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

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.

Palliative chemotherapy after failure of high-dose chemotherapy in breast cancer--toxicity and efficacy.

We evaluated the toxicity and efficacy of the first palliative chemotherapy regimen after failure of high-dose chemotherapy in 148 patients with primary or metastatic breast cancer treated with high-dose chemotherapy (one full dose CTC, (cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, carboplatin 1600 mg/m2) or multiple courses CTC or 'tiny' CTC (tCTC) (two-thirds of the agents of the full-dose regimen), all divided over 4 days). After a median follow-up time of 46.8 (range 1-120) months, 79 patients had a relapse or progressive disease and 41 patients were treated with palliative chemotherapy. The most commonly used regimens were classical CMF (n = 13), docetaxel (n = 16) and less frequently anthracycline (n = 4), paclitaxel (n = 5), capecitabine (n = 2) and vinorelbine (n = 2). In both the CMF and docetaxel group, 3 patients required a dose reduction because of hematological toxicity. Objective responses were seen with CMF (23%) and docetaxel (69%) with a median duration of 161 (range 28-481) and 196 (range 62-437) days, respectively. We found no relationship of toxicity and response with treatment-free interval after high-dose chemotherapy. This report shows that conventional-dose palliative chemotherapy regimens may be safe and effective after failure of high-dose chemotherapy.