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-like
CGH
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-like
CGH
tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-like
CGH
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-like
CGH
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.
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