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

Journal article (2011)

Authors

M. A. Vollebergh Antoni van Leeuwenhoek Hospital
Esther H. Lips Antoni van Leeuwenhoek Hospital
P. M. Nederlof Antoni van Leeuwenhoek Hospital
L.F.A. Wessels Antoni van Leeuwenhoek Hospital, Pattern Recognition and Bioinformatics - EEMCS
M. K. Schmidt Antoni van Leeuwenhoek Hospital
E. H. van Beers Antoni van Leeuwenhoek Hospital
S. Cornelissen Antoni van Leeuwenhoek Hospital
M. Holtkamp Antoni van Leeuwenhoek Hospital
F. E. Froklage Antoni van Leeuwenhoek Hospital
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Research Group
Pattern Recognition and Bioinformatics (EEMCS) (TU Delft)
Breast cancer BRCA1 Array comparative genomic hybridisation High-dose chemotherapy Platinum salt Predictive marker
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Published Date

04-07-2011

Language

English

Reuse Rights

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Faculty

Electrical Engineering, Mathematics and Computer Science

Department

Intelligent Systems

Research Group

Pattern Recognition and Bioinformatics

Abstract

Background: Breast 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 methods: We 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). Results: We 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). Conclusion: BRCA1 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.