| Contributors: |
Toss, A.; Blondeaux, E.; Tenedini, E.; Bonamici, L.; Graffeo, R.; Livraghi, L.; Villarreal-Garza, C.; Bernstein Molho, R.; Kwong, A.; Balmana, J.; Wildiers, H.; Agostinetto, E.; Phillips, K. A.; Pogoda, K.; Renaud, T.; Rousset-Jablonski, C.; Ferrari, A.; Moore, H. C. F.; Peccatori, F. A.; Paluch-Shimon, S.; Fruscio, R.; Micheri, C.; Wong, S. M.; Cui, W.; Vernieri, C.; Lee, M. K.; De Marchis, L.; Couch, F. J.; Del Mastro, L.; Puglisi, F.; Meireles, P. A.; 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.; Marino-Marino, M.; Parokonnaya, A.; Okano, M.; Antone, N.; Saavedra, C.; Sonnenblick, A.; Duchnowska, R.; Pais, H. L.; Harbeck, N.; Cortesi, L.; Delucchi, V.; De Angelis, C.; Lambertini, M. |
| Description: |
Background: The 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 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 ... |