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ANGELA TOSS

Ricercatore t.d. art. 24 c. 3 lett. B
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

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 - Abstracts from the 55th European Society of Human Genetics (ESHG) Conference: Hybrid Posters [Abstract in Rivista]
Tenedini, Elena; Piana, Simonetta; Toss, Angela; Marino, Marco; Barbieri, Elena; Artuso, Lucia; Venturelli, Marta; Gasparini, Elisa; Dario Mandato, Vincenzo; Marchi, Isabella; Castellano, Sara; Luppi, Mario; Trenti, Tommaso; Cortesi, Laura; Tagliafico, Enrico
abstract

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 - LOW-FREQUENCY ALLELE VARIANTS IN NGS MULTI-GENE PANELS FOR HEREDITARY CANCER TESTING: ARTIFACTS, CHIP OR MOSAICS? MANAGING THE RESULTS IN THE LABORATORY ROUTINE [Abstract in Rivista]
Tenedini, E.; Bonamici, L.; Artuso, L.; Marino, M.; Botticelli, L.; Barbieri, E.; Toss, A.; Venturelli, M.; Trenti, T.; Dominici, M.; Cortesi, L.; Tagliafico, E.
abstract

2023 - Management of PALB2-associated breast cancer: A literature review and case report [Articolo su rivista]
Toss, Angela; Ponzoni, Ornella; Riccò, Beatrice; Piombino, Claudia; Moscetti, Luca; Combi, Francesca; Palma, Enza; Papi, Simona; Tenedini, Elena; Tazzioli, Giovanni; Dominici, Massimo; Cortesi, Laura
abstract

Key Clinical Message Germline pathogenic variants (PV) of the PALB2 tumor suppressor gene are associated with an increased risk of breast, pancreatic, and ovarian cancer. In previous research, PALB2-associated breast cancer showed aggressive clinicopathological phenotypes, particularly triple-negative subtype, and higher mortality regardless of tumor stage, type of chemotherapy nor hormone receptor status. The identification of this germline alteration may have an impact on clinical management of breast cancer (BC) from the surgical approach to the systemic treatment choice. We herein report the case of a patient with a germline PV of PALB2, diagnosed with locally advanced PD-L1 positive triple-negative BC, who progressed after an immune checkpoint inhibitor (ICI)-containing regimen and then experienced a pathologic complete response after platinum-based chemotherapy. This case report hints a major role of the germline PALB2 alteration compared to the PD-L1 expression as cancer driver and gives us the opportunity to extensively review and discuss the available literature on the optimal management of PALB2-associated BC. Overall, our case report and review of the literature provide additional evidence that the germline analysis of PALB2 gene should be included in routine genetic testing for predictive purposes and to refine treatment algorithms.

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 - Talking about sex: erectile dysfunction in the oncology patient [Articolo su rivista]
Romeo, Marilina; Spaggiari, Giorgia; Furini, Chiara; Granata, Antonio R M; Toss, Angela; Simoni, Manuela; Santi, Daniele
abstract

: Cancer-related diagnosis and treatments can profoundly affect every aspect of an individual's life. The negative impact on the sexual sphere can manifest with onset or worsening of the most frequent male form of sexual dysfunction, that is the erectile dysfunction (ED), with an estimated incidence ranging from 40 to 100% in patients living with cancer. Cancer and ED are strictly related for many reasons. First, the psychological distress, the so-called 'Damocles syndrome', afflicting cancer patients contributes to ED onset. Second, all cancer therapies can variably lead to sexual dysfunction, even more than the disease itself, having both direct or indirect effects on sexual life. Indeed, alongside pelvic surgery and treatments directly impairing the hypothalamus-pituitary-gonadal axis, the altered personal-body-image frequently experienced by people living with cancer may represent a source of distress contributing to sexual dysfunction. It is undeniable that sexual issues are currently neglected or at least under-considered in the oncological setting, mainly due to the subjective lack of preparation experienced by healthcare professionals and to scant information provided to oncological patients on this topic. To overcome these management problems, a new multidisciplinary medical branch called 'oncosexology' was set up. The aim of this review is to comprehensively evaluate ED as an oncology-related morbidity, giving new light to sexual dysfunction management in the oncological setting.

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 - A 10-miRNA risk score-based prediction model for pathological complete response to neoadjuvant chemotherapy in hormone receptor-positive breast cancer [Articolo su rivista]
Gong, C.; Cheng, Z.; Yang, Y.; Shen, J.; Zhu, Y.; Ling, L.; Lin, W.; Yu, Z.; Li, Z.; Tan, W.; Zheng, C.; Zheng, W.; Zhong, J.; Zhang, X.; Zeng, Y.; Liu, Q.; Huang, R. S.; Komorowski, A. L.; Yang, E. S.; Bertucci, F.; Ricci, F.; Orlandi, A.; Franceschini, G.; Takabe, K.; Klimberg, S.; Ishii, N.; Toss, A.; Tan, M. P.; Cherian, M. A.; Song, E.
abstract

Patients with hormone receptor (HR)-positive tumors breast cancer usually experience a relatively low pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). Here, we derived a 10-microRNA risk score (10-miRNA RS)-based model with better performance in the prediction of pCR and validated its relation with the disease-free survival (DFS) in 755 HR-positive breast cancer patients (273, 265, and 217 in the training, internal, and external validation sets, respectively). This model, presented as a nomogram, included four parameters: the 10-miRNA RS found in our previous study, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and volume transfer constant (Ktrans). Favorable calibration and discrimination of 10-miRNA RS-based model with areas under the curve (AUC) of 0.865, 0.811, and 0.804 were shown in the training, internal, and external validation sets, respectively. Patients who have higher nomogram score (>92.2) with NAC treatment would have longer DFS (hazard ratio=0.57; 95%CI: 0.39–0.83; P=0.004). In summary, our data showed the 10-miRNA RS-based model could precisely identify more patients who can attain pCR to NAC, which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HR-positive breast cancer.

2022 - BRCA mutation carriers’ perception about benefits and risks associated with combined hormonal contraceptives use [Articolo su rivista]
Grandi, G.; Monari, F.; Boggio Sola, V.; Cortesi, L.; Toss, A.; del Savio, M. C.; Melotti, C.; Centurioni, M. G.; Gustavino, C.; Varesco, L.; Facchinetti, F.; Barra, F.
abstract

To evaluate the actual perceptions about combined hormonal contraceptives (CHCs) use in BRCA mutation carriers in comparison to women from the general population.

2022 - Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores [Articolo su rivista]
Barnes, D. R.; Silvestri, V.; Leslie, G.; Mcguffog, L.; Dennis, J.; Yang, X.; Adlard, J.; Agnarsson, B. A.; Ahmed, M.; Aittomaki, K.; Andrulis, I. L.; Arason, A.; Arnold, N.; Auber, B.; Azzollini, J.; Balmana, J.; Barkardottir, R. B.; Barrowdale, D.; Barwell, J.; Belotti, M.; Benitez, J.; Berthet, P.; Boonen, S. E.; Borg, A.; Bozsik, A.; Brady, A. F.; Brennan, P.; Brewer, C.; Brunet, J.; Bucalo, A.; Buys, S. S.; Caldes, T.; Caligo, M. A.; Campbell, I.; Cassingham, H.; Christensen, L. L.; Cini, G.; Claes, K. B. M.; Cook, J.; Coppa, A.; Cortesi, L.; Damante, G.; Darder, E.; Davidson, R.; De La Hoya, M.; De Leeneer, K.; De Putter, R.; Del Valle, J.; Diez, O.; Ding, Y. C.; Domchek, S. M.; Donaldson, A.; Eason, J.; Eeles, R.; Engel, C.; Evans, D. G.; Feliubadalo, L.; Fostira, F.; Frone, M.; Frost, D.; Gallagher, D.; Gehrig, A.; Giraud, S.; Glendon, G.; Godwin, A. K.; Goldgar, D. E.; Greene, M. H.; Gregory, H.; Gross, E.; Hahnen, E.; Hamann, U.; Hansen, T. V. O.; Hanson, H.; Hentschel, J.; Horvath, J.; Izatt, L.; Izquierdo, A.; James, P. A.; Janavicius, R.; Jensen, U. B.; Johannsson, O. T.; John, E. M.; Kramer, G.; Kroeldrup, L.; Kruse, T. A.; Lautrup, C.; Lazaro, C.; Lesueur, F.; Lopez-Fernandez, A.; Mai, P. L.; Manoukian, S.; Matrai, Z.; Matricardi, L.; Maxwell, K. N.; Mebirouk, N.; Meindl, A.; Montagna, M.; Monteiro, A. N.; Morrison, P. J.; Muranen, T. A.; Murray, A.; Nathanson, K. L.; Neuhausen, S. L.; Nevanlinna, H.; Nguyen-Dumont, T.; Niederacher, D.; Olah, E.; Olopade, O. I.; Palli, D.; Parsons, M. T.; Pedersen, I. S.; Peissel, B.; Perez-Segura, P.; Peterlongo, P.; Petersen, A. H.; Pinto, P.; Porteous, M. E.; Pottinger, C.; Pujana, M. A.; Radice, P.; Ramser, J.; Rantala, J.; Robson, M.; Rogers, M. T.; Ronlund, K.; Rump, A.; Sanchez De Abajo, A. M.; Shah, P. D.; Sharif, S.; Side, L. E.; Singer, C. F.; Stadler, Z.; Steele, L.; Stoppa-Lyonnet, D.; Sutter, C.; Tan, Y. Y.; Teixeira, M. R.; Teule, A.; Thull, D. L.; Tischkowitz, M.; Toland, A. E.; Tommasi, S.; Toss, A.; Trainer, A. H.; Tripathi, V.; Valentini, V.; Van Asperen, C. J.; Venturelli, M.; Viel, A.; Vijai, J.; Walker, L.; Wang-Gohrke, S.; Wappenschmidt, B.; Whaite, A.; Zanna, I.; Offit, K.; Thomassen, M.; Couch, F. J.; Schmutzler, R. K.; Simard, J.; Easton, D. F.; Chenevix-Trench, G.; Antoniou, A. C.; Ottini, L.
abstract

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods: 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)-negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

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 - Cancer Predisposition Genes in Adolescents and Young Adults (AYAs): a Review Paper from the Italian AYA Working Group [Articolo su rivista]
Toss, A.; Quarello, P.; Mascarin, M.; Banna, G. L.; Zecca, M.; Cinieri, S.; Peccatori, F. A.; Ferrari, A.
abstract

Purpose of Review: The present narrative systematic review summarizes current knowledge on germline gene mutations predisposing to solid tumors in adolescents and young adults (AYAs). Recent Findings: AYAs with cancer represent a particular group of patients with specific challenging characteristics and yet unmet needs. A significant percentage of AYA patients carry pathogenic or likely pathogenic variants (PV/LPVs) in cancer predisposition genes. Nevertheless, knowledge on spectrum, frequency, and clinical implications of germline variants in AYAs with solid tumors is limited. Summary: The identification of PV/LPV in AYA is especially critical given the need for appropriate communicative strategies, risk of second primary cancers, need for personalized long-term surveillance, potential reproductive implications, and cascade testing of at-risk family members. Moreover, these gene alterations may potentially provide novel biomarkers and therapeutic targets that are lacking in AYA patients. Among young adults with early-onset phenotypes of malignancies typically presenting at later ages, the increased prevalence of germline PV/LPVs supports a role for genetic counseling and testing irrespective of tumor type.

2022 - Carboplatin-paclitaxel in triple-negative metastatic breast cancer during pregnancy with neoplastic thrombosis [Articolo su rivista]
Monari, F.; Grandi, G.; Guidotti, I.; Torcetta, F.; Battista, R.; Coluccio, V.; Piombino, C.; Moscetti, L.; Neri, I.; Toss, A.
abstract

The treatment of breast cancer (BC) diagnosed during pregnancy is a challenging situation for the patient, family and healthcare providers. Here we describe the case of a 35-year-old woman diagnosed with a triple-negative breast cancer relapse during pregnancy. She previously underwent neoadjuvant chemotherapy without any response, subsequent left skin sparing mastectomy plus axillary node dissection and radiation therapy to the chest wall and supraclavicular lymph nodes. Two years later, during her first single pregnancy, the patient presented a subclavian vein thrombosis and a BC relapse to locoregional lymph nodes. At 24 weeks of gestation, a first line treatment with weekly paclitaxel and carboplatin was started. Considering the disease progression after two complete cycles of chemotherapy, the patient had an elective caesarean section at 32+6 weeks. A full-body CT-scan and a PET-scan after the delivery showed a massive neoplastic thrombosis involving the left jugular, brachiocephalic and internal mammary vein, as well the superior vena cava and the right atrium. Few data are available on platinum-based chemotherapy during pregnancy in BC patients. Nevertheless, the choice of therapy was conditioned by the previous absence of response to anthracycline and taxane. In case of BC diagnosis during pregnancy, a multidisciplinary management as in the case described is recommended to increase the chance of survival both for the patients and their babies.

2022 - Constitutional Mosaicism: A Critical Issue in the Definition of BRCA-Inherited Cancer Risk [Articolo su rivista]
Tenedini, Elena; Piana, Simonetta; Toss, Angela; Marino, Marco; Barbieri, Elena; Artuso, Lucia; Venturelli, Marta; Gasparini, Elisa; Mandato, Vincenzo Dario; Marchi, Isabella; Castellano, Sara; Luppi, Mario; Trenti, Tommaso; Cortesi, Laura; Tagliafico, Enrico
abstract

2022 - Italian pediatric and adult oncology communities join forces for a national project dedicated to adolescents and young adults with cancer [Articolo su rivista]
Ferrari, A.; Quarello, P.; Mascarin, M.; Luigi Banna, G.; Toss, A.; Sironi, G.; Zecca, M.; Cinieri, S.; Alessandro Peccatori, F.
abstract

Adolescents and young adults with cancer have substantially different clinical and psychological needs compared to those of pediatric patients and of older adult patients. We describe the development of an Italian national project dedicated to adolescents and young adults with cancer.

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 - 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.

2021 - Automated capture-based NGS workflow: one thousand patients experience in a clinical routine framework [Articolo su rivista]
Tenedini, E; Celestini, F; Iapicca, P; Marino, M; Castellano, S; Artuso, L; Biagiarelli, F; Cortesi, L; Toss, A; Barbieri, E; Roncucci, L; Pedroni, M; Manfredini, R; Luppi, M; Trenti, T; Tagliafico, E
abstract

Objectives: The Next Generation Sequencing (NGS) based mutational study of hereditary cancer genes is crucial to design tailored prevention strategies in subjects with different hereditary cancer risk. The ease of amplicon-based NGS library construction protocols contrasts with the greater uniformity of enrichment provided by capture-based protocols and so with greater chances for detecting larger genomic rearrangements and copy-number variations. Capture-based protocols, however, are characterized by a higher level of complexity of sample handling, extremely susceptible to human bias. Robotics platforms may definitely help dealing with these limits, reducing hands-on time, limiting random errors and guaranteeing process standardization.Methods: We implemented the automation of the CE-IVD SOPHiA Hereditary Cancer Solution (TM) (HCS) libraries preparation workflow by SOPHiA GENETICS on the Hamilton's STARlet platform. We present the comparison of results between this automated approach, used for more than 1,000 DNA patients' samples, and the performances of the manual protocol evaluated by SOPHiA GENETICS onto 240 samples summarized in their HCS evaluation study.Results: We demonstrate that this automated workflow achieved the same expected goals of manual setup in terms of coverages and reads uniformity, with extremely lower standard deviations among samples considering the sequencing reads mapped onto the regions of interest.Conclusions: This automated solution offers same reliable and affordable NGS data, but with the essential advantages of a flexible, automated and integrated framework, minimizing possible human errors and depicting a laboratory's walk-away scenario.

2021 - Automation of a capture-based NGS workflow: one thousand patients experience in a diagnostic clinical routine framework [Abstract in Rivista]
Tenedini, E.; Celestini, F.; Iapicca, P.; Marino, M.; Castellano, S.; Artuso, L.; Biagiarelli, F.; Cortesi, L.; Toss, A.; Barbieri, E.; Roncucci, L.; Pedroni, M.; Manfredini, R.; Luppi, M.; Trenti, T.; Tagliafico, E.
abstract

2021 - BRCA mutation carriers' perceptions on postmenopausal hormone therapy: An Italian study [Articolo su rivista]
Grandi, Giovanni; Boggio Sola, Valentina; Cortesi, Laura; Toss, Angela; Giuliani, Giulia Andrea; Del Savio, Maria Chiara; Facchinetti, Fabio
abstract

Objective To evaluate the actual perceptions of postmenopausal hormone therapy (HT) in BRCA mutation carriers (BRCAmc) in comparison with women from the general population.Methods Questionnaire-based study of 83 BRCAmc and a control group of 89 women without a genetic mutation. Perceptions were evaluated by specific questions and Likert scales (-5-+5).Results Present and past users of HT were more frequent in the control group (p = 0.01), with a longer time of use (p = 0.03). The preferred route of administration of HT was 'oral' (54.6%). The most frequently reported adverse effect of HT was venous thrombosis (0.8), while a protective effect on bone health was reported. No noticeable beneficial effects of HT have been recognised for hot flushes (0.2) and vaginal dryness (0.1). The most frequently perceived beneficial and adverse effects of HT were not significantly different between BRCA mutation carriers and controls. The greatest oncological fear was breast cancer (1.0). The protective role of HT on colorectal cancer was not known (0.1). These oncological impacts were mostly overestimated in BRCAmc, however this was not significant. Few BRCAmc would think of taking HT after risk-reducing surgeries.Conclusions Knowledge of the effects of HT on BRCAmc is relatively poor and they are likely to overstate its negative effects and underestimate its health benefits; however, this is not significant in comparison to the general population. More and better information should be given to BRCAmc to allow them to make informed decisions about the use of HT, especially before undergoing risk-reducing surgeries.

2021 - BRCA mutation rate and characteristics of prostate tumor in breast and ovarian cancer families: analysis of 6,591 Italian pedigrees [Articolo su rivista]
Cortesi, L.; Domati, F.; Guida, A.; Marchi, I.; Toss, A.; Barbieri, E.; Marcheselli, L.; Venturelli, M.; Piana, S.; Cirilli, C.; Federico, M.
abstract

Objective: As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selection criteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associated with breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcome among BRCA1 and BRCA2 carriers. Methods: Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovarian cancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. The characteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ2) test and Kaplan-Meier methods, respectively. Results: Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modena selection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positive for BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis and in the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fell in the prostate cancer cluster region (PCCR) at the 3′ terminal of the 7914 codon. Conclusions: It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancer and PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.

2021 - CLINICAL AND PATHOLOGICAL FEATURES OF BREAST CANCER IN PATIENTS WITH SYSTEMIC SCLEROSIS: PRELIMINARY DATA FROM THE SCLERO-BREAST STUDY [Abstract in Rivista]
Toss, Angela; Spinella, Amelia; Isca, Chrystel; Vacchi, Caterina; Ficarra, Guido; Fabbiani, Luca; Iannone, Anna; Magnani, Luca; Castrignanò, Paola; Macripo', Pierluca; Gasparini, Elisa; Piana, Simonetta; Cortesi, Laura; Maiorana, Antonino; Salvarani, Carlo; Dominici, Massimo; Giuggioli, Dilia
abstract

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients.

2021 - Characterization of new ATM deletion associated with hereditary breast cancer [Articolo su rivista]
Parenti, S.; Rabacchi, C.; Marino, M.; Tenedini, E.; Artuso, L.; Castellano, S.; Carretta, C.; Mallia, S.; Cortesi, L.; Toss, A.; Barbieri, E.; Manfredini, R.; Luppi, M.; Trenti, T.; Tagliafico, E.
abstract

Next-generation sequencing (NGS)-based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described to increase tumor susceptibility. In particular, families carrying heterozygous germ-line variants of ATM gene have a 5-to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 missense variants and several truncating mutations have been identified in ATM gene. Here, we present the molecular characterization of a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed us to identify a new inactivating deletion of exons 19–27 of ATM gene. The deletion was characterized both at the DNA and RNA level.

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 - Clinical and Pathological Features of Breast Cancer in Systemic Sclerosis: Results from the Sclero-Breast Study [Articolo su rivista]
Toss, Angela; Spinella, Amelia; Isca, Chrystel; Vacchi, Caterina; Ficarra, Guido; Fabbiani, Luca; Iannone, Anna; Magnani, Luca; Castrignanò, Paola; Macripò, Pierluca; Gasparini, Elisa; Piana, Simonetta; Cortesi, Laura; Maiorana, Antonino; Salvarani, Carlo; Dominici, Massimo; Giuggioli, Dilia
abstract

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients.

2021 - Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants [Articolo su rivista]
Lambertini, M.; Ceppi, M.; Hamy, A. -S.; Caron, O.; Poorvu, P. D.; Carrasco, E.; Grinshpun, A.; Punie, K.; Rousset-Jablonski, C.; Ferrari, A.; Paluch-Shimon, S.; Toss, A.; Senechal, C.; Puglisi, F.; Pogoda, K.; Perez-Fidalgo, J. A.; De Marchis, L.; Ponzone, R.; Livraghi, L.; Estevez-Diz, M. D. P.; Villarreal-Garza, C.; Dieci, M. V.; Clatot, F.; Duhoux, F. P.; Graffeo, R.; Teixeira, L.; Cordoba, O.; Sonnenblick, A.; Ferreira, A. R.; Partridge, A. H.; Di Meglio, A.; Saule, C.; Peccatori, F. A.; Bruzzone, M.; t'Kint de Roodenbeke, M. D.; Ameye, L.; Balmana, J.; Del Mastro, L.; Azim, H. A.
abstract

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR−]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I–III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60–0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94–2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients’ counseling on treatment, prevention, and surveillance strategies.

2021 - Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers [Articolo su rivista]
Toss, Angela; Tenedini, Elena; Piombino, Claudia; Venturelli, Marta; Marchi, Isabella; Gasparini, Elisa; Barbieri, Elena; Razzaboni, Elisabetta; Domati, Federica; Caggia, Federica; Grandi, Giovanni; Combi, Francesca; Tazzioli, Giovanni; Dominici, Massimo; Tagliafico, Enrico; Cortesi, Laura
abstract

The most common breast cancer (BC) susceptibility genes beyond BRCA1/2 are ATM and CHEK2. For the purpose of exploring the clinicopathologic characteristics of BC developed by ATM or CHEK2 mutation carriers, we reviewed the archive of our Family Cancer Clinic. Since 2018, 1185 multi-gene panel tests have been performed. Nineteen ATM and 17 CHEK2 mutation carriers affected by 46 different BCs were identified. A high rate of bilateral tumors was observed in ATM (26.3%) and CHEK2 mutation carriers (41.2%). While 64.3% of CHEK2 tumors were luminal A-like, 56.2% of ATM tumors were luminal B-like/HER2-negative. Moreover, 21.4% of CHEK2-related invasive tumors showed a lobular histotype. About a quarter of all ATM-related BCs and a third of CHEK2 BCs were in situ carcinomas and more than half of ATM and CHEK2-related BCs were diagnosed at stage I-II. Finally, 63.2% of ATM mutation carriers and 64.7% of CHEK2 mutation carriers presented a positive BC family history. The biological and clinical characteristics of ATM and CHEK2-related tumors may help improve diagnosis, prognostication and targeted therapeutic approaches. Contralateral mastectomy should be considered and discussed with ATM and CHEK2 mutation carriers at the first diagnosis of BC.

2021 - Germline mutations in other homologous recombination repair-related genes than brca1/2: Predictive or prognostic factors? [Articolo su rivista]
Cortesi, L.; Piombino, C.; Toss, A.
abstract

The homologous recombination repair (HRR) pathway repairs double-strand DNA breaks, mostly by BRCA1 and BRCA2, although other proteins such as ATM, CHEK2, and PALB2 are also involved. BRCA1/2 germline mutations are targeted by PARP inhibitors. The aim of this commentary is to explore whether germline mutations in HRR-related genes other than BRCA1/2 have to be considered as prognostic factors or predictive to therapies by discussing the results of two articles published in December 2020. The TBCRC 048 trial published by Tung et al. showed an impressive objective response rate to olaparib in metastatic breast cancer patients with germline PALB2 mutation compared to germline ATM and CHEK2 mutation carriers. Additionally, Yadav et al. observed a significantly longer overall survival in pancreatic adenocarcinoma patients with germline HRR mutations compared to non-carriers. In our opinion, assuming that PALB2 is a high-penetrant gene with a key role in the HRR system, PALB2 mutations are predictive factors for response to treatment. Moreover, germline mutations in the ATM gene provide a better outcome in pancreatic adenocarcinoma, being more often associated to wild-type KRAS. In conclusion, sequencing of HRR-related genes other than BRCA1/2 should be routinely offered as part of a biological characterization of pancreatic and breast cancers.

2021 - Obesity in Postmenopausal Breast Cancer Patients: It Is Time to Improve Actions for a Healthier Lifestyle. The Results of a Comparison Between Two Italian Regions With Different “Presumed” Lifestyles [Articolo su rivista]
Cortesi, L.; Galli, G. R.; Domati, F.; Conte, L.; Manca, L.; Berio, M. A.; Toss, A.; Iannone, A.; Federico, M.
abstract

Background: Adult body fatness is a convincing risk factor for postmenopausal breast cancer. With the aim to compare the different breast cancer (BC) features in Northern and Southern Italy, we investigated the relationship between BMI and BC characteristic in two groups of patients referred in the Modena and Lecce breast units. Materials and Methods: A retrospective analysis of a continuous series of BC patients referred to the Città di Lecce Hospital and the Modena Cancer Center, from January 2019 to December 2020 was performed. We identified four groups of BMI at BC diagnosis: underweight, BMI <18.5 kg/m2; normal weight, BMI ≥ 18.5–24.9 kg/m2; overweight, BMI ≥ 25.0–29.9 kg/m2; obese, BMI ≥30.0 kg/m2. BC characteristics and clinical outcomes were analyzed by the Kolmogorov-Smirnov test and Mann-Whitney U test; categorical data were compared using Pearson’s chi-square test, and dicotomic data were compared by odds ratio. Results: Nine hundred seventy-seven BC patients were included in the analysis. Overall, 470 were from Modena and 507 from Lecce. No differences were observed in the mean age of BC patients of Modena (61,42) and Lecce (62,08). No statistical differences between the two populations were shown in terms of tumor characteristics and pathological stage. Conversely, a statistical difference of BMI between the BC patients coming from Modena and Lecce (25.87 and 27.81, respectively; p = 0.000001) was found. BC patients diagnosed in Lecce at age ≥70 years had higher median BMI compared with the ones from Modena (p = 0.000002). The increased BMI in this aged population was also associated to larger tumor size (p = 0.040). Conclusion: The rate of overweight and obesity was higher in BC women living in Southern Italy, despite the presumed nutrition according to the so-called Mediterranean type dietary pattern. Unexpectedly, an increased BMI rate and a relationship with larger tumor size were found in Southern BC patients aged ≥70 years. Our findings strongly support the need for promoting a healthier lifestyle model in Italy, with the aim of reducing the rate of the obesity and, consequently, the increased risk of BC.

2021 - Prophylactic risk-reducing salpingo-oophorectomy in BRCA mutation carriers: what is going on in a region of northern Italy? [Articolo su rivista]
Grandi, G.; Perrone, A. M.; Perrone, A.; Mandato, V. D.; Comerci, G.; Sammarini, M.; Merisio, C.; Amadori, A.; Stefanetti, M.; Martinello, R.; Facchinetti, F.; De Iaco, P.; Aguzzoli, L.; Arcangeli, V.; Berretta, R.; Cortesi, L.; De Domenico, R.; Nuzzo, M. D.; Friso, S.; Greco, P.; Rosati, F.; Scutiero, G.; Toss, A.
abstract

Background: BRCA1 mutation carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO) between the ages of 35 and 40 or when child bearing is complete, with a possible delay until age 40–45 for BRCA2 mutation carriers. Study Question: Primary outcome was the rate of unsuspected cancer findings during RRSO in a region of northern Italy (Emilia Romagna) and secondary outcomes were details of RRSO: age at surgical intervention, the venue of the procedures in relation to the surgical/pathological quality and the rate/role of concomitant opportunistic hysterectomies. Study Design: Multicentre data collection by invitation to report current RRSO practices. Results: A total of 222 RRSOs (54.5 % BRCA1, 34.7 % BRCA2, 1.8 % BRCA1 and BRCA2 combined, 5.8 % BRCA-VUS and 3.2 % BRCA not better specified) were reported from 9 different centres, half in non-university hospitals and the remainder in university hospitals. Breast cancer survivors (56.3 %) underwent the RRSO at a younger age (47.8 vs 50.6 years, p = 0.02). The mean and median ages at surgical intervention (49.0 and 48.0, respectively) were similar for BRCA1 and BRCA2 mutation carriers, as was the temporal trend in age distribution, and proportions treated in university and non-university hospitals. A diagnosis of ovarian invasive cancer was reported in 3.5 % of subjects, all BRCA1 or BRCA-combined subjects, at a median and mean age of 57 years (range 42–68). Abnormal tubal findings, such as serous tubal intraepithelial lesions (STIL) (100 %), secretory cell outgrowth (SCOUT) (100 %) and STIC (71.4 %), were mainly reported by pathologists in university hospitals. Of the 222 procedures, 15 (6.7 %) included hysterectomies: in none of these cases was a primitive uterine endometrioid or serous cancer found. Conclusions: The results from this multicentre regional study should guide future preventive health policies for RRSO in BRCA mutation carriers.

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 - 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 - Response to: COVID-related upsurge in diagnoses of advanced breast cancer-is a disruption in mammography screening the one to be blamed? [Articolo su rivista]
Toss, A.
abstract

2021 - Satisfaction with prophylactic risk-reducing salpingo-oophorectomy in BRCA mutation carriers is very high and little dependent on the participants' characteristics at surgery: a prospective study [Articolo su rivista]
Grandi, Giovanni; Sammarini, Margaret; Cortesi, Laura; Toss, Angela; Botticelli, Laura; Varliero, Federico; Sighinolfi, Giovanna; Barbieri, Elena; Facchinetti, Fabio
abstract

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 - The challenging screen detection of ovarian cancer in BRCA mutation carriers adhering to a 6-month follow-up program: results from a 6-years surveillance [Articolo su rivista]
Grandi, G.; Fiocchi, F.; Cortesi, L.; Toss, A.; Boselli, F.; Sammarini, M.; Sighinolfi, G.; Facchinetti, F.
abstract

OBJECTIVE: Approximately 25% of ovarian cancer (OC) cases are related to an inherited predisposition. Genetic mutations for the oncosuppressor genes BRCA1 and 2 have the best-known linkage to a higher incidence of OC and breast cancer, in approximately 70% to 80% of hereditary OC cases. To provide the first comprehensive clinical description of screen-detected (SD) OCs during a 6-years surveillance of a cohort of young BRCA carriers and carriers who refuse risk-reducing salpingo-oophorectomy. METHODS: A prospective cohort study in a university hospital describing 191 women with BRCA1 and 2 mutations adhering continuously to our surveillance between 2015 and 2020, including a 6-monthly evaluation of cancer antigen 125 (CA 125) with concomitant transvaginal ultrasound (TVUS) performed by a dedicated specialist. Main outcomes were tumor's laterality, CA 125 at diagnosis, TVUS and computed tomography (CT) findings. RESULTS: Risk-reducing salpingo-oophorectomy was performed in 58/191 (30.4%) of mutation carriers during the study period (one OC case identified). Nine SD-OCs and no interval OCs were found in the remaining 133 women. OCs (FIGO stage I or II: 88.9%) occur mainly in BRCA 1 (77.8%), being bilateral in 85.7% BRCA 1 and unilateral in 100% BRCA 2. No lesions involved only the tubes: left ovaries/tubes were more frequently involved. We have described three new possible scenarios regarding imaging: 1) Evident cases (33.3%, TVUS and CT obvious for OC, CA 125 sensitivity: 100%), 2) Possible cases (55.6%, TVUS and CT are in general accordance, documenting new TVUS signs: increased solid pattern of the ovary with peripheral cortical small cysts, hypoechoic circular mass near the ovary, intraparenchymal small hyperechoic foci), and 3) Hidden cases (11.1%, the smallest lesion but the highest stage (IIIA2), with CA 125 44.2 U/mL and concomitant endometrial hyperplasia). CONCLUSIONS: Different diagnostic tools must integrate to ensure early diagnosis of OC in BRCA mutation carriers adhering to a follow-up program.

2021 - The prognostic and predictive role of somatic brca mutations in ovarian cancer: Results from a multicenter cohort study [Articolo su rivista]
Toss, A.; Piombino, C.; Tenedini, E.; Bologna, A.; Gasparini, E.; Tarantino, V.; Filieri, M. E.; Cottafavi, L.; Giovanardi, F.; Madrigali, S.; Civallero, M.; Marcheselli, L.; Marchi, I.; Domati, F.; Venturelli, M.; Barbieri, E.; Grandi, G.; Tagliafico, E.; Cortesi, L.
abstract

Previous research involving epithelial ovarian cancer patients showed that, compared to germline BRCA (gBRCA) mutations, somatic BRCA (sBRCA) mutations present a similar positive impact with regard to overall survival (OS) and platinum and PARP (poly (ADP-ribose) polymerase) inhibitor sensitivity. Nevertheless, molecular testing in these studies did not include copy number variation (CNV) analyses of BRCA genes. The aim of this study was to explore the prognostic and predictive role of sBRCA mutations as compared to gBRCA mutations in patients who were also tested for CNVs. Among the 158 patients included in the study, 17.09% of patients carried a pathogenic or likely pathogenic gBRCA variant and 15.19% of patients presented pathogenetic or likely pathogenic sBRCA variants and/or CNVs. Overall, 81.6% of the patients included in this study were diagnosed with a serous histotype, and 77.2% were in advanced stages. Among women diagnosed in advanced stages, gBRCA patients showed better progression-free survival and OS as compared to sBRCA and wild-type patients, whereas sBRCA patients did not show any advantage in outcome as compared to wild-type patients. In this study, the introduction of CNV analyses increased the detection rate of sBRCA mutations, and the resulting classification among gBRCA, sBRCA and wild-type patients was able to properly stratify the prognosis of OC patients. Particularly, sBRCA mutation patients failed to show any outcome advantage as compared to wild-type patients.

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 - 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 - Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness [Articolo su rivista]
Patel, V. L.; Busch, E. L.; Friebel, T. M.; Cronin, A.; Leslie, G.; McGuffog, L.; Adlard, J.; Agata, S.; Agnarsson, B. A.; Ahmed, M.; Aittom, K.; Alducci, E.; Andrulis, I. L.; Arason, A.; Arnold, N.; Artioli, G.; Arver, B.; Auber, B.; Azzollini, J.; Balmana, J.; Barkardottir, R. B.; Barnes, D. R.; Barroso, A.; Barrowdale, D.; Belotti, M.; Benitez, J.; Bertelsen, B.; Blok, M. J.; Bodrogi, I.; Bonadona, V.; Bonanni, B.; Bondavalli, D.; Boonen, S. E.; Borde, J.; Borg, A.; Bradbury, A. R.; Brady, A.; Brewer, C.; Brunet, J.; Buecher, B.; Buys, S. S.; Cabezas-Camarero, S.; Caldes, T.; Caliebe, A.; Caligo, M. A.; Calvello, M.; Campbell, I. G.; Carnevali, I.; Carrasco, E.; Chan, T. L.; Chu, A. T. W.; Chung, W. K.; Claes, K. B. M.; Cook, J.; Cortesi, L.; Couch, F. J.; Daly, M. B.; Damante, G.; Darder, E.; Davidson, R.; De La Hoya, M.; Della Puppa, L.; Dennis, J.; Diez, O.; Ding, Y. C.; Ditsch, N.; Domchek, S. M.; Donaldson, A.; Dworniczak, B.; Easton, D. F.; Eccles, D. M.; Eeles, R. A.; Ehrencrona, H.; Ejlertsen, B.; Engel, C.; Evans, D. G.; Faivre, L.; Faust, U.; Feliubadalo, L.; Foretova, L.; Fostira, F.; Fountzilas, G.; Frost, D.; Garcia-Barberan, V.; Garre, P.; Gauthier-Villars, M.; Geczi, L.; Gehrig, A.; Gerdes, A. -M.; Gesta, P.; Giannini, G.; Glendon, G.; Godwin, A. K.; Goldgar, D. E.; Greene, M. H.; Gutierrez-Barrera, A. M.; Hahnen, E.; Hamann, U.; Hauke, J.; Herold, N.; Hogervorst, F. B. L.; Honisch, E.; Hopper, J. L.; Hulick, P. J.; Izatt, L.; Jager, A.; James, P.; Janavicius, R.; Jensen, U. B.; Jensen, T. D.; Johannsson, O. Th.; John, E. M.; Joseph, V.; Kang, E.; Kast, K.; Kiiski, J. I.; Kim, S. -W.; Kim, Z.; Ko, K. -P.; Konstantopoulou, I.; Kramer, G.; Krogh, L.; Kruse, T. A.; Kwong, A.; Larsen, M.; Lasset, C.; Lautrup, C.; Lazaro, C.; Lee, J.; Lee, J. W.; Lee, M. H.; Lemke, J.; Lesueur, F.; Liljegren, A.; Lindblom, A.; Llovet, P.; Lopez-Fernandez, A.; Lopez-Perolio, I.; Lorca, V.; Loud, J. T.; Ma, E. S. K.; Mai, P. L.; Manoukian, S.; Mari, V.; Martin, L.; Matricardi, L.; Mebirouk, N.; Medici, V.; Meijers-Heijboer, H. E. J.; Meindl, A.; Mensenkamp, A. R.; Miller, C.; Gomes, D. M.; Montagna, M.; Mooij, T. M.; Moserle, L.; Mouret-Fourme, E.; Mulligan, A. M.; Nathanson, K. L.; Navratilova, M.; Nevanlinna, H.; Niederacher, D.; Cilius Nielsen, F. C.; Nikitina-Zake, L.; Offit, K.; Olah, E.; Olopade, O. I.; Ong, K. -R.; Osorio, A.; Ott, C. -E.; Palli, D.; Park, S. K.; Parsons, M. T.; Pedersen, I. S.; Peissel, B.; Peixoto, A.; Perez-Segura, P.; Peterlongo, P.; Petersen, A. H.; Porteous, M. E.; Pujana, M. A.; Radice, P.; Ramser, J.; Rantala, J.; Rashid, M. U.; Rhiem, K.; Rizzolo, P.; Robson, M. E.; Rookus, M. A.; Rossing, C. M.; Ruddy, K. J.; Santos, C.; Saule, C.; Scarpitta, R.; Schmutzler, R. K.; Schuster, H.; Senter, L.; Seynaeve, C. M.; Shah, P. D.; Sharma, P.; Shin, V. Y.; Silvestri, V.; Simard, J.; Singer, C. F.; Skytte, A. -B.; Snape, K.; Solano, A. R.; Soucy, P.; Southey, M. C.; Spurdle, A. B.; Steele, L.; Steinemann, D.; Stoppa-Lyonnet, D.; Stradella, A.; Sunde, L.; Sutter, C.; Tan, Y. Y.; Teixeira, M. R.; Teo, S. H.; Thomassen, M.; Tibiletti, M. G.; Tischkowitz, M.; Tognazzo, S.; Toland, A. E.; Tommasi, S.; Torres, D.; Toss, A.; Trainer, A. H.; Tung, N.; Van Asperen, C. J.; Van Der Baan, F. H.; Van Der Kolk, L. E.; Van Der Luijt, R. B.; Van Hest, L. P.; Varesco, L.; Varon-Mateeva, R.; Viel, A.; Vierstrate, J.; Villa, R.; Von Wachenfeldt, A.; Wagner, P.; Wang-Gohrke, S.; Wappenschmidt, B.; Weitzel, J. N.; Wieme, G.; Yadav, S.; Yannoukakos, D.; Yoon, S. -Y.; Zanzottera, C.; Zorn, K. K.; D'Amico, A. V.; Freedman, M. L.; Pomerantz, M. M.; Chenevix-Trench, G.; Antoniou, A. C.; Neuhausen, S. L.; Ottini, L.; Nielsen, H. R.; Rebbeck, T. R.
abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8þ) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 30 region of BRCA2 (c.7914þ) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001c.7913 [HR ¼ 1.78; 95% confidence interval (CI), 1.25–2.52; P ¼ 0.001], as well as elevated risk of Gleason 8þ prostate cancer (HR ¼ 3.11; 95% CI, 1.63–5.95; P ¼ 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR ¼ 2.83; 95% CI, 1.71–4.68; P ¼ 0.00004) and elevated risk of Gleason 8þ prostate cancer (HR ¼ 4.95; 95% CI, 2.12–11.54; P ¼ 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer.

2020 - Brca detection rate in an italian cohort of luminal early-onset and triple-negative breast cancer patients without family history: When biology overcomes genealogy [Articolo su rivista]
Toss, A.; Molinaro, E.; Venturelli, M.; Domati, F.; Marcheselli, L.; Piana, S.; Barbieri, E.; Grandi, G.; Piombino, C.; Marchi, I.; Tenedini, E.; Tagliafico, E.; Tazzioli, G.; Cortesi, L.
abstract

NCCN Guidelines recommend BRCA genetic testing in individuals with a probability >5% of being a carrier. Nonetheless, the cost-effectiveness of testing individuals with no tumor family history is still debated, especially when BRCA testing is offered by the national health service. Our analysis evaluated the rate of BRCA pathogenic or likely-pathogenic variants in 159 triplenegative breast cancer (TNBC) patients diagnosed ≤60 years, and 109 luminal-like breast cancer (BC) patients diagnosed ≤35 without breast and/or ovarian family histories. In TNBC patients, BRCA mutation prevalence was 22.6% (21.4% BRCA1). Mutation prevalence was 64.2% ≤30 years, 31.8% in patients aged 31–40, 16.1% for those aged 41–50 and 7.9% in 51–60s. A total of 40% of patients with estrogen receptors (ER) 1–9% were BRCA1 carriers. BRCA detection rate in early-onset BCs was 6.4% (4.6% BRCA2). Mutation prevalence was 0% between 0–25 years, 9% between 26–30 years and 6% between 31–35 years. In conclusion, BRCA testing is recommended in TNBC patients diagnosed ≤60 years, regardless of family cancer history or histotype, and by using immunohistochemical staining <10% for both ER and/PR. In luminal-like early-onset BC, a lower BRCA detection rate was observed, suggesting a role for other predisposing genes along with BRCA genetic testing.

2020 - Breast cancer screening of mutation carriers in the era of COVID-19 pandemic [Articolo su rivista]
Toss, A.; Lambertini, M.; Punie, K.; Grandi, G.; Cortesi, L.
abstract

2020 - Cancer Surveillance in Healthy Carriers of Germline Pathogenic Variants in BRCA1/2: A Review of Secondary Prevention Guidelines [Articolo su rivista]
Dullens, B.; De Putter, R.; Lambertini, M.; Toss, A.; Han, S.; Van Nieuwenhuysen, E.; Van Gorp, T.; Vanderstichele, A.; Van Ongeval, C.; Keupers, M.; Prevos, R.; Celis, V.; Dekervel, J.; Everaerts, W.; Wildiers, H.; Nevelsteen, I.; Neven, P.; Timmerman, D.; Smeets, A.; Denayer, E.; Van Buggenhout, G.; Legius, E.; Punie, K.
abstract

Germline pathogenic alterations in the breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are the most prevalent causes of hereditary breast and ovarian cancer. The increasing trend in proportion of cancer patients undergoing genetic testing, followed by predictive testing in families of new index patients, results in a significant increase of healthy germline BRCA1/2 mutation carriers who are at increased risk for breast, ovarian, and other BRCA-related cancers. This review aims to give an overview of available screening guidelines for female and male carriers of pathogenic or likely pathogenic germline BRCA1/2 variants per cancer type, incorporating malignancies that are more or less recently well correlated with BRCA1/2. We selected guidelines from national/international organizations and/or professional associations that were published or updated between January 1, 2015, and February 1, 2020. In total, 12 guidelines were included. This review reveals several significant discordances between the different guidelines. Optimal surveillance strategies depend on accurate age-specific cancer risk estimates, which are not reliably available for all BRCA-related cancers. Up-to-date national or international consensus guidelines are of utmost importance to harmonize counseling and proposed surveillance strategies for BRCA1/2 carriers.

2020 - Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: Young oncologists' perspective [Articolo su rivista]
Lambertini, M.; Toss, A.; Passaro, A.; Criscitiello, C.; Cremolini, C.; Cardone, C.; Loupakis, F.; Viscardi, G.; Meattini, I.; Dieci, M. V.; Ferrara, R.; Giusti, R.; Maio, M. D.
abstract

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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 - Effect of Adjuvant Paclitaxel and Carboplatin on Survival in Women with Triple-Negative Breast Cancer: A Phase 3 Randomized Clinical Trial [Articolo su rivista]
Yu, K. -D.; Ye, F. -G.; He, M.; Fan, L.; Ma, D.; Mo, M.; Wu, J.; Liu, G. -Y.; Di, G. -H.; Zeng, X. -H.; He, P. -Q.; Wu, K. -J.; Hou, Y. -F.; Wang, J.; Wang, C.; Zhuang, Z. -G.; Song, C. -G.; Lin, X. -Y.; Toss, A.; Ricci, F.; Shen, Z. -Z.; Shao, Z. -M.
abstract

Importance: The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. Objective: To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T). Design, Setting, and Participants: This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol. Interventions: Participants were randomized to receive PCb (paclitaxel 80 mg/m2and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and fluorouracil 500 mg/m2every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2every 3 weeks for 3 cycles). Main Outcomes and Measures: The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. Results: A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P =.03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P =.22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P =.14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P =.04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. Conclusions and Relevance: These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated. Trial Registration: ClinicalTrials.gov Identifier: NCT01216111.

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 - Lifestyle intervention on body weight and physical activity in patients with breast cancer can reduce the risk of death in obese women: The EMILI study [Articolo su rivista]
Cortesi, L.; Sebastiani, F.; Iannone, A.; Marcheselli, L.; Venturelli, M.; Piombino, C.; Toss, A.; Federico, M.
abstract

Background obesity and sedentary lifestyle have been shown to negatively affect survival in breast cancer (BC). The purpose of this study was to test the efficacy of a lifestyle intervention on body mass index (BMI) and physical activity (PA) levels among BC survivors in Modena, Italy, in order to show an outcome improvement in obese and overweight patients. Methods: This study is a single-arm experimental design, conducted between November 2009 and May 2016 on 430 women affected by BC. Weight, BMI, and PA were assessed at baseline, at 12 months, and at the end of the study. Survival curves were estimated among normal, overweight, and obese patients. Results: Mean BMI decreased from baseline to the end of the study was equal to 2.9% (p = 0.065) in overweight patients and 3.3% in obese patients (p = 0.048). Mean PA increase from baseline to the end of the study was equal to 125% (p < 0.001) in normal patients, 200% (p < 0.001) in overweight patients and 100% (p < 0.001) in obese patients. After 70 months of follow-up, the 5-year overall survival (OS) rate was 96%, 96%, and 93%, respectively in normal, obese, and overweight patients. Overweight patients had significantly worse OS than normal ones (HR = 3.69, 95%CI = 1.82–4.53 p = 0.027) whereas no statistically significant differences were seen between obese and normal patients (HR 2.45, 95%CI = 0.68–8.78, p = 0.169). Conclusions: A lifestyle intervention can lead to clinically meaningful weight loss and increase PA in patients with BC. These results could contribute to improving the OS in obese patients compared to overweight ones.

2020 - Male Bilateral Risk-Reducing Mastectomy: Report of a Case [Articolo su rivista]
Combi, Francesca; Razzaboni, Elisabetta; Toss, Angela; Gambini, Anna; Papi, Simona; Cortesi, Laura; Tazzioli, Giovanni
abstract

Male prophylactic mastectomy is described only in sporadic cases and always performed in men with BRCA mutation with a contralateral breast cancer diagnosis. This case may suggest that we need to tailor counseling and decision‐making process for males carrying BRCA mutation and take into consideration risk‐reduction surgery when wished and strongly motivated by the consultant or in the presence of multiple risk factors in addition to gene mutation.

2020 - Male mammary myofibroblastoma: Two case reports and brief review of literature [Articolo su rivista]
Venturelli, M.; Toss, A.; Cortesi, L.; Gambini, A.; Andreotti, A.; Cascinu, S.; Tazzioli, G.; Moscetti, L.
abstract

Myofibroblastoma of the breast is a rare benign stromal tumor that occurs in both sexes with a higher prevalence in male breast of older populations. Furthermore, myofibroblastoma can arise in extra mammary sites, along the milk-line. A variety of morphological variants in addition to the classic type have been identified. The differential diagnosis includes both benign and malignant entities that, through the use of clinical and radiological imaging, is difficult to characterize. Histopathological examination and immunohistochemistry are fundamental in the establishment of appropriate management of the disease and avoidance of overtreatment. The present study focuses on two cases of male mammary myofibroblastoma, with a short literature review.

2020 - Postmenopausal hormone therapy in BRCA gene mutation carriers: to whom and which? [Articolo su rivista]
Grandi, G.; Caroli, M.; Cortesi, L.; Toss, A.; Tazzioli, G.; Facchinetti, F.
abstract

Introduction: Risk-reducing-salpingo-oophorectomy (RRSO) inevitably leads BRCA mutation carriers to premature menopause. Areas covered: To evaluate the existing evidence for use of postmenopausal hormone therapy (HT) in BRCAmc, after RRSO or menopause occurring naturally, for both breast cancer (BC) survivors and those without BC. Expert opinion: All BC survivors are excluded from any HT treatment: in other BRCAmc, before 51 years of age the benefits of HT overcome the risks after RRSO and/or premature ovarian insufficiency (POF). After 51 years of age, it is important to treat only women with important vasomotor symptoms, after the failure of alternative therapies. Estrogens-only therapy plays a key role in hysterectomized women (HW). In the case of an intact uterus (UW), associations with the lowest dose of progestins/natural progesterone derivatives have to be preferred, as progestins has been shown to play an important role in BC transformation, especially in BRCA1mc. No studies have been performed in BRCAmc with regard to ‘progestin-free’ HT, in particular the old tibolone (both in HW and UW) and the new tissue-selective estrogen complex (in UW). However, preliminary data obtained from the general population are reassuring about the use of these ‘progestin-free’ preparations and BC safety.

2020 - Primary fallopian tube carcinoma (PFTC) in a BRIP-1 mutation carrier: the first case report [Articolo su rivista]
Grandi, G.; Caroli, M.; Alboni, C.; Cortesi, L.; Toss, A.; Barbieri, E.; Botticelli, L.; Facchinetti, F.
abstract

Some hereditary ovarian cancer cases can be associated with a mutation of a gene involved in the DNA double-strand break repair system other than BRCA, such as BRIP1. This mutation is an emerging indication for prophylactic risk-reducing salpingo-oophorectomy (RRSO): however, anomalous tubal pathologic lesions have not yet been reported during RRSO performed for this specific indication (BRIP1), as largely reported for BRCA mutation carriers.An asymptomatic 64-year-old woman with a family history of ovarian and breast cancer agreed to undergo RRSO for a pathogenic variant of the BRIP1 gene (heterozygous NM_032043.2: c.124delT, p. Cys42Valfs) with normal BRCA genes. Histological examination showed the presence of high-grade serous carcinoma of the fimbria of the right tube of a maximum diameter of 0.4 cm (final FIGO stage IIB).The pathogenic mechanism that leads to the development of high-grade serous ovarian/fallopian tube cancer in patients with mutations of BRIP1 should be the same as for patients with mutations of BRCA1 and 2. Our case confirms to consider BRIP1 mutation to be sufficient to justify RRSO at 45–50 years old.

2020 - Secondary Prevention in Hereditary Breast and/or Ovarian Cancer Syndromes Other Than BRCA [Articolo su rivista]
Piombino, C.; Cortesi, L.; Lambertini, M.; Punie, K.; Grandi, G.; Toss, A.
abstract

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndromes are among the best-known and most extensively studied hereditary cancer syndromes. Nevertheless, many patients who proved negative at BRCA genetic testing bring pathogenic mutations in other suppressor genes and oncogenes associated with hereditary breast and/or ovarian cancers. These genes include TP53 in Li-Fraumeni syndrome, PTEN in Cowden syndrome, mismatch repair (MMR) genes in Lynch syndrome, CDH1 in diffuse gastric cancer syndrome, STK11 in Peutz-Jeghers syndrome, and NF1 in neurofibromatosis type 1 syndrome. To these, several other genes can be added that act jointly with BRCA1 and BRCA2 in the double-strand break repair system, such as PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D. Management of primary and secondary cancer prevention in these hereditary cancer syndromes is crucial. In particular, secondary prevention by screening aims to discover precancerous lesions or cancers at their initial stages because early detection could allow for effective treatment and a full recovery. The present review aims to summarize the available literature and suggest proper screening strategies for hereditary breast and/or ovarian cancer syndromes other than BRCA.

2020 - The generally low sensitivity of CA125 for FIGO stage I ovarian cancer diagnosis increases for endometrioid histotype [Articolo su rivista]
Grandi, G.; Perrone, A. M.; Toss, A.; Vitagliano, A.; Friso, S.; Facchinetti, F.; Cortesi, L.; Cascinu, S.; Deiaco, P.
abstract

BACKGROUND: The serum marker CA125 is still the most widely used biomarker for ovarian cancer (OC) diagnosis in gynecological and oncological setting, but its predictive role in early-stage OCis still debated. The aim of this study was to explore the value of CA125 in distinguishing between early-stage OCand borderline ovarian tumor (BOT) and to evaluate the accuracy of CA125 in the detection of early stage OC. METHODS: Aretrospective cohort study was performed at the University Hospital of Bologna (Italy) on 1296 consecutive women suffering from OCor BOT (diagnosed at histology) between 1988-2017. Patients for whom CA125 level was determined preoperatively were included. The positive cut-off level used was >35 U/mL. RESULTS: Of 910 patients, 192 (21.1%) were diagnosed with BOT and 718 (78.9%) with OC. The sensitivity of CA125 for stage IOCwas 54.4 (95% CI: 45.3-63.3) (51.5 for IA, 54.6 for IB, 58.3 for IC), but it increased to 78.0 (95% CI: 63.7-88.0) for stage II. Interestingly, in stage I OC, CA 125 presented a significantly higher sensitivity for the endometrioid histotype [72.4 (95% CI: 52.5-86.5) vs. 49.0 (95% CI: 38.6-59.4), P=0.026]. The positive likelihood ratio of CA125 for early-stage OCcompared to BOT was 1.29 (95% CI: 1.06-1.58). CONCLUSIONS: Despite its limited sensitivity for early-stage OCs, CA125 still represents a useful serum marker to early differentiate between OCs and BOTs. Its sensitivity for stage IOCincreases in endometrioid histotype.

2020 - The reduction of CA 125 serum levels in BRCA 1/2 mutation carriers after risk-reducing salpingo-oophorectomy is only partially associated with surgery: A prospective cohort, other biomarker controlled, study [Articolo su rivista]
Grandi, G.; Del Savio, M. C.; Sammarini, M.; Cortesi, L.; Toss, A.; Piombino, C.; Facchinetti, F.
abstract

Objectives A significant reduction in CA 125 postoperative serum levels was observed after risk-reducing salpingo-oophorectomy (RRSO) in BRCA mutation carriers. In contrast to previous studies, where control groups were absent, we conducted a prospective study including also a screening only group (RSSO refusal) and a group having previously undergone RRSO. Methods Consecutive BRCA1 and BRCA2 mutation carriers, not hysterectomised, >35 years old and with completed childbearing, were recruited. Some women had previously undergone RRSO (previous RRSO group). The others, who had either chosen RRSO (actual RRSO group) or screening only (screening only group), were enrolled (patient-preference trial). A prospective evaluation (basal and 6-month) of CA 125 and CEA (control biomarker) was performed. Results The study consisted of 116 women, 44.8% BRCA1 and 55.2% BRCA2 mutation carriers (n = 25 in the previous RRSO group, n = 29 in the actual RRSO group, n = 62 in the screening only group). For all subjects, we observed a 6-month decrease in CA 125 (-7.8%, P = 0.003), which was significantly linked only to endometriosis history (odds ratio 1.4; 95% confidence interval 1.1-1.8; P = 0.002). Between different groups, we recorded a non-significantly different decrease in CA 125. CEA showed a 6 months significant increase (+15.4%, P < 0.0001), which was similar between groups. Conclusion The decrease in CA 125 in BRCA mutation carriers after RRSO was only partially associated with surgery, depending also on a physiological decline: This is extremely important in their longitudinal monitoring for the prevention of ovarian cancer.

2020 - The spectrum of fancm protein truncating variants in European breast cancer cases [Articolo su rivista]
Figlioli, G.; Kvist, A.; Tham, E.; Soukupova, J.; Kleiblova, P.; Muranen, T. A.; Andrieu, N.; Azzollini, J.; Balmana, J.; Barroso, A.; Benitez, J.; Bertelsen, B.; Blanco, A.; Bonanni, B.; Borg, A.; Brunet, J.; Calistri, D.; Calvello, M.; Chvojka, S.; Cortesi, L.; Darder, E.; Del Valle, J.; Diez, O.; Eon-Marchais, S.; Fostira, F.; Gensini, F.; Houdayer, C.; Janatova, M.; Kiiski, J. I.; Konstantopoulou, I.; Kubelka-Sabit, K.; Lazaro, C.; Lesueur, F.; Manoukian, S.; Marcinkute, R.; Mickys, U.; Moncoutier, V.; Myszka, A.; Nguyen-Dumont, T.; Nielsen, F. C.; Norvilas, R.; Olah, E.; Osorio, A.; Papi, L.; Peissel, B.; Peixoto, A.; Plaseska-Karanfilska, D.; Pocza, T.; Rossing, M.; Rudaitis, V.; Santamarina, M.; Santos, C.; Smichkoska, S.; Southey, M. C.; Stoppa-Lyonnet, D.; Teixeira, M.; Torngren, T.; Toss, A.; Urioste, M.; Vega, A.; Vlckova, Z.; Yannoukakos, D.; Zampiga, V.; Kleibl, Z.; Radice, P.; Nevanlinna, H.; Ehrencrona, H.; Janavicius, R.; Peterlongo, P.
abstract

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

2019 - BRCA mutations among triple negative breast cancer without family history of breast and ovarian cancer: The Modena family cancer clinic experience [Abstract in Rivista]
Molinaro, E.; Venturelli, M.; Toss, A.; Piombino, C.; Barbieri, E.; Marcheselli, L.; Marchi, I.; Tagliafico, E.; Cascinu, S.; Cortesi, L.
abstract

2019 - Breast ultrasonography (BU) in the screening protocol for women at hereditary-familial risk of breast cancer: has the time come to rethink the role of BU according to different risk categories? [Articolo su rivista]
Cortesi, Laura; Canossi, Barbara; Battista, Rachele; Pecchi, Annarita; Drago, Antonella; Dal Molin, Chiara; Toss, Angela; De Matteis, Elisabetta; Marchi, Isabella; Torricelli, Pietro; Cascinu, Stefano
abstract

This article evaluates the breast cancer (BC) screening efficacy of biannual ultrasound (US) in three different risk categories. In a single-center, prospective, nonrandomized comparison study, BRCA mutation carriers and women with high risk (HR) or intermediate risk (IR) received mammography (MMG), ultrasound, (US) and Magnetic Resonance Imaging (MRI), scheduled according to the risk categories. Single and combined sensitivity were evaluated in specific groups of risk and the US performance at six-monthly interval was notably considered. Among 2,313 asymptomatic women at different risk (136 mutation carriers, 1,749 at HR and 428 at IR) 211 developed a BC, of which 193 (91.5%) were screen detected BC (SDBC) and 18 (8.5%) were interval BC (IBC). The SDBC detection rate (DR) was 11.2 per 1.000 person-years (37.9, 8.5 and 16.1 for BRCA, HR and IR, respectively); 116 BC were detected by MMG (DR = 6.6 × 1,000 persons-years), 62 by US (DR = 3.6 × 1,000 persons-years) and 15 by MRI, that was applied only in 60 BRCA women (DR = 37 × 1,000 persons-years). At the six-monthly US, 52 BC were detected (DR = 3.0 × 1,000 persons/years), of which 8 were BRCA-related. The most sensitive technique was MRI (93.7%) followed by MMG (55%) and US (29.4%). Combined sensitivity for MMG plus US was 100% in HR and 80.4% for IR women (p < 0.01). In BRCA mutated patients, MRI alone with annual US performed after six months, could be offered. In HR patients, MMG plus biannual US provide the most sensitive diagnosis and for IR group an annual MMG could be sufficient.

2019 - Breast ultrasound in high-risk women [Articolo su rivista]
Cortesi, Laura; Barbieri, Elena; Toss, Angela
abstract

not available

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 - Combined hormonal contraceptives in BRCA gene mutation carriers: why not? [Articolo su rivista]
Grandi, Giovanni; Sammarini, Margaret; del savio, maria chiara; Toss, Angela; Facchinetti, Fabio
abstract

not available

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 - 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 - Hereditary ovarian cancers: State of the art [Articolo su rivista]
Toss, A.; Molinaro, E.; Sammarini, M.; Del Savio, M. C.; Cortesi, L.; Facchinetti, F.; Grandi, G.
abstract

The identification of a mutation in ovarian cancer (OC) predisposition genes plays a crucial role in the management of cancer prevention, diagnosis, and treatment. In healthy carriers, the detection of a specific mutation might justify more intensive and personalised surveillance programmes, chemopreventive measures, and prophylactic surgeries. Moreover, the identification of a mutation in affected OC patients might provide fundamental knowledge of the tumour pathogenesis, thus guiding treatment choices. This is a comprehensive review of the molecular pathways involved in the pathogenesis of hereditary ovarian cancers, the clinical-pathological features of these tumours, and the potential implications for their prevention and clinical management.

2019 - Hereditary pancreatic cancer: A retrospective single-center study of 5143 Italian families with history of BRCA-related malignancies [Articolo su rivista]
Toss, Angela; Venturelli, Marta; Molinaro, Eleonora; Pipitone, Stefania; Barbieri, Elena; Marchi, Isabella; Tenedini, Elena; Artuso, Lucia; Castellano, Sara; Marino, Marco; Tagliafico, Enrico; Razzaboni, Elisabetta; De Matteis, Elisabetta; Cascinu, Stefano; Cortesi, Laura
abstract

The identification of BRCA mutations plays a crucial role in the management of hereditary cancer prevention and treatment. Nonetheless, BRCA-testing in pancreatic cancer (PC) patients is not universally introduced in clinical practice. A retrospective analysis was conducted, firstly, to evaluate the rate of BRCA-positive families among those presenting a family history of PC besides breast and/or ovarian cancer. Secondly, the relationship between BRCA pathogenic variants and PC risk was evaluated. Finally, the characteristics of PC developed in BRCA families were described. Among 5143 family trees reporting breast and/or ovarian cancer cases, 392 showed a family history of PC. A total of 35 families (24.5% selected by the Modena Criteria and 21.3% by the NCCN Criteria) were positive to BRCA testing. Among the BRCA1 mutations, 36.8% were found within a region defined by c.3239–c.3917, whilst 43.7% of BRCA2 mutations were located within c.7180–c.8248. This study confirmed that an increase in the rate of positive tests in families with PC when associated to breast and/or ovarian tumors. Moreover, this analysis indicated two possible Pancreatic Cancer Cluster Regions that should be verified in future research. Finally, PC in families with breast and/or ovarian cancer history, particularly in BRCA families, were diagnosed at younger age and showed better one-year overall survival.

2019 - Increasing BMI is associated with both endometrioid and serous histotypes among endometrial rather than ovarian cancers: a case-to-case study [Articolo su rivista]
Grandi, G.; Perrone, A. M.; Chiossi, G.; Friso, S.; Toss, A.; Sammarini, Margaret; Facchinetti, F.; Botticelli, L.; Palma, F.; De Iaco, P.
abstract

Aim: Although obesity has been associated with endometrioid (type I) and, to a lesser extent, with serous (type II) endometrial cancer (EC), the association with the same histotypes of ovarian cancer (OC) remains unclear. Therefore, we intended to compare the role of BMI in carcinogenesis of endometrioid and the serous malignancies, at both ovarian and endometrial level. Methods: A retrospective case-to-case study was performed in the University Hospital of Bologna (Italy), through the review of primary EC matched with the corresponding OC cases in the same period (1988–2017). Results: We included 1052 women diagnosed with EC (n = 897 endometrioid, n = 52 serous) and 955 women affected by OC (n = 132 endometrioid, n = 627 serous). EC patients had higher median BMI than women diagnosed with OC (27.3 [23.4–31.9] vs 24.9 [21.7–27.5], p < 0.01). After controlling for confounding, 1 unit increase in BMI was associated with a 5% higher odds of endometrial as opposed to ovarian cancer (OR for ovarian as opposed to endometrial cancer 0.95; 95% CI 0.91–0.98, p = 0.004). Conclusions: Increasing BMI is associated with endometrial rather than ovarian cancer, among both serous and endometrioid histotypes.

2019 - Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification [Articolo su rivista]
Parsons, Michael T.; Tudini, Emma; Li, Hongyan; Hahnen, Eric; Wappenschmidt, Barbara; Feliubadaló, Lidia; Aalfs, Cora M.; Agata, Simona; Aittomäki, Kristiina; Alducci, Elisa; Alonso-Cerezo, María Concepción; Arnold, Norbert; Auber, Bernd; Austin, Rachel; Azzollini, Jacopo; Balmaña, Judith; Barbieri, Elena; Bartram, Claus R.; Blanco, Ana; Blümcke, Britta; Bonache, Sandra; Bonanni, Bernardo; Borg, Åke; Bortesi, Beatrice; Brunet, Joan; Bruzzone, Carla; Bucksch, Karolin; Cagnoli, Giulia; Caldés, Trinidad; Caliebe, Almuth; Caligo, Maria A.; Calvello, Mariarosaria; Capone, Gabriele L.; Caputo, Sandrine M.; Carnevali, Ileana; Carrasco, Estela; Caux-Moncoutier, Virginie; Cavalli, Pietro; Cini, Giulia; Clarke, Edward M.; Concolino, Paola; Cops, Elisa J.; Cortesi, Laura; Couch, Fergus J.; Darder, Esther; de la Hoya, Miguel; Dean, Michael; Debatin, Irmgard; del Valle, Jesús; Delnatte, Capucine; Derive, Nicolas; Diez, Orland; Ditsch, Nina; Domchek, Susan M.; Dutrannoy, Véronique; Eccles, Diana M.; Ehrencrona, Hans; Enders, Ute; Evans, D. Gareth; Faust, Ulrike; Felbor, Ute; Feroce, Irene; Fine, Miriam; Galvao, Henrique C. R.; Gambino, Gaetana; Gehrig, Andrea; Gensini, Francesca; Gerdes, Anne-Marie; Germani, Aldo; Giesecke, Jutta; Gismondi, Viviana; Gómez, Carolina; Gómez Garcia, Encarna B.; González, Sara; Grau, Elia; Grill, Sabine; Gross, Eva; Guerrieri-Gonzaga, Aliana; Guillaud-Bataille, Marine; Gutiérrez-Enríquez, Sara; Haaf, Thomas; Hackmann, Karl; Hansen, Thomas V. O.; Harris, Marion; Hauke, Jan; Heinrich, Tilman; Hellebrand, Heide; Herold, Karen N.; Honisch, Ellen; Horvath, Judit; Houdayer, Claude; Hübbel, Verena; Iglesias, Silvia; Izquierdo, Angel; James, Paul A.; Janssen, Linda A. M.; Jeschke, Udo; Kaulfuß, Silke; Keupp, Katharina; Kiechle, Marion; Kölbl, Alexandra; Krieger, Sophie; Kruse, Torben A.; Kvist, Anders; Lalloo, Fiona; Larsen, Mirjam; Lattimore, Vanessa L.; Lautrup, Charlotte; Ledig, Susanne; Leinert, Elena; Lewis, Alexandra L.; Lim, Joanna; Loeffler, Markus; López-Fernández, Adrià; Lucci-Cordisco, Emanuela; Maass, Nicolai; Manoukian, Siranoush; Marabelli, Monica; Matricardi, Laura; Meindl, Alfons; Michelli, Rodrigo D.; Moghadasi, Setareh; Moles-Fernández, Alejandro; Montagna, Marco; Montalban, Gemma; Monteiro, Alvaro N.; Montes, Eva; Mori, Luigi; Moserle, Lidia; Müller, Clemens R.; Mundhenke, Christoph; Naldi, Nadia; Nathanson, Katherine L.; Navarro, Matilde; Nevanlinna, Heli; Nichols, Cassandra B.; Niederacher, Dieter; Nielsen, Henriette R.; Ong, Kai-ren; Pachter, Nicholas; Palmero, Edenir I.; Papi, Laura; Pedersen, Inge Sokilde; Peissel, Bernard; Pérez-Segura, Pedro; Pfeifer, Katharina; Pineda, Marta; Pohl-Rescigno, Esther; Poplawski, Nicola K.; Porfirio, Berardino; Quante, Anne S.; Ramser, Juliane; Reis, Rui M.; Revillion, Françoise; Rhiem, Kerstin; Riboli, Barbara; Ritter, Julia; Rivera, Daniela; Rofes, Paula; Rump, Andreas; Salinas, Monica; Sánchez de Abajo, Ana María; Schmidt, Gunnar; Schoenwiese, Ulrike; Seggewiß, Jochen; Solanes, Ares; Steinemann, Doris; Stiller, Mathias; Stoppa-Lyonnet, Dominique; Sullivan, Kelly J.; Susman, Rachel; Sutter, Christian; Tavtigian, Sean V.; Teo, Soo H.; Teulé, Alex; Thomassen, Mads; Tibiletti, Maria Grazia; Tognazzo, Silvia; Toland, Amanda E.; Tornero, Eva; Törngren, Therese; Torres-Esquius, Sara; Toss, Angela; Trainer, Alison H.; van Asperen, Christi J.; van Mackelenbergh, Marion T.; Varesco, Liliana; Vargas-Parra, Gardenia; Varon, Raymonda; Vega, Ana; Velasco, Ángela; Vesper, Anne-Sophie; Viel, Alessandra; Vreeswijk, Maaike P. G.; Wagner, Sebastian A.; Waha, Anke; Walker, Logan C.; Walters, Rhiannon J.; Wang-Gohrke, Shan; Weber, Bernhard H. F.; Weichert, Wilko; Wieland, Kerstin; Wiesmüller, Lisa; Witzel, Isabell; Wöckel, Achim; Woodward, Emma R.; Zachariae, Silke; Zampiga, Valentina; Zeder-Göß, Christine; Lázaro, Conxi; De Nicolo, Arcangela; Radice, Paolo; Engel, Christoph; Schmutzler, Rita K.; Goldgar, David E.; Spurdle, Amanda B.
abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

2019 - NUT midline carcinoma of the head and neck: current perspectives [Articolo su rivista]
Napolitano, Martina; Venturelli, Marta; Molinaro, Eleonora; Toss, Angela
abstract

NUT midline carcinoma (NMC) is a rare and aggressive subtype of squamous carcinoma that typically arises from midline supradiaphragmatic structures, frequently from the head and neck area. NMC is genetically driven by a chromosomal rearrangement involving the NUT gene, which forms oncoproteins considered major pathogenic drivers of cellular transformation. Diagnosis of NMC has been made remarkably easier with the availability of a commercial antibody against NUT, and can be established through positive nuclear immunohistochemical staining. Although NMC remains an underrecognized malignancy, in recent years there has appeared to be increasing awareness of disease and frequency of diagnosis in adults. To date, a standard treatment for head and neck NMC has not been established and a multimodal approach with systemic chemotherapy, surgery and radiation therapy is currently adopted in clinical practice. Recently, BET inhibitors and histone deacetylase inhibitors have emerged as two promising classes of targeted agents, currently investigated in clinical trials for adults with head and neck NMC. At the same time, combination approaches and novel targeted agents, such as next-generation BET inhibitors and CDK9 inhibitors, have shown preclinical activity. The present review explores the clinical pathological characteristics of NMC of the head and neck and presents the current state of the art on diagnosis, prognosis, and treatment of this rare but lethal disease.

2019 - Occult breast cancer: the uncommon presentation of a common disease [Articolo su rivista]
Toss, Angela; Moscetti, Luca; Cascinu, Stefano
abstract

not available

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 - Combined Hormonal Contraceptive Use and Risk of Breast Cancer in a Population of Women With a Family History [Articolo su rivista]
Grandi, Giovanni; Toss, Angela; Cagnacci, Angelo; Marcheselli, Luigi; Pavesi, Silvia; Facchinetti, Fabio; Cascinu, Stefano; Cortesi, Laura
abstract

We estimated the association between combined hormonal contraceptive (CHC) use and breast cancer (BC) incidence in a well-selected population of women at familial risk of BC at the Modena Family Cancer Clinic.

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 - 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 - 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 - 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 - 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 - PARP inhibitors for the treatment of ovarian cancer [Articolo su rivista]
Cortesi, Lisa; Toss, A.; Cucinotto, I.
abstract

The standard of treatment for advanced ovarian cancer is represented by optimal surgical debulking preceded or followed by chemotherapeutic regimens including taxanes and platinum agents, possibly associated with bevacizumab and/or intraperitoneal therapy. Despite this comprehensive treatment strategy, almost 75% of patients relapse or progress and are therefore candidates for a second-line treatment, showing, at this point, less chemo-sensitivity and worse prognosis. An interesting approach to improve outcomes of these patients has been developed in the last decade, in BRCA-related ovarian cancer. Mutations in one of the BRCA genes result in impaired homologous-recombination DNA repair, which causes genetic abnormalities that promote carcinogenesis. Interestingly, this defect has been exploited by the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors to provide specific cancer cell cytotoxicity. Particularly, the inhibition of PARP in BRCA-mutation carriers leads to the persistence of DNA damage usually repaired by the homologous-recombination system, resulting in cell cycle arrest and thus apoptosis. Despite the mechanism of action, an activity of PARP inhibitors was also observed in “BRCAness” ovarian tumors, and in BRCA-related tumors other than ovarian, suggesting that these agents may be active regardless of BRCA mutation status or site of origin. This review aims to describe the principal evidence that led to the development and the study of PARP inhibitors and to discuss their main implications in our daily clinical practice.

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.

2017 - Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study [Articolo su rivista]
Cortesi, Laura; De Matteis, Elisabetta; Toss, Angela; Marchi, Isabella; Medici, Veronica; Contu, Giannina; Xholli, Anjeza; Grandi, Giovanni; Cagnacci, Angelo; Federico, Massimo
abstract

Objective: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). Methods: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. Results: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event-free survival were 75 and 64%, respectively. Conclusions: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers.

2017 - Fertility and pregnancy issues in BRCA-mutated breast cancer patients [Articolo su rivista]
Lambertini, M.; Goldrat, O.; Toss, A.; Azim, H. A.; Peccatori, F. A.; Ignatiadis, M.; Del Mastro, L.; Demeestere, I.
abstract

Fertility and pregnancy-related issues represent one of the main areas of concerns for young women with breast cancer. Carrying a germline deleterious BRCA mutation adds additional burden on this regard due to the specific issues that should be considered during the oncofertility counseling of this special patient group. Despite the availability of a growing amount of data in the general breast cancer population on the feasibility and safety of fertility preservation and pregnancy after diagnosis, numerous challenges remain for BRCA-mutated breast cancer patients in whom very limited studies have been performed so far. Therefore, studies aiming to address the specific issues of these patients, including the impact of the mutation on their fertility potential, the safety and efficacy of the different strategies for fertility preservation, and the feasibility of having a pregnancy after diagnosis, should be considered a research priority. The aim of the present manuscript is to perform an in depth overview on the role of BRCA mutations in breast cancer with a specific focus on their impact on reproductive potential, and to discuss the fertility and pregnancy issues faced by BRCA-mutated breast cancer patients. The final goal of this manuscript is to highlight current and upcoming knowledge in this field for trying to help physicians dealing with these patients during oncofertility counseling.

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 - Prediction of breast and prostate cancer risks in male BRCA1 and BRCA2 mutation carriers using polygenic risk scores [Articolo su rivista]
Lecarpentier, J.; Kuchenbaecker, K. B.; Barrowdale, D.; Dennis, J.; McGuffog, L.; Leslie, G.; Lee, A.; Al Olama, A. A.; Tyrer, J. P.; Frost, D.; Ellis, S.; Easton, D. F.; Antoniou, A. C.; Tischkowitz, M.; Evans, D. G.; Henderson, A.; Brewer, C.; Eccles, D.; Cook, J.; Ong, K. -R.; Walker, L.; Side, L. E.; Hodgson, S.; Izatt, L.; Eeles, R.; Orr, N.; Porteous, M. E.; Davidson, R.; Adlard, J.; Silvestri, V.; Rizzolo, P.; Navazio, A. S.; Valentini, V.; Zelli, V.; Ottini, L.; Toss, A.; Medici, V.; Cortesi, L.; Zanna, I.; Palli, D.; Radice, P.; Manoukian, S.; Peissel, B.; Azzollini, J.; Peterlongo, P.; Viel, A.; Cini, G.; Damante, G.; Tommasi, S.; Alducci, E.; Tognazzo, S.; Montagna, M.; Caligo, M. A.; Soucy, P.; Simard, J.; Mulligan, A. M.; Andrulis, I. L.; Glendon, G.; Southey, M.; Campbell, I.; James, P.; Mitchell, G.; Spurdle, A. B.; Holland, H.; Chenevix-Trench, G.; John, E. M.; Steele, L.; Ding, Y. C.; Neuhausen, S. L.; Weitzel, J. N.; Conner, T. A.; Buys, S. S.; Goldgar, D. E.; Godwin, A. K.; Sharma, P.; Rebbeck, T. R.; Vijai, J.; Robson, M.; Lincoln, A.; Musinsky, J.; Gaddam, P.; Offit, K.; Loud, J. T.; Greene, M. H.; Toland, A. E.; Senter, L.; Huo, D.; Nielsen, S. M.; Olopade, O. I.; Nathanson, K. L.; Domchek, S. M.; Lorenchick, C.; Jankowitz, R. C.; Couch, F. J.; Janavicius, R.; Hansen, T. V. O.; Bojesen, A.; Nielsen, H. R.; Skytte, A. -B.; Sunde, L.; Jensen, U. B.; Pedersen, I. S.; Krogh, L.; Kruse, T. A.; Thomassen, M.; Osorio, A.; De La Hoya, M.; Garcia-Barberan, V.; Caldes, T.; Segura, P. P.; Balmana, J.; Gutierrez-Enriquez, S.; Diez, O.; Teule, A.; Del Valle, J.; Feliubadalo, L.; Pujana, M. A.; Lazaro, C.; Izquierdo, A.; Darder, E.; Brunet, J.; Fostira, F.; Hamann, U.; Sutter, C.; Meindl, A.; Ditsch, N.; Gehrig, A.; Dworniczak, B.; Engel, C.; Wand, D.; Niederacher, D.; Steinemann, D.; Hahnen, E.; Hauke, J.; Rhiem, K.; Wappenschmidt, B.; Schmutzler, R. K.; Kast, K.; Arnold, N.; Wang-Gohrke, S.; Lasset, C.; Damiola, F.; Barjhoux, L.; Mazoyer, S.; Stoppa-Lyonnet, D.; Belotti, M.; Van Heetvelde, M.; Poppe, B.; De Leeneer, K.; Claes, K. B. M.; Kiiski, J. I.; Khan, S.; Nevanlinna, H.; Aittomaki, K.; Vvan Asperen, C. J.; Vaszko, T.; Kasler, M.; Olah, E.; Arason, A.; Agnarsson, B. A.; Johannsson, O. Th.; Barkardottir, R. B.; Teixeira, M. R.; Pinto, P.; Lee, J. W.; Lee, M. H.; Lee, J.; Kim, S. -W.; Kang, E.; Park, S. K.; Kim, Z.; Tan, Y. Y.; Berger, A.; Singer, C. F.; Yoon, S. -Y.; Teo, S. -H.; Von Wachenfeldt, A.
abstract

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations.We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction. Materials and Methods Wegenotyped 1,802male carriers ofBRCA1/2mutations fromthe Consortiumof Investigators ofModifiers of BRCA1/2 by using the custom Illumina OncoArray.We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks formale carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variantswas associatedwith breast cancer risk (odds ratio per standard deviation of PRS, 1.36;95%CI, 1.19 to 1.56; P = 8.6 3 1026). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95%CI, 1.35 to 1.81; P=3.23 1029). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7%to 26%for carriers of BRCA1 mutations and from 19%to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

2017 - The impact of reproductive life on breast cancer risk in women with family history or BRCA mutation [Articolo su rivista]
Toss, A.; Grandi, G.; Cagnacci, A.; Marcheselli, L.; Pavesi, S.; De Matteis, E.; Razzaboni, E.; Tomasello, C.; Cascinu, S.; Cortesi, L.
abstract

Reproductive history and exogenous hormonal exposures are acknowledged risk factors for breast cancer in the general population. In women at increased breast cancer risk for genetic predisposition or positive family history, data regarding these risk factors are limited or conflicting, and recommendations for these categories are unclear. We evaluated the characteristics of reproductive life in 2522 women at increased genetic or familial breast cancer risk attending our Family Cancer Center. Breast cancers in BRCA mutation carriers were more likely to be hormone receptor negative, diagnosed at 35 years or before and multiple during the lifetime than tumors in women at increased familial risk, while the distribution of invasive cancers and HER2 positive tumors was similar in the different risk groups. At least one full-term pregnancy (HR 0.27; 95% CI 0.12-0.58; p = 0.001), breastfeeding either less (HR 0.24; 95% CI 0.09-0.66; p = 0.005) or more (HR 0.25; 95% IC 0.08-0.82; p = 0.022) than one year and late age at menopause (HR 0.10; 95% CI 0.01-0.82; p = 0.033) showed to be protective factors in BRCA mutation carriers, while in women at increased familial risk early age at first full-term pregnancy (HR 0.62; 95% IC 0.38-0.99; p = 0.048) and late menarche (HR 0.61; 95% CI 0.42-0.85; p = 0.004) showed to be the main protective factors. Finally, for the entire population, combined hormonal contraceptives demonstrated to do not increase breast cancer risk. The results of our study suggest that women at high familial risk and mutation carries develop tumors with different clinical-pathological characteristics and, consequently, are influenced by different protective and risk factors.

2016 - Clinical-pathological features and treatment modalities associated with recurrence in DCIS and micro-invasive carcinoma: Who to treat more and who to treat less [Articolo su rivista]
Toss, A.; Palazzo, J.; Berger, A.; Guiles, F.; Sendecki, J. A.; Simone, N.; Anne, R.; Avery, T.; Jaslow, R.; Lazar, M.; Tsangaris, T.; Cristofanilli, M.
abstract

The primary aim in the management of DCIS is the prevention of recurrence and contralateral tumor. Risk factors for DCIS recurrence and appropriate treatments are still widely debated. Adjuvant therapies after surgical resection reduce recurrences and contralateral disease, but these treatments have significant financial costs, side effects and there is a group of low-risk patients who would not gain additional benefit. The aim of our analysis was to identify clinical-pathological features and treatment modalities associated with recurrence in DCIS and microinvasive carcinoma. In the Thomas Jefferson University Cancer Registry of Philadelphia, we identified 865 patients with DCIS or micro-invasive carcinoma treated between 2003 and 2013. Associations between recurrence and demographic factors (age at diagnosis, ethnicity), biological features (ER, PR and HER2) and treatment modalities (surgery, radiotherapy and endocrine treatment) were assessed. Our single institution register-based study showed that distribution of age at diagnosis and biological features did not significantly differ among ethnic groups. Younger women and micro-invasive carcinoma patients were more likely to undergo mastectomy, while African Americans were more likely to take endocrine therapy and undergo radiotherapy. In our sample only ER/PR negative DCIS were associated with significantly higher recurrence rate. Moreover, we reported a high rate of HER2 positive recurrences, suggesting that expression of this oncogene may represent a potential biomarker for DCIS at high risk of recurrence. To better define the molecular profile of the subgroup at worse prognosis might help to identify biomarkers predictive of recurrence or second tumors, identifying patients candidates for more appropriate 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 - 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 - 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.

2015 - Hereditary Ovarian Cancer: Not Only BRCA 1 and 2 Genes [Articolo su rivista]
Toss, Angela; Tomasello, Chiara; Razzaboni, Elisabetta; Contu, Giannina; Grandi, Giovanni; Cagnacci, Angelo; Schilder, Russel; Cortesi, Laura
abstract

More than one-fifth of ovarian tumors have hereditary susceptibility and, in about 65–85% of these cases, the genetic abnormality is a germline mutation in BRCA genes. Nevertheless, several other suppressor genes and oncogenes have been associated with hereditary ovarian cancers, including the mismatch repair (MMR) genes in Lynch syndrome, the tumor suppressor gene, TP53, in the Li-Fraumeni syndrome, and several other genes involved in the double-strand breaks repair system, such as CHEK2, RAD51, BRIP1, and PALB2. The study of genetic discriminators and deregulated pathways involved in hereditary ovarian syndromes is relevant for the future development ofmolecular diagnostic strategies and targeted therapeutic approaches.The recent development and implementation of next-generation sequencing technologies have provided the opportunity to simultaneously analyzemultiple cancer susceptibility genes, reduce the delay and costs, and optimize the molecular diagnosis of hereditary tumors. Particularly, the identification of mutations in ovarian cancer susceptibility genes in healthy women may result in a more personalized cancer risk management with tailored clinical and radiological surveillance, chemopreventive approaches, and/or prophylactic surgeries. On the other hand, for ovarian cancer patients, the identification of mutations may provide potential targets for biologic agents and guide treatment decision-making.

2015 - Impressive response to dose-dense chemotherapy in a patient with NUT midline carcinoma [Articolo su rivista]
Maur, Michela; Toss, Angela; Dominici, Massimo; Frassoldati, Antonio; Corradini, Paolo; Maiorana, Antonio; Fontana, Annalisa; Conte, Pierfranco
abstract

Objective: Rare disease Background: NUT midline carcinoma (NMC) is a rare, highly lethal malignancy that results from a chromosome translocation and mostly arises in the midline organs. To date, no treatment has been established. Most patients receive combinations of chemotherapy regimens and radiation, and occasionally subsequent resection; nevertheless, patients have an average survival hardly exceeding 7 months. Case Report: A 21-year-old patient was admitted to our division with a large mediastinal mass with lung nodules, multiple vertebral metastases, and massive nodal involvement. In a few days, the patient developed a superior vena cava syndrome and an acute respiratory failure. Due to the rapid course of the disease, based on preliminary histology of poorly differentiated carcinoma, a dose-dense biweekly chemotherapy with paclitaxel, ifosfamide, and cisplatin was started. In the meantime, the diagnosis of NMC was confirmed. A surprising clinical benefit was obtained after the first cycle of chemotherapy, and after 6 cycles a PET-CT scan showed a very good response. At this point, radiotherapy was started but the disease progressed outside of the radiation field. The patient entered into a compassionate use protocol with Romidepsin, but a PET/CT scan after the first course showed disease progression with peritoneal and retroperitoneal carcinosis. A treatment with Pemetrexed was then started but the patient eventually died with rapid progressive disease. Conclusions: Our case history adds some interesting findings to available knowledge: NMC can be chemosensitive and radiosensitive. This opens the possibility to study more aggressive treatments, including high-dose consolidation chemotherapy and to evaluate the role of biological agents as maintenance treatments.

2015 - Molecular characterization and targeted therapeutic approaches in breast cancer [Articolo su rivista]
Toss, A.; Cristofanilli, M.
abstract

Despite the wide improvements in breast cancer (BC) detection and adjuvant treatment, BC is still responsible for approximately 40,000 deaths annually in the United States. Novel biomarkers are fundamental to assist clinicians in BC detection, risk stratification, disease subtyping, prediction of treatment response, and surveillance, allowing a more tailored approach to therapy in both primary and metastatic settings. In primary BC, the development of molecular profiling techniques has added prognostic and predictive information to conventional biomarkers - estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Moreover, the application of next-generation sequencing and reverse-phase protein microarray methods in the metastatic setting holds the promise to further advance toward a personalized management of cancer. The improvement in our understanding on BC biology associated with the study of the genomic aberrations characterizing the most common molecular subtypes allows us to explore new targets for drug development. Finally, the integration of cancer stem cell-targeted therapies and immune therapies in future combination regimens increases our chances to successfully treat a larger proportion of women with more aggressive and resistant metastatic disease. This article reviews the current state of novel biological markers for BC, the evidence to demonstrate their clinical validity and utility, and the implication for therapeutic targeting.

2015 - Reproductive risk factors in women with family history of breast cancer attending an Italian Family Cancer Clinic [Abstract in Rivista]
Toss, Angela; Grandi, Giovanni; Marcheselli, Luigi; DE MATTEIS, Elisabetta; Razzaboni, Elisabetta; Tomasello, Chiara; Cagnacci, Angelo; Cortesi, Laura
abstract

The investigation performed in women at a 3 times higher risk of breast cancer (RER3) shows that use of oral contraceptives was not associated with an increased risk of developing breast cancer.

2015 - The Association between Endometriomas and Ovarian Cancer: Preventive Effect of Inhibiting Ovulation and Menstruation during Reproductive Life [Articolo su rivista]
Grandi, Giovanni; Toss, Angela; Cortesi, Laura; Botticelli, Laura; Volpe, Annibale; Cagnacci, Angelo
abstract

Although endometriosis frequently involves multiple sites in the pelvis, malignancies associated with this disease are mostly confined to the ovaries, evolving from an endometrioma. Endometriomas present a 2-3-fold increased risk of transformation in clear-cell, endometrioid, and possibly low-grade serous ovarian cancers, but not in mucinous ovarian cancers. These last cancers are, in some aspects, different from the other epithelial ovarian cancers, as they do not appear to be decreased by the inhibition of ovulation and menstruation.The step by step process of transformation fromtypical endometrioma, through atypical endometrioma, finally to ovarian cancer seems mainly related to oxidative stress, inflammation, hyperestrogenism, and specific molecular alterations. Particularly, activation of oncogenic KRAS and PI3K pathways and inactivation of tumor suppressor genes PTEN and ARID1A are suggested as major pathogenic mechanisms for endometriosis associated clear-cell and endometrioid ovarian cancer. Both the risk for endometriomas and their associated ovarian cancers seems to be highly and similarly decreased by the inhibition of ovulation and retrograde menstruation, suggesting a common pathogenetic mechanism and common possible preventive strategies during reproductive life.

2015 - Twenty-years experience with de novo metastatic breast cancer [Articolo su rivista]
Cortesi, Laura; Toss, Angela; Cirilli, Claudia; Marcheselli, Luigi; Braghiroli, Barbara; Sebastiani, Federica; Federico, Massimo
abstract

Although new treatments have been widely studied to improve the survival of patients with metastatic breast cancer (BC), prognosis continues to be poor with an average survival time no longer than 3 years. We carried on a population-based study with the purpose of evaluating the outcome of metastatic breast cancer in the province of Modena from 1990 to 2009. We examined the Modena Cancer Registry and evaluated the 5-year overall survival (OS) of women diagnosed with a de novo metastatic breast cancer between 1990 and 2009, defining 5 periods of 4 years each. After a median follow-up time of 29 months, the 5-year OS was 11% for years 1990-1993, 15% for years 1994-1997, 12% for years 1998-2001, 20% for years 2002-2005 and 29% for years 2006-2009 (p = 0.012). Overall, although no OS differences were noted in the first decade analyzed, a real advantage has been shown in the last two cohorts. In a multivariate analysis, the 5-year OS was significantly increased only for hormone receptor positive and HER2+ tumors, whereas chemotherapy treatments were not significant independent predictors of survival in "de novo" metastatic BC (p = 0.08). Our analysis confirms that the prognosis of de novo metastatic breast cancer has improved overtime, particularly in the last decade. Trastuzumab, LH-RH analogues and aromatase inhibitors have determined a significant clinical benefit and cost-effectiveness in metastatic breast cancer treatment.

2014 - A rapid genetic counselling and testing in newly diagnosed breast cancer is associated with high rate of risk-reducing mastectomy in BRCA1/2-positive italian women [Articolo su rivista]
Cortesi, Laura; Razzaboni, Elisabetta; Toss, Angela; DE MATTEIS, Elisabetta; Marchi, I.; Medici, Veronica; Tazzioli, Giovanni; Andreotti, Alberto; DE SANTIS, Giorgio; Pignatti, Marco; Federico, Massimo
abstract

BACKGROUND: Risk-reducing mastectomy (RRM) decreases breast cancer (BC) risk in BRCA1/2 mutation carriers by up to 95%, but the Italian attitude towards this procedure is reluctant. PATIENTS AND METHODS: This is an observational study with retrospective design, using quantitative and qualitative research methods, aimed at evaluating the attitude towards RRM by rapid genetic counselling and testing (RGCT), at the time of BC diagnosis, compared with traditional genetic counselling and testing (TGCT), after previous BC surgery. Secondary aims were to investigate patient satisfaction after RRM and the rate of occult tumour in healthy breasts. A total of 1168 patients were evaluated: 1058 received TGCT, whereas 110 underwent RGCT. RESULTS: In TGCT, among 1058 patients, 209 (19.7%) mutation carriers were identified, with the rate of RRM being 4.7% (10 of 209). Conversely in RGCT, among 110 patients, 36 resulted positive, of which, 15 (41.7%) underwent bilateral mastectomy at the BC surgery time, showing an overall good satisfaction, measured by interpretative phenomenological analysis 12 months after the intervention. CONCLUSIONS: Our study shows that RGCT in patients with a hereditary profile is associated with a high rate of RRM at the BC surgery time, this being the pathway offered within a multidisciplinary organization. KEYWORDS: BRCA1/2 mutation carriers; acceptability; genetic counselling; risk-reducing mastectomy

2014 - CTC enumeration and characterization: Moving toward personalized medicine [Articolo su rivista]
Toss, A.; Mu, Z.; Fernandez, S.; Cristofanilli, M.
abstract

The primary cause of tumor-related death in breast cancer (BC) is still represented by distant metastasization. The dissemination of tumor cells from the primary tumor to distant sites through bloodstream cannot be early detected by standard imaging methods. The enumeration of circulating tumor cells (CTCs) represents an effective prognostic and predictive biomarker, which is able to monitor efficacy of adjuvant therapies, detect early development of (micro)metastases and at last, assess therapeutic responses of advanced disease earlier than traditional imaging methods. Moreover, since repeated tissue biopsies are invasive, costly and not always feasible, the assessment of tumor characteristics on CTCs, by a peripheral blood sample as a 'liquid biopsy', represents an attractive opportunity. The implementation of molecular and genomic characterization of CTCs could contribute to improve the treatment selection and thus, to move toward more personalized treatments. This review describes the current state of the art on CTC detection strategies, the evidence to demonstrate their clinical validity, and their potential impact for both future clinical trial design and, decision-making process in our daily practice.

2014 - Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour [Articolo su rivista]
Stacchiotti, S.; Tortoreto, M.; Baldi, G. G.; Grignani, G.; Toss, A.; Badalamenti, G.; Cominetti, D.; Morosi, C.; Dei Tos, A. P.; Festinese, F.; Fumagalli, E.; Provenzano, S.; Gronchi, A.; Pennacchioli, E.; Negri, T.; Dagrada, G. P.; Spagnuolo, R. D.; Pilotti, S.; Casali, P. G.; Zaffaroni, N.
abstract

Background To explore the activity of pazopanib in solitary fibrous tumour (SFT). Patients and methods In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm3. Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure. Results In the xenograft model, pazopanib showed the lowest antitumour activity (21%TVI), while regorafenib was the most active (95%TVI). Sorafenib, bevacizumab, sunitinib were markedly active (78/70/65%TVI). Axitinib was marginally active (51%TVI). In the retrospective case-series, three patients carried malignant-SFT (MSFT), three DSFT. Best Response Evaluation Criteria in Solid Tumour (RECIST) responses were: three stable disease (SD), all MSFT, three progressive disease (PD), all DSFT, corresponding to one partial response (PR), two SD, three PD by Choi criteria. Median-progression-free survival was 3 months (range 1-15). In one patient, sunitinib was started after pazopanib failure, with a response. Conclusions In dedifferentiated-SFT xenograft pazopanib induced a marginal antitumour activity, while regorafenib appeared the most active and promising agent. When administered in patients, pazopanib showed a modest activity in terms of tumour growth stabilisation, observed only in non-dedifferentiated cases.

2013 - Acceptability and adherence in a chemoprevention trial among women at increased risk for breast cancer attending the Modena Familial Breast and Ovarian Cancer Center [Articolo su rivista]
Razzaboni, Elisabetta; Toss, Angela; Cortesi, Laura; Marchi, I.; Sebastiani, Federica; DE MATTEIS, Elisabetta; Federico, Massimo
abstract

Chemoprevention for women at risk for breast cancer has been shown to be effective, but in actual practice, women's uptake of chemoprevention has been poor. We explored factors that influence acceptability, adherence, and dropout in the International Breast (Prevention) Intervention Study during our first 3 years of activity at the Modena Familial Breast and Ovarian Cancer Center. We evaluated socio-demographic characteristics, health status, adherence, and side effect intensity. Semi-structured interviews analyzed reasons for accepting/refusing/stopping the trial. A total of 471 postmenopausal women were invited to participate, of which 319 declined to participate (68%), 137 accepted to participate (29%), and 15 participants did not make a final decision (3%). Breast cancer-related worries and trust in our preventive and surveillance programs were the most frequent reasons for accepting. Side effect-related worry was the most frequent reason for refusing. General practitioners' and family members' opinions played an important role in the decision-making process. Adherence significantly decreased after a 12-month follow-up, but it remained unchanged after 24- and 36-month follow-ups. Mild/moderate side effects reported by women did not change after 12 months of treatment. Forty percent of women withdrew from the study due to complaints of side effects. We concluded that chemoprevention trials are difficult medical experiments and that the process of deciding about whether or not to participate is based mainly on beliefs and values. This study has important clinical implications. During counselling with prospective participants, it is important to emphasize the potential benefits and to promote an informed choice. How participants make decisions, their belief systems, and their perception of risk are all factors that should be investigated in future research.

2013 - Molecular mechanisms of PARP inhibitors In BRCA-related ovarian cancer [Articolo su rivista]
Toss, A.; Laura, C.
abstract

Ovarian cancer continues to be the main cause of death among all gynecological tumors. After standard treatments, most of patients are destined to recur within a short period, thus new therapies are urgently needed. The increasing knowledge of molecular mechanisms in ovarian cancer pathogenesis allowed identifying several targeted agents that are now entering in clinical practice. The family of poly(ADP-ribose) polymerase inhibitors represents a widely investigated and promising alternative for the targeted therapy of ovarian malignancies. PARP inhibitors exploit the synthetic lethality concept to prevent the repair of DNA damage, causing cancer cell death. This review describes the molecular mechanisms at the basis of PARP inhibition, particularly in BRCA-related ovarian malignancies and analyzes the main agents under investigations in preclinical and clinical studies. © 2013 Toss A, et al.

2013 - Ovarian cancer: can proteomics give new insights for therapy and diagnosis? [Articolo su rivista]
Toss, Angela; DE MATTEIS, Elisabetta; Rossi, Elena; Casa, L. D.; Iannone, Anna; Federico, Massimo; Cortesi, Laura
abstract

The study of the ovarian proteomic profile represents a new frontier in ovarian cancer research, since this approach is able to enlighten the wide variety of post-translational events (such as glycosylation and phosphorylation). Due to the possibility of analyzing thousands of proteins, which could be simultaneously altered, comparative proteomics represent a promising model of possible biomarker discovery for ovarian cancer detection and monitoring. Moreover, defining signaling pathways in ovarian cancer cells through proteomic analysis offers the opportunity to design novel drugs and to optimize the use of molecularly targeted agents against crucial and biologically active pathways. Proteomic techniques provide more information about different histological types of ovarian cancer, cell growth and progression, genes related to tumor microenvironment and specific molecular targets predictive of response to chemotherapy than sequencing or microarrays. Estimates of specificity with proteomics are less consistent, but suggest a new role for combinations of biomarkers in early ovarian cancer diagnosis, such as the OVA1 test. Finally, the definition of the proteomic profiles in ovarian cancer would be accurate and effective in identifying which pathways are differentially altered, defining the most effective therapeutic regimen and eventually improving health outcomes.

2013 - Relative and disease-free survival for breast cancer in relation to subtype: a population-based study [Articolo su rivista]
Minicozzi, P.; Bella, F.; Toss, Angela; Giacomn, A.; Fusco, M.; Zarcone, M.; Tumino, R.; Falcini, F.; Cesaraccio, R.; Candela, G.; La Rosa, F.; Federico, Massimo; Sant, M.
abstract

PURPOSE: No population-based study has investigated breast cancer (BC) subtypes defined by including Ki67. The aim of this study was to evaluate the relative proportions of immunohistochemical subtypes and differences in relative and disease-free survival between subtypes, in relation to patient and other cancer characteristics in Italian BC patient. METHODS: Information on estrogen, progesterone, human epidermal growth factor (HER2), Ki67, and relapses was obtained for 3,381 cases, sampled randomly and anonymously from cases diagnosed in 2003-2005 in nine Italian cancer registries. Relative excess risks (RERs) of death and risks of relapse 5 years after diagnosis were estimated. RESULTS: Luminal A cancers were 42 % of the total, luminal B 27 %, luminal-HER2 14 %, triple-negative 11 %, and HER2-enriched 7 %. For non-metastatic (3,302) cases, 4 and 7 % developed locoregional and distant metastases, respectively. RERs of death and risks of relapse were significantly greater for all cancer subtypes than luminal A, particularly for triple-negative and HER2-enriched cancers, which were more frequent in women <40 years. CONCLUSIONS: Our population-based findings confirm that subtype is an independent prognostic factor for BC. Triple-negative and HER2-enriched subtypes would benefit from the development and wide application, respectively, of targeted treatments, which would also improve survival for younger patients.

2013 - Tumor size, node status, grading, HER2 and estrogen receptor status still retain a strong value in patients with operable breast cancer diagnosed in recent years. [Articolo su rivista]
Cortesi, Laura; Marcheselli, Luigi; Guarneri, Valentina; Cirilli, Claudia; Braghiroli, Barbara; Toss, Angela; Sant, Milena; Ficarra, Guido; Conte, Pier Franco; Federico, Massimo
abstract

Breast cancer prognosis has improved greatly in recent years. Consequently, a thorough search for sensitive prognostic factors, able to help clinicians offer appropriate therapy, has become a priority in this area. In this study, we considered all new cases of invasive breast cancer diagnosed in the Province of Modena, Italy, between 1997 and 2007, registered by the Modena Cancer Registry. The principal endpoint of this study was relapse-free survival (RFS). A set of 11 clinic and pathological parameters was investigated. After a median follow-up of 73 months, 494 relapses were recorded. Tumor size, node status, grading, HER2 and estrogen receptor status were retained as independent factors in a multivariate analysis. Using these variables, a prognostic model was devised to identify three groups at different risk. In the training sample, the 5-year RFS rates resulted 96.0%, 82.9% and 63.7% in patients at low, intermediate and high risk, respectively (p < 0.0001). In the validation sample, the 5-year RFS was 96.2%, 85.4% and 66.9%, respectively. To conclude our study demonstrates that a very simple prognostic index based on easily available clinical data may represent a useful tool for the identification of patients at different risk of relapse and may be a notable device to predict who truly benefits from medical treatment.

2012 - Chemoprevention strategies for high risk women [Articolo su rivista]
Toss, A.; Sebastiani, F.; Razzaboni, E.; de Matteis, E.; Marchi, I.; Proietto, M.; Cortesi, L.
abstract

The prospects for making a vast impact on the morbidity and mortality from breast cancer lie more likely in the area of chemoprevention. Tamoxifen was the first agent considered in a preventive setting. Different studies analyzed the role of tamoxifen in prevention and, although the first results were apparently contradictory, they showed notable reductions in breast cancer. In the same period, in the MORE trial, raloxifene unexpectedly produced a larger reduction of breast cancer than was seen for tamoxifen. This result led to other chemoprevention studies to establish the role of raloxifene. Particularly, the STAR trial showed that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of adverse event. At the same time, the third-generation aromatase inhibitors (AIs) have shown good efficacy in advanced breast cancer and a low toxicity profile. They offer another approach to prevention, which may be superior or complimentary to the use of Selective Estrogen Receptor Modifiers (SERMs). Currently no AIs have yet been fully evaluated. New studies comparing the different agents together are needed and further follow up of the existing chemoprevention trials are necessary to determine which women will truly benefit from this kind of prophylaxis. © 2012 Bentham Science Publishers.

2012 - Chemoprevention strategies for high risk women [Articolo su rivista]
Toss, A.; Sebastiani, F.; Razzaboni, E.; de Matteis, E.; Marchi, I.; Proietto, M.; Cortesi, L.
abstract

The prospects for making a vast impact on the morbidity and mortality from breast cancer lie more likely in the area of chemoprevention. Tamoxifen was the first agent considered in a preventive setting. Different studies analyzed the role of tamoxifen in prevention and, although the first results were apparently contradictory, they showed notable reductions in breast cancer. In the same period, in the MORE trial, raloxifene unexpectedly produced a larger reduction of breast cancer than was seen for tamoxifen. This result led to other chemoprevention studies to establish the role of raloxifene. Particularly, the STAR trial showed that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of adverse event. At the same time, the third-generation aromatase inhibitors (AIs) have shown good efficacy in advanced breast cancer and a low toxicity profile. They offer another approach to prevention, which may be superior or complimentary to the use of Selective Estrogen Receptor Modifiers (SERMs). Currently no AIs have yet been fully evaluated. New studies comparing the different agents together are needed and further follow up of the existing chemoprevention trials are necessary to determine which women will truly benefit from this kind of prophylaxis. © 2012 Bentham Science Publishers.

2012 - Radiological screening programs for women at high risk of developing breast cancer [Articolo su rivista]
Cortesi, L.; de Matteis, E.; Sebastiani, F.; Toss, A.; Marchi, I.; Battista, R.; Canossi, B.; Pecchi, A.; Federico, M.
abstract

The aim of this review is to identify the evidence for the surveillance of women at high risk of breast cancer with the different modalities. The definition of high risk refers to the subpopulation of women with a family history of breast cancer, including both those with and without identified genetic mutations. The following topic has been evaluated: clinical breast examination (CBE), mammography, ultrasound and MRI accuracy of detecting breast cancer among women at high risk. The search was limited to full reports published in English and published between 1996 and March, 2010. We found consistent evidence that adding MRI provides a highly sensitive screening strategy (sensitivity range: 93-100%) compared to mammography alone (32-86%) or mammography plus ultrasound +/- CBE (26-93%). Three studies that compared MRI plus mammography versus mammography alone showed the sensitivity of MRI plus mammography as 93% (95% CI 86-100%) and the incremental sensitivity of MRI as 60%. Incremental sensitivity of MRI was lower when added to mammography plus ultrasound (43%) or to the combination of mammography, ultrasound plus CBE. Estimates of screening specificity with MRI were less consistent but suggested a 3-5-fold higher risk of patient recall for investigation of false positive results. No studies assessed whether adding MRI reduces patient mortality, interval or advanced breast cancer rates, even if we found strong evidence that MRI leads to the detection of earlier stage disease. This review suggests that a surveillance strategy would be accurate and effective in improving health outcomes for women at high risk of breast cancer, but randomized studies should be considered for a better evaluation of these topics. © 2012 Bentham Science Publishers.

2012 - Radiological screening programs for women at high risk of developing breast cancer [Articolo su rivista]
Cortesi, L.; de Matteis, E.; Sebastiani, F.; Toss, A.; Marchi, I.; Battista, R.; Canossi, B.; Pecchi, A; Federico, M.
abstract

The aim of this review is to identify the evidence for the surveillance of women at high risk of breast cancer with the different modalities. The definition of high risk refers to the subpopulation of women with a family history of breast cancer, including both those with and without identified genetic mutations. The following topic has been evaluated: clinical breast examination (CBE), mammography, ultrasound and MRI accuracy of detecting breast cancer among women at high risk. The search was limited to full reports published in English and published between 1996 and March, 2010. We found consistent evidence that adding MRI provides a highly sensitive screening strategy (sensitivity range: 93-100%) compared to mammography alone (32-86%) or mammography plus ultrasound +/- CBE (26-93%). Three studies that compared MRI plus mammography versus mammography alone showed the sensitivity of MRI plus mammography as 93% (95% CI 86-100%) and the incremental sensitivity of MRI as 60%. Incremental sensitivity of MRI was lower when added to mammography plus ultrasound (43%) or to the combination of mammography, ultrasound plus CBE. Estimates of screening specificity with MRI were less consistent but suggested a 3-5-fold higher risk of patient recall for investigation of false positive results. No studies assessed whether adding MRI reduces patient mortality, interval or advanced breast cancer rates, even if we found strong evidence that MRI leads to the detection of earlier stage disease. This review suggests that a surveillance strategy would be accurate and effective in improving health outcomes for women at high risk of breast cancer, but randomized studies should be considered for a better evaluation of these topics. © 2012 Bentham Science Publishers.