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

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-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.

• Authors: M A Vollebergh, E H Lips, P M Nederlof, L F A Wessels, M K Schmidt, E H van Beers, S Cornelissen, M Holtkamp, F E Froklage, E G E de Vries, J G Schrama, J Wesseling, M J van de Vijver, H van Tinteren, M de Bruin, M Hauptmann, S Rodenhuis, S C Linn
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 22 Issue 7 Pg. 1561-1570 (Jul 2011) ISSN: 1569-8041 [Electronic] England
• PMID: 21135055 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• Receptors, Estrogen
• Receptors, Progesterone
• Epirubicin
• Cyclophosphamide
• Thiotepa
• Carboplatin
• Receptor, ErbB-2
• Fluorouracil

Topics

• Adult
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• BRCA1 Protein (genetics)
• Breast Neoplasms (classification, drug therapy, genetics)
• Carboplatin (administration & dosage)
• Carcinoma, Basal Cell (classification, drug therapy, genetics)
• Comparative Genomic Hybridization
• Cyclophosphamide (administration & dosage)
• DNA Methylation
• Epirubicin (administration & dosage)
• Female
• Fluorouracil (administration & dosage)
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• In Situ Hybridization, Fluorescence
• Mutation (genetics)
• Promoter Regions, Genetic
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Survival Rate
• Thiotepa (administration & dosage)
• Treatment Outcome