Clinical behavior of breast cancer in young BRCA carriers and prognostic impact of the timing of genetic testing: Results from an international cohort study.

10503 Background: Germline BRCA testing is recommended in all patients (pts) diagnosed with breast cancer (BC) at a young age (40 years or younger). Limited evidence exists regarding clinical behavior of BC in young BRCA1and BRCA2 carriers or the impact of the timing of genetic testing (before or at diagnosis) on tumor characteristics and pts outcomes. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including pts harboring germline pathogenic variants (PVs) in BRCA1or BRCA2 and diagnosed with stage I-III invasive BC at 40 years or younger between January 2000 and December 2020 (NCT03673306). Baseline pt, tumor, and treatment characteristics, as well as survival outcomes (disease-free survival DFS and overall survival OS) were compared between BRCA1and BRCA2carriers. A further comparison was performed between pts who underwent genetic testing before (i.e. any time up to 2 months prior to BC diagnosis) or at (i.e. between 2 months prior and up to 6 months after diagnosis) BC diagnosis. Results: From 78 centers worldwide, 4,752 pts were included, of whom 3069 harbored BRCA1and 1683 BRCA2 PVs. Compared to BRCA2carriers, BRCA1 carriers were significantly younger, had more grade 3 tumors, less nodal involvement, lobular histology, hormone receptor and HER2 positivity, and received chemotherapy more frequently and endocrine therapy less frequently. Median follow-up was 7.8 years (range 4.4-12.6 years). Second primary BCs (13.7% vs. 9.3%) and non-breast new primary malignancies (4.5% vs. 3.0%) were significantly more frequent among BRCA1 carriers, while distant recurrences were less frequent (9.7% vs. 13.6%). No differences in DFS or OS were observed between BRCA1 and BRCA2 carriers. However, BRCA1 carriers had worse DFS and OS in the first 5 years due to a peak in DFS events in the first 2 years while BRCA2 carriers had a constant risk of recurrence over time and worse OS after year 9. Compared to pts tested for BRCA at BC diagnosis (n = 1671), those tested before BC diagnosis (n = 411) had significantly smaller tumors (T1: 61.3% vs 32.4%) and less nodal involvement (N0: 65.9% vs 50.8%). 8-year DFS and OS in patients tested before and at BC diagnosis were 73% vs 70% (HR 1.25; 95% CI 0.99-1.58) and 91% vs 87% (HR 1.65; 95% CI 1.08-2.52), respectively. Conclusions: In this global study of young BRCA carriers, different pts, tumor, and treatment characteristics, as well as pattern and risk of DFS/OS events over time were observed between BRCA1and BRCA2. Identification of carrying a BRCA PV in healthy individuals led to earlier BC diagnosis and improved OS. These findings highlight the importance of conducting efforts to identify women at risk for carrying a BRCA1or BRCA2PV to offer them genetic counseling and testing to inform not only prevention, but tailored earlier detection, treatment and follow-up strategies once diagnosed.