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
- Author(s)
- Toss, A; Lee, MK; Blondeaux, E; Mariño-Mariño, M; Tenedini, E; Bonamici, L; Graffeo, R; Livraghi, L; Villarreal-Garza, C; Bernstein Molho, R; Kwong, A; Balmana, J; Wildiers, H; Agostinetto, E; Phillips, KA; Pogoda, K; Renaud, T; Rousset-Jablonski, C; Ferrari, A; Moore, HCF; Peccatori, FA; Paluch-Shimon, S; Fruscio, R; Micheri, C; Wong, SM; Cui, W; Vernieri, C; De Marchis, L; Couch, FJ; Del Mastro, L; Puglisi, F; Meireles, PA; Kemp, Z; Matikas, A; Plichta, J; Del Pilar Estevez-Diz, M; Di Meglio, A; Cichowska-Cwalinska, N; Gianni, C; Yerushalmi, R; Sanchez-Bayona, R; Mrinakova, B; Matos, L; Bianchini, G; Caleffi, M; Krivokuca, A; Abdou, Y; Parokonnaya, A; Okano, M; Antone, N; Saavedra, C; Sonnenblick, A; Duchnowska, R; Pais, HL; Harbeck, N; Cortesi, L; Delucchi, V; De Angelis, C; Lambertini, M;
- Details
- Publication Year 2026-03,Volume 37,Issue #3,Page 364-377
- Journal Title
- Annals of Oncology
- Publication Type
- Research article
- Abstract
- BACKGROUND: The clinical implications of specific pathogenic and likely pathogenic variant (LP/PV) types and locations in the BRCA1 orBRCA2 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 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. Clinicopathological features and survival outcomes [disease-free survival (DFS) and overall survival (OS)] were investigated according to LP/PV type [insertion-deletion (indel) versus single-nucleotide variants versus copy number variations; truncating versus non-truncating LP/PVs; frameshift versus nonsense versus splicing versus 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 clinicopathological features. BRCA1 protein-truncating variants were associated with worse OS compared with non-truncating variants [hazard ratio (HR) 2.00, 95% confidence interval (CI) 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, 95% CI 0.28-0.84) and BRCA2 carriers (HR 0.17, CI 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 with 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 variant-specific features will drive future research and support the development of tailored clinical strategies based on individual BRCA variant.
- Publisher
- Elsevier
- Keywords
- Humans; Female; *Breast Neoplasms/genetics/pathology/mortality; *BRCA2 Protein/genetics; *BRCA1 Protein/genetics; *Germ-Line Mutation; Adult; Prognosis; Retrospective Studies; Phenotype; Young Adult; Brca1; Brca2; hereditary breast cancer; overall survival; protein-truncating variant; variant type
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1016/j.annonc.2025.11.004
- Open Access at Publisher's Site
https://doi.org/10.1016/j.annonc.2025.11.004- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-12-05 02:49:48
Last Modified: 2026-03-02 05:02:25