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.
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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, Mariño-Mariño 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
Аннотация
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.