Background: Clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 or BRCA2 tumor-suppressor genes remain to be elucidated. Patients and methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA mutation carriers diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on LP/PVs in the BRCA genes were included. Clinicopathologic features and survival outcomes (disease-free survival [DFS] and overall survival [OS]) were investigated according to LP/PV type (insertion-deletion mutations [INDEL] vs single nucleotide variants [SNV] vs copy number variations [CNV]; truncating vs non-truncating LP/PVs; frameshift vs nonsense vs splicing vs missense LP/PVs) and location (exon involved and protein domain). Results: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2). The distribution of LP/PV types showed no meaningful associations with baseline clinicopathologic features. BRCA1 protein truncating variants were associated with worse OS compared to non-truncating variants (HR 2.00 [1.17-3.41]). A similar, though non-significant, trend was observed for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48 [0.28-0.84]) and BRCA2 mutation carriers (HR 0.17 [0.03-0.96]). Regarding variant location, BRCA1 LP/PVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, LP/PVs located in exons 15-26 and other regions were linked to worse DFS compared to those in exon 10, with no significant differences in OS. Conclusions: This study advances our understanding of the influence of specific types of BRCA LP/PVs on breast cancer characteristics and outcomes. A deeper understanding of these mutation-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant.
ASSOCIATION BETWEEN TYPE AND LOCATION OF GERMLINE BRCA1/2 PATHOGENIC OR LIKELY PATHOGENIC VARIANTS WITH PHENOTYPE AND PROGNOSIS IN YOUNG PATIENTS WITH BREAST CANCER: RESULTS FROM AN INTERNATIONAL COHORT STUDY
Blondeaux, E;Del Mastro, L;Lambertini, M
2025-01-01
Abstract
Background: Clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 or BRCA2 tumor-suppressor genes remain to be elucidated. Patients and methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study that included BRCA mutation carriers diagnosed with invasive breast cancer at the age of ≤40 years between January 2000 and December 2020. In this analysis, only patients with detailed available information on LP/PVs in the BRCA genes were included. Clinicopathologic features and survival outcomes (disease-free survival [DFS] and overall survival [OS]) were investigated according to LP/PV type (insertion-deletion mutations [INDEL] vs single nucleotide variants [SNV] vs copy number variations [CNV]; truncating vs non-truncating LP/PVs; frameshift vs nonsense vs splicing vs missense LP/PVs) and location (exon involved and protein domain). Results: Out of 5660 patients from 109 centers worldwide, 3294 were eligible for the present analysis (2080 BRCA1 and 1214 BRCA2). The distribution of LP/PV types showed no meaningful associations with baseline clinicopathologic features. BRCA1 protein truncating variants were associated with worse OS compared to non-truncating variants (HR 2.00 [1.17-3.41]). A similar, though non-significant, trend was observed for BRCA2. Missense variants were linked to better OS for both BRCA1 (HR 0.48 [0.28-0.84]) and BRCA2 mutation carriers (HR 0.17 [0.03-0.96]). Regarding variant location, BRCA1 LP/PVs outside exons 2, 10, and 19 were associated with improved OS. In BRCA2, LP/PVs located in exons 15-26 and other regions were linked to worse DFS compared to those in exon 10, with no significant differences in OS. Conclusions: This study advances our understanding of the influence of specific types of BRCA LP/PVs on breast cancer characteristics and outcomes. A deeper understanding of these mutation-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
