Abstract PS3-03-17: Analysis of second breast cancers in BRCA1/2 and other predisposing gene carriers at the Reggio Emilia Hereditary Cancer Center, Italy

Abstract Background Hereditary breast cancer (HBC) accounts for 5-10% of all breast cancers (BC). Many high and moderate penetrance genes are responsible for HBC. The identification of HBC led to the development of preventive strategies for BC and ovarian cancer (OC). In recent years BRCA1/2 germline pathogenic variants (gPV) have been used as predictive role for PARP inhibitors treatment of BC, OC and prostate cancer improving overall survival. So far, criteria for selecting patients to test remain fundamental to identify mutation carriers to offer adequate treatment. Among those, second BC represents one of the typical characteristics to take in account, mostly in case of metachronous development. Our study aimed to analyze differences in second BC between BRCA1/2 and other mutation carriers, in terms of age, clinical characteristics and prognosis at the Reggio Emilia Hereditary Center. Methods The Reggio Emilia Hereditary Cancer Center was established in 2012, identifying patients at high HBC risk, based on personal/family history and Tyrer-Cuzick likelihood model. Among criteria utilized for multigene panel testing (MGPT), two BC arisen until 50 years alone, or at any age associated to first-degree BC, were considered sufficient to be analyzed with Sophia Genetic Hereditary Cancer Syndrome (HCS) panel, including 27 predisposing genes. From the clinical point of view, patients and BC characteristics were registered in hospital-based record charts. The record chart registered height, weight, BMI, smoking habit, hormonal status, pregnancies, vital status, histology, clinical and pathological status, grading, hormonal receptors, proliferative rate, HER2 expression, type of surgery, type of neoadjuvant/adjuvant treatments, other tumors, prophylactic surgeries and gPV in different genes. The comparisons between BRCA1/2 and other gPV carriers were made by Fisher’ exact test or by Chi-squared test when more than two variables were analyzed. Loco-regional breast cancer-free survival (LRBCFS) was defined as the time from diagnosis of BC to the date of the first local recurrence (including diagnosis of second BC and regional relapse). Overall survival (OS) was defined as the time from diagnosis of BC to death or last follow-up. OS and LRBCFS curves were calculated using Kaplan-Meier method. Results Among 220 multiple BC patients analyzed by MGPT, 44 (20%) resulted gPV carriers in predisposing genes (26 in BRCA1/2 genes and 18 in other ones). Out of 18 not BRCA1/2 genes, 5 MUTYH, 3 CHEK2, 3 PALB2, 3 Mismatch Repair genes, 2 ATM, 1 RAD50 and 1 TP53 gPV carriers were identified. Regarding the first BC, BRCA1/2 carriers showed a younger age at onset (45 vs. 53 years), more advanced disease, grading III and triple negative BC (TNBC) phenotype. The median LRBCFS was equal to 11.2 years (12.6 vs 10.9 in BRCA1/2 and other carriers, respectively). Of interest, 95% of BRCA1/2 carriers had contralateral BC, whereas 27% of other carriers had ipsilateral BC. The second BC characteristics reflect those of the first BC. Other gPV carriers had more non-second BC than BRCA1/2 (17.6% vs.9.5%). The bilateral salpingo-oophorectomy was performed in 62% of BRCA1/2 vs. 12% of not BRCA1/2. Finally, 92% of all patients were alive at 17.5 median follow-up years. Conclusions Second BC represents an important feature to consider for eligibility to MGPT. A high rate of gPV in predisposing genes (20%) was found in patients with two BC. More TNBC were shown, as expected, in BRCA1/2 gPV carriers, underlying the need to treat those patients with more aggressive regimens. The older age at the first BC onset and the lower rate of contralateral BC in not BRCA1/2 gPV carriers do not justify a bilateral mastectomy at the surgical time. However, the OS curves do not differ between the two groups suggesting that the second BC do not impact on the patients’ outcome Citation Format: E. Gasparini, M. Rotolo, G. Moretti, A. Bologna, R. Di Cicilia, C. Casartelli, L. Mangone, F. Leoni, C. Pinto, M. Dominici, L. Cortesi. Analysis of second breast cancers in BRCA1/2 and other predisposing gene carriers at the Reggio Emilia Hereditary Cancer Center, Italy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-17.