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An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients

2010; Elsevier BV; Volume: 22; Issue: 7 Linguagem: Inglês

10.1093/annonc/mdq624

1569-8041

Marieke A. Vollebergh, Esther H. Lips, Petra M. Nederlof, Lodewijk F.A. Wessels, Marjanka K. Schmidt, Erik H. van Beers, Sten Cornelissen, M. Holtkamp, Femke E. Froklage, Elisabeth G.E. de Vries, J.G. Schrama, Jelle Wesseling, Marc J. van de Vijver, Harm van Tinteren, Michiel de Bruin, Michael Hauptmann, Sjoerd Rodenhuis, Sabine C. Linn,

Cancer Genomics and Diagnostics

BackgroundBreast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents.Patients and methodsWe evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup).ResultsWe observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-likeCGH tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-likeCGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-likeCGH tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12).ConclusionBRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.