovannelli, S.; Maiorana, A.; Conte, Pf.
abstract
Introduzione: p53 gioca un ruolo chiave nel meccanismo di risposta della cellula a vari stress: agendo infatti come fattore di trascrizione multifunzionale, regola una serie di geni implicati nella proliferazione cellulare, apoptosi, angiogenesi e riparo di danni al DNA. Una sua mutazione si verifica in una minoranza di carcinomi mammari, mentre in altri casi sono le alterazioni dei geni target o di altri componenti regolatori a ridurre in qualche modo la capacità di p53 di reagire agli insulti cellulari. L’espressione di p53 descritta dall’immunoistochimica non necessariamente correla con le possibili mutazioni di questa oncoproteina. Il potere predittivo e prognostico di p53 nel carcinoma mammario rimane dibattuto.
Pazienti e metodi: sono state incluse nella presente analisi pazienti con carcinoma mammario in stadio I-III trattate con chemioterapia primaria (TP). Sono stati valutati con metodica ICH i seguenti parametri: ER, PgR, HER2, Ki-67/MIB1, p53, EGFR.
Risultati: sono state analizzate 91 pazienti, età mediana (range): 52 anni (29-73). Le caratteristiche biologiche alla diagnosi bioptica sono risultate le seguenti: recettori ormonali (ER e/o PgR) positivi, 78%; HER2+, 22%; grado 3, 57%; EGFR >/= 1%, 11%. Nel 42% dei casi si è osservata una iperespressione di p53 >/=10%. Le pazienti hanno ricevuto 4-6 cicli di TP (45% antraciclina-based; 53% antraciclina-taxani). Dopo TP, il 64% delle pazienti è stato sottoposto a mastectomia; in tutte è stata eseguita linfoadenectomia ascellare. Una risposta patologica completa (pCR) si è osservata in sei casi (6.7%). Nelle pazienti con p53>/=10% il tasso di pCR è risultato significativamente maggiore (p=0.003). p53 è stata misurata anche sul residuo tumorale dopo TP, senza osservare significative variazioni. A 5 anni la sopravvivenza libera da malattia (DFS) risulta 80% (95%CI 64;89) per le pazienti con p53 <10% e 45% (95%CI 26;62) per quelle con p53>/=10% (p=0.0018). Nei due gruppi la sopravvivenza globale (OS) a 5 anni è pari a 98% (95%CI 87;99) e a 53% (95%CI 32;91) rispettivamente (p<0.001). In analisi multivariata, le pazienti con p53>/=10% e linfonodi positivi dopo TP hanno un maggior rischio di recidiva (HR 2.93, p=0.003 e HR 3.07, p=0.022, rispettivamente).
Conclusioni: nella presente analisi, l’iperespressione di p53 si è dimostrata predittiva di risposta alla TP; in particolare il tasso di pRC è risultato significativamente più elevato nei casi con p53>/=10% alla diagnosi. Tuttavia, l’overespressione di p53 è risultato un fattore prognostico negativo, sia in termini sia di DFS che di OS. Sono in corso ulteriori analisi che permetteranno, ampliando la casistica, di chiarire l’implicazione clinica di questi dati.
2007
- CHER-LOB: PREOPERATIVE CHEMOTHERAPY PLUS TRASTUZUMAB, LAPATINIB OR BOTH IN HER2-POSITIVE OPERABLE BREAST CANCER – PRELIMINARY SAFETY REPORT WITH FOCUS ON CARDIAC TOLERABILITY
[Poster]
Guarneri, V.; Frassoldati, A.; Cagossi, K.; Bottini, A.; Cavanna, L.; Michelotti, A.; Jovic, G.; Piacentini, F.; Oliva, C.; Conte, Pf.
abstract
Introduction and aims: This is a phase IIb randomized trial evaluating activity and safety of chemotherapy (CT) plus trastuzumab (T), lapatinib (L), or the combination of T+L as preoperative therapy for HER2+ operable breast cancer (BC). Primary endpoint: %of pCR. Secondary aims: breast objective response, breast conservative surgery, safety, molecular responses, gene expression related to pCR.
Patients and methods: patients with HER2+ stage II-IIIA BC are randomized to: Arm A: CT+T; Arm B: CT+L; Arm C: CT+T+L. CT consists in: paclitaxel (P) 80 mg/m2 wkly for 12 wks, followed by 4 courses of FEC (5FU 600 mg/m2 + Epirubicin 75 mg/m2 + Cyclophosphamide 600 mg/m2 iv) q3wks. T is administered at 2 mg/kg wkly in arms A and C; L is administered at 1500 mg po daily in arm B, and at 1000 mg po daily in arm C. T and L are administered throughout the duration of CT (26wks).
Sample size: assuming a 50% increase in the pCR rate for the CT+T+L arm vs CT+T or CT+L, in the first stage 52 patients will be enrolled; in case we observe 16 pCR, additional 68 patients will be enrolled, for a total of 120 patients (Simon’s design). Left ventricular ejection fraction (LVEF) is evaluated at baseline, prior to start FEC, and at the completion of treatment. The first IDMC evaluation of the protocol cardiac safety is pre-planned after the first 15 evaluable pts.
Results 13 patients have been randomized: 4 in Arm A, 4 in Arm B, and 5 in Arm C. A total of 101 doses of wkly P +T, L or T+L, and 19 courses of FEC+T, L or T+L are evaluable. No G2-4 hematologic toxicity has been reported during P+ T, L or T+L; G3-4 neutropenia occurred in 42% of FEC+T, L or T+L cycles. Non-hematologic toxicity reported in >5% of the P+ T, L or T+L cycles were: G1 diarrhea (19%), G2 rash (6%), and G1 neurotoxicity (9%). Non-hematologic toxicity reported in >5% of the FEC + T, L or T+L cycles were: G1/2 nausea/vomiting (53%), G1 diarrhea (5%), G1 stomatitis (5%). The mean LVEF was 62.7% (range 54-74%) at baseline, and 62.2% (60-71%) after 12 wks of P + T, L or T+L.
Conclusions These very preliminary data are encouraging regarding the safety of these combinations. Updated results will be presented at the Meeting. Supported by GlaxoSmithKline
2007
- LAPATINIB IN ASSOCIAZIONE A CAPECITABINA IN PAZIENTI CON CARCINOMA MAMMARIO METASTTICO HER2 POSITIVO IN PROGRESSIONE DOPO TERAPIA CON TRASTUZUMAB
[Abstract in Atti di Convegno]
Giovannelli, S.; Bengala, C.; Grisolia, D.; Frassoldati, A.; Piacentini, F.; Guarneri, V.; Sabbatini, R.; Ferrari, A.; Conte, Pf.
abstract
NA
2007
- LET-LOB: preoperative letrozole plus lapatinib or placebo in hormone-receptor positive HER2 negative operable breats cancer. Preliminary report of activity and cardiac tolerability
[Abstract in Rivista]
Frassoldati, A; Guarneri, Valentina; Cagossi, K.; Bottini, A; Cavanna, L; Jovic, Gordana; Piacentini, Federico; Oliva, C; Conte, Pierfranco
abstract
The crosstalk between hormone- and EGFR-family pathways is considered a possible cause of hormone-resistance. To evaluate the effects of a combined blockade of these two pathways, we activated an international multicentre phase IIb double blind randomized trial in neoadjuvant setting.
2007
- Preliminary safety data of preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2-positive operable breast cancer
[Abstract in Rivista]
Guarneri, Valentina; Frassoldati, A; Piacentini, Federico; Cagossi, K; Cavanna, L; Michelotti, A; Jovic, Gordana; Giovannelli, Simona; Ficarra, G; Oliva, C; Conte, Pierfranco
abstract
Introduction and aims: Lapatinib (L) is a TKI of EGFR and HER2. The inhibition of these two pathways can affect tumor growth by reducing the EGFR-dependent proliferative stimulus, by restoring apoptosis, and possibly by enhancing sensitivity to chemotherapy (CT). On these premises, the combination of L with CT or CT and trastuzumab (T) is promising. We have therefore designed a phase II randomized trial to evaluate activity and safety of this combination as preoperative therapy for HER2+ operable breast cancer (BC). Primary endpoint: %of pCR. Secondary aims: breast objective response, breast conservative surgery, safety, molecular responses, gene expression related to pCR.
Patients and methods: After a core biopsy for diagnosis, biomarker evaluation and storage of fresh tissue for molecular analyses, patients with HER2+ stage II-IIIA BC are randomized to: Arm A: CT+T; Arm B: CT+L; Arm C: CT+T+L. CT consists in: paclitaxel 80 mg/sqm wkly for 12 wks, followed by 4 courses of FEC (5FU 600 mg/smq + Epirubicin 75 mg/sqm + Cyclophosphamide 600 mg/sqm iv) q3wks. T is administered at the dose of 2 mg/kg wkly in arms A and C; L is administered at 1500 mg po daily in arm B, and at 1000 mg po daily in arm C. Both T and L are administered throughout the duration of CT. The following biomarkers are evaluated at baseline, and at surgery: EGFR, HER2, pTEN, pAKT, pMAPK, Apoptosis (TUNEL Test), Ki67.
Sample size: assuming a 50% increase in the pCR rate for the CT+T+L arm vs CT+T or CT+L, in the first stage 52 patients will be enrolled; in case we observe 16 pCR, additional 68 patients will be enrolled, for a total of 120 patients (Simon’s design).
Results 12 patients have been randomized so far. Preliminary safety data will be presented at the meeting.
2007
- PROLIFERATION AND APOPTOSIS BEFORE AND AFTER PRIMARY SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER
[Abstract in Atti di Convegno]
Guarneri, V.; Piacentini, F.; Frassoldati, A.; Ficarra, G.; Jovic, G.; Pugliesi, F.; Michelotti, A.; Bisagni, G.; Berardi, R.; Conte, Pf.
abstract
Background: The identification of biological markers able to predict tumor sensitivity to primary systemic therapy (PST) may have an important clinical output. Moreover, the effect of treatment on these biomarkers might have prognostic relevance. Aims of this analysis: to evaluate the predictive role of proliferation (Ki-67), apoptotic index (AI) and growth index (GI) before PST, the effect of PST on these parameters and their relation with tumor response and patients outcome.
Methods: Ki-67, AI (Tunel Test), and GI were assessed at baseline and at surgery in 90 stage II-IIIB breast cancer patients enrolled in a phase II randomized trial of PST with 4 cycles of epirubicin-paclitaxel +/- gefitinib. Pathologic response was defined as tumor regression grade (TRG) (criteria of Miller and Payne).
Results: patients characteristics were as follows: median age, 51 yrs (range 29-69); stage IIA 41%, IIB-IIIA 59%. A significant correlation between Ki-67 and AI was found at baseline (p=0.001). A significantly higher Ki-67 and AI were observed in ER- vs ER+ tumors (median Ki-67: 62% vs 25%, p<0.0001; median AI: 1.33 vs 0.85, p=0.009). A significantly higher Ki-67 and GI were observed in EGFR+ vs EGFR- tumors (median Ki-67: 60% vs 25%, p=0.0006; median GI: 48 vs 30.7, p=0.03). No significant differences were observed according to HER2 expression. After PST, 84% of pts was classified as having a TRG 4 or 5, and 16% as having a TRG 1-3. No significant correlation among baseline Ki-67, AI and GI and TRG was observed. After PST, Ki 67 and AI were significantly reduced from baseline. Lower Ki 67 and lower AI were significantly correlated with higher TRG (p=0.008 and 0.01 respectively). We observed 1 cancer death and 5 relapses only, therefore correlation with patient outcome has been planned for the time of the meeting
Conclusions: ER- and EGFR+ tumors show more aggressive behaviour. PST significantly reduces Ki-67 and AI, and this reduction is significantly correlated with TRG. In particular, the reduced AI at surgery was not found to be a marker of resistance, more probably reflecting the reduced Ki-67 of responding tumors.
2007
- SVILUPPO DI IPOGAMMAGLOBULINEMIA IN PAZIENTI TRATTATI CON IMATINIB PER LEUCEMIA MIELOIDE CRONICA O TUMORI STROMALI GASTROINTESTINALI
[Abstract in Atti di Convegno]
Santachiara, R.; Leonardi, G.; Vallisa, D.; Maffei, R.; Martinelli, S.; Ferrari, A.; Alfieri, P.; Luppi, G.; Bertolini, F.; Piacentini, F.; Marasca, R.; Torelli, G.
abstract
NA
2006
- Biomarker expression and survival after primary chemotherapy for breast cancer.
[Abstract in Rivista]
Guarneri, Valentina; Piacentini, Federico; Jovic, Gordana; Frassoldati, A; Ficarra, G; Giovannelli, Simona; Maur, M; Borghi, F; Vicini, Roberto; Conte, Pierfranco
abstract
Purpose: Preoperative chemotherapy (PCT) allows for a direct assessment of treatment effects on the tumor and its microenvironment. Aims of this analysis: to evaluate the correlation of biomarker expression with responses in breast cancer patients treated with PCT; to evaluate treatment induced modification in the biomarker expression and its relation with outcome.
Patients and Methods: 189 stage II-IIIB breast cancer patients were evaluated. The following parameters were assessed at baseline, and, after 3-4 courses of PCT, at surgery: ER, PgR, grading, HER2, Ki-67, p53, EGFR and VEGFR. PCT regimens: anthracycline-based (16%) or anthracycline-taxane (84%) combinations.
Results: Patients characteristics were as follows: median age 51 yrs (range: 27-73); clinical stage: IIA-IIB 78.5%, IIIA-IIIB: 21.5%; ER and/or PgR positivity: 77%; grade 3: 58.5%, HER2 positivity: 20%.The ORR (CR+PR) was 70.6%; 39% of patients underwent conservative surgery, and a pCR (breast and axillary lymph-nodes) was observed in 8.3% of patients. The probability of pCR was significantly associated with ER status ( ER+: 3% vs ER-: 20%, p=0.005), and with grade (grade 3: 14% vs grade 1-2: 2%, p=0.049). Median biomarker expression at baseline: ER 62.5%, PgR 9%, Ki-67 25%, p53 2%, EGFR 0%, VEGFR 2%. Median expression after PCT: ER 60% , PgR 3%, Ki-67 15%, p53 4%, EGFR 0%, VEGFR 0%.The differences in biomarker expression before and after PCT were evaluated with the Wilcoxon matched pairs signed rank test: a significant reduction in the expression of PgR (p=0.017), Ki-67 (p<0.0001), and VEGFR (p=0.006) was observed. Baseline Ki67 < 15% predicts a better DFS while ER positivity and p53 <10% predict prolonged OS. After PCT, Ki67>15% and VEGFR positivity are associated with a significantly shorter DFS.
Conclusions: In this series of patients, PCT induced a significant reduction of Ki-67 and of the expression of PgR and VEGFR. Treatment-induced modulation of ki67 and VEGFR can be helpful to select patients with different risk of relapse after PCT
2006
- CARCINOMI MAMMARI HER2 POSITIVI: CASISTICA DI MODENA
[Abstract in Atti di Convegno]
Giovannelli, S.; Guarneri, V.; Ficarra, G.; Frassoldati, A.; Ferrari, Alessia; Piacentini, F.; Maiorana, A.; Conte, P. F.
abstract
NA
2006
- CHEMOTHERAPY-INDUCED MODULATION OF BIOMARKERS EXPRESSION IN PRIMARY BREAST CANCER PATIENTS TREATED WITH PREOPERATIVE CHEMOTHERAPY
[Relazione in Atti di Convegno]
Guarneri, V.; Piacentini, F.; Frassoldati, A.; Jovic, G.; Ficarra, G.; Maur, M.; Giovannelli, S.; Giardina, D.; Conte, P. F.
abstract
NA
2006
- MODULAZIONE DELL’ESPRESSIONE DI BIOMARCATORI E PROGNOSI IN PAZIENTI AFFETTE DA CARCINOMA MAMMARIO OPERABILE SOTTOPOSTE A CHEMIOTERAPIA PREOPERATORIA
[Abstract in Atti di Convegno]
Guarneri, Valentina; Piacentini, F.; Jovic, G.; Frassoldati, A.; Ficarra, G.; Maiorana, A.; Giovannelli, S.; Tazzioli, G.; Natalizi, G.; Mauri, C.; Battista, R.; Canossi, B.; Conte, P. F.
abstract
Obiettivi. La terapia preoperatoria (TP) offre l’opportunità di valutare in vivo l’effetto del trattamento sul tumore e sul suo microambiente. Questa analisi si propone di correlare l’espressione di una serie di biomarcatori cellulari alla risposta dopo TP e di valutare l’effetto della TP sull’espressione di tali biomarkers (ed il loro significato prognostico).
Pazienti e metodi. Sono state incluse 189 pazienti (pz.) con diagnosi di carcinoma mammario in stadio II-IIIB all’esordio e trattate con TP (antracicline e taxani nel 84% dei casi). I seguenti biomarcatori sono stati valutati sul prelievo bioptico (basale) e, dopo 3-4 cicli di TP, sul pezzo operatorio: RE, RPg, grading, HER2, Ki-67, p53, EGFR e VEGFR.
Risultati. Caratteristiche delle pz. Età mediana alla diagnosi: 51 anni (27-73 anni); stadio clinico: IIA-B 78%, IIIA-B 22%; RE+ e/o RPg+: 77%; HER2+: 20%; grado istologico 3: 58%. Una risposta obiettiva si è osservata nel 70% dei casi; il 39% delle pz. si è sottoposta a chirurgia conservativa. Una risposta patologica completa (pRC) si è ottenuta nel 8.3% dei casi. La probabilità di ottenere una pRC è risultata significativamente maggiore nelle pz. con RE- rispetto a quelle con RE+ (20% vs 3%, p=0.005) e con grado istologico 3 verso 1-2 (14% vs 2%, p=0.049). L’espressione mediana dei biomarcatori al basale è risultata: RE 62.5%, RPg 9%, Ki-67 25%, p53 2%, EGFR 0%, VEGFR 2%. L’espressione mediana dopo TP è risultata: RE 60%, RPg 3%, Ki-67 15%, p53 4%, EGFR 0%, VEGFR 0%. La differenza nell’espressione dei biomarcatori prima e dopo TP è stata valutata con il Wilcoxon-matched- pairs-signed-rank-test: si è osservata una riduzione significativa nell’espressione di RPg (p=0.017), Ki-67 (p<0.0001) e VEGFR (p=0.006). Una migliore sopravvivenza libera da malattia (DFS) si è osservata nelle pz. con Ki-67<15% al basale; una migliore sopravvivenza globale si è osservata nelle pz. con ER+ e con p5310% al basale. Dopo TP, il Ki-67 >15% e la positività per il VEGFR predicono una ridotta DFS.
Conclusioni. In questa casistica, la TP induce una significativa riduzione di Ki-67 e dell’espressione di RPg e VEGFR. La modulazione di Ki-67 e di VEGFR indotta dal trattamento può rivelarsi utile per selezionare pazienti a diverso rischio di ripresa di malattia dopo TP.
2006
- RISULTATI DELLA RADIOTERAPIA PANENCEFALICA (WBRT) NELLE METASTASI CEREBRALI DA CARCINOMA DELLA MAMMELLA: STUDIO RETROSPETTIVO SUL RUOLO PROGNOSTICO DEI FATTORI BIOLOGICI
[Abstract in Atti di Convegno]
Antognoni, P.; Tolento, G.; Bertoni, F.; Falchi, A. M.; Giacobazzi, P.; Parmiggiani, M.; Pratissoli, S.; Ramundo, Dafne; Vicari, A.; Maur, M.; Piacentini, F.
abstract
NA
2006
- VALUTAZIONE DEL RISCHIO DI TOSSICITA’ CARDIACA DI TRASTUZUMAB IN PAZIENTI AFFETTE DA CARCINOMA MAMMARIO IN TRATTAMENTO ADIUVANTE
[Abstract in Atti di Convegno]
Piacentini, F.; Guarneri, V.; Barbieri, E.; Frassoldati, A.; Giovannelli, S.; Conte, P. F.
abstract
Introduzione e obiettivi. Trastuzumab è un anticorpo monoclonale IgG1 umanizzato ricombinante contro HER2; rappresenta un componente essenziale nel trattamento del carcinoma mammario che iperesprime tale recettore. Il suo impiego può però comportare una riduzione subclinica della funzionalità cardiaca e, più raramente, scompenso cardiaco sintomatico. Questa analisi si propone di valutare la funzionalità cardiaca in pazienti (pz.) affette da carcinoma mammario HER2 + in trattamento adiuvante con trastuzumab.
Pazienti e metodi. Sono state incluse 20 pz. con diagnosi di carcinoma mammario in stadio I-IIIB all’esordio. Lo schema di trattamento prevede la somministrazione, a completamento di un programma di chemioterapia (CT) adiuvante o neoadiuvante, di trastuzumab 6 mg/kg ogni 3 settimane per un anno. La funzionalità cardiaca è stata valutata mediante la misurazione ecocardiografica della frazione di eiezione ventricolare (FE) prima dell’inizio del trattamento con trastuzumab e, successivamente, ogni tre mesi. I criteri per definire un evento cardiaco sono i seguenti: 1) calo della FE al di sotto del 50%; 2) decremento di 20 punti percentuali della FE rispetto al valore basale; 3) segni o sintomi di scompenso cardiaco congestizio.
Risultati. L’età mediana delle pz. è pari a 53 anni (range 31-70 anni). Tutte le pz. hanno ricevuto un regime a base di epirubicina (dose cumulativa mediana 355 mg/m2: range 75-540 mg/m2) prima del trastuzumab, nel 70% dei casi in combinazione con taxani. Il tempo mediano intercorso tra l’ultima somministrazione di antraciclina e l’inizio di trastuzumab è stato di 2,7 mesi (range 0.8-7.8 mesi). 18 pz. sono attualmente in corso di terapia. Tutte le pz. avevano normale FE prima di iniziare trastuzumab (FE mediana 60%: range 55-70%); a 3 e a 6 mesi di distanza la FE mediana si è mantenuta invariata. Non si sono verificati eventi cardiaci.
Conclusioni. Seppur in una casistica limitata, questa analisi conferma che il trattamento con trastuzumab in pz. prive di preesistenti alterazioni della funzionalità cardiaca non comporta tossicità di rilievo; in particolare la precedente esposizione ad epirubicina alla dose cumulativa standard nei regimi chemioterapici non sembra potenziare la cardiotossicità di trastuzumab.
2005
- IMPROVED SURVIVAL AFTER RADIOTHERAPY FOR BRAIN METASTASES IN PATIENTS WITH HER2 POSITIVE BREAST TUMORS
[Abstract in Atti di Convegno]
Maur, M.; Frassoldati, A.; Piacentini, F.; Ramundo, D.; Sabbatini, R.; Giovannelli, S.; Ficarra, G.; Bertolini, F.; Falchi, Am.; Conte, Pf.
abstract
NA
2005
- Varicella zoster virus reactivation in patients with breast cancer and multiple myeloma after autologous stem cell transplantation
[Abstract in Rivista]
Maur, M; Sabbatini, R; Cuoghi, A; Cafarelli, L; Dominici, Massimo; Piacentini, Federico; Giovannelli, S; Conte, Pierfranco
abstract
not available
2004
- LOCAL RECURRENCE AFTER NEO-ADJUVANT CHEMOTHERAPY AND BREAST CONSERVING SURGERY
[Abstract in Rivista]
Maur, M.; Frassoldati, A.; Piacentini, F.; Sabbatini, R.; Nicolini, Massimiliano; D’Ambrosio, C.; Conte, P. F.
abstract
This study describes our experience with adjuvant chemo-hormonal therapy in male
breast cancer (MBC). A retrospective review of all MBC patients referred to our
institution between 1991 and 2003 was conducted.
Twenty-four men were diagnosed with a breast ductal carcinoma; 20/24 pts had
invasive carcinoma; 2/24 were metastatic (lung metastasis; supraclavicular lymph
node involvement). All pts underwent radical mastectomy with axillary lymph node
dissection. Twelve pts (10 adjuvant, two metastatic) were treated with chemotherapy
(seven with anthracycline, five with CMF) and 18 pts received adjuvant hormonal
therapy (17 tamoxifen, one anastrozole). Ten pts received postoperative radiotherapy
to chest wall and axilla and/or supraclavicular site according to the guidelines of our
institution.
Median age was 59 years; median tumor size was 1.5 cm (0.5–3.5 cm). Tumors
were ER positive in 20 pts and PgR positive in 17 samples. Pathological node involvement
was seen in 10 pts and 50% of tumors were high grade. To date, 6/18 pts
with early disease relapsed. Four of six pts who relapsed had received chemotherapy
and radiotherapy; all tumors that recurred were >1 cm diameter at diagnosis
(2/6 >2 cm). The ER and PgR were positive in 4/6 and 3/6 of pts, respectively.
About 50% of cancers that recurred had a high proliferation rate. At relapse, patients
received chemotherapy with anthracycline or navelbine or taxotere in addition totrastuzumab for 1 pt with erbB2 overexpression, plus hormonal therapy. One patient
died from metastatic disease, 2 pts with metastatic disease are still alive.
Phenotypic characteristics of MBC are more similar to those of menopausal women.
Our results demonstrated a balance in the biological characterization of relapses so
we cannot draw conclusions on the benefit from different adjuvant treatments.