Association between type of BRCA1/2 pathogenic/likely pathogenic variants and outcome in young patients with breast cancer: Results from an international cohort study.

Abstract

10509 Background: Pathogenic/likely pathogenic variants (P/LPVs) in the BRCA1 or BRCA2 genes significantly increase the risk of developing breast cancer (BC) and other malignancies, with distinct clinicopathologic features depending on the gene involved. However, the clinical implications of the type of P/LPVs within BRCA1 or BRCA2 genes remain to be elucidated. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA carriers diagnosed with invasive BC at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on P/LPVs in the BRCA genes were included. Clinicopathologic features and survival outcomes (disease-free survival [DFS] and overall survival [OS]) were investigated according to P/LPV types (insertion-deletion mutations [INDEL] vs single nucleotide variants [SNV] vs copy number variations [CNV]; truncating vs non-truncating P/LPVs; frameshift vs nonsense vs splicing vs missense P/LPVs). Results: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2 ). Overall, 61.3% of patients carried INDEL, 32.7% SNV and 6.0% CNV; 76.5% of patients exhibited truncating P/LPVs and 8.4% non-truncating P/LPVs (15.1% not classifiable). Frameshift mutations were the most common (60.3%), followed by nonsense (21.2%), splicing (9.6%), and missense (8.4%) P/LPVs. In both BRCA1 and BRCA2 carriers, no statistically significant differences in baseline clinicopathologic variables and P/LPV types were observed except for fewer patients with nodal involvement among CNV of BRCA2. Median follow-up was 7.9 (IQR 4.5-12.9) years. No association between the type of P/LPV in both BRCA1 and BRCA2 carriers and DFS was observed, except for better DFS in patients with missense variants of BRCA2 gene. Compared to patients with non-truncating variants, patients with truncating variants in BRCA1 had a shorter OS (HR 2.00; 95%CI 1.17-3.41). Albeit not statistically significant, a numerically worse OS was observed among BRCA2 patients with truncating P/LPVs (HR 6.27 95% CI 0.86-45.87). In BRCA1 carriers, compared to patients with frameshift P/LPVs, those with missense variants were associated with better OS (HR 0.48 95%CI 0.28-0.84 for missense). In BRCA2 carriers, similar results were observed. Conclusions: In this global cohort of young BRCA carriers with BC, truncating P/LPVs were associated with poorer prognosis, and missense P/LPVs with improved prognosis. This study advances our understanding of the influence of specific types of BRCA1/2 P/LPVs on BC characteristics and outcomes, potentially suggesting more personalized prevention strategies and treatment approaches. Clinical trial information: NCT03673306 .