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.


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).


CONCLUSIONS
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.
Division of Molecular Biology; Division of Medical Oncology.
M A
MA
Vollebergh
Division of Experimental Therapy.
E H
EH
Lips
Division of Experimental Therapy; Division of Molecular Pathology.
P M
PM
Nederlof
Department of Bioinformatics and Statistics, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft.
L F A
LFA
Wessels
Division of Experimental Therapy; Department of Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam.
M K
MK
Schmidt
Division of Experimental Therapy.
E H
EH
van Beers
Division of Experimental Therapy.
S
S
Cornelissen
Division of Medical Oncology.
M
M
Holtkamp
Division of Medical Oncology.
F E
FE
Froklage
Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen.
E G E
EGE
de Vries
Division of Medical Oncology.
J G
JG
Schrama
Department of Pathology.
J
J
Wesseling
Department of Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam; Department of Pathology, Academic Medical Center.
M J
MJ
van de Vijver
Department of Biometrics, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
H
H
van Tinteren
Division of Molecular Biology.
M
M
de Bruin
Department of Bioinformatics and Statistics, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam.
M
M
Hauptmann
Division of Medical Oncology.
S
S
Rodenhuis
Division of Molecular Biology; Division of Medical Oncology. Electronic address: s.linn@nki.nl.
S C
SC
Linn
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D002280:Basal Cell Carcinoma / Q000145:classification / Q000188:drug therapy* / Q000235:genetics; D055028:Comparative Genomic Hybridization; D003520:Cyclophosphamide / Q000008:administration & dosage; D019175:DNA Methylation; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D013852:Thiotepa / Q000008:administration & dosage; D016896:Treatment Outcome
D019313:BRCA1 Protein; D016190:Carboplatin; D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013852:Thiotepa; C492913:BRCA1 protein, human