Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy

Introduction BRCA -mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating...

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Vydáno v:	Breast cancer research : BCR Ročník 16; číslo 3; s. R47
Hlavní autoři:	Vollebergh, Marieke A, Lips, Esther H, Nederlof, Petra M, Wessels, Lodewyk FA, Wesseling, Jelle, vd Vijver, Marc J, de Vries, Elisabeth GE, van Tinteren, Harm, Jonkers, Jos, Hauptmann, Michael, Rodenhuis, Sjoerd, Linn, Sabine C
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 15.05.2014 BioMed Central Ltd
Témata:	Adult Analysis Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biomarkers, Tumor - genetics Biomedical and Life Sciences Biomedicine BRCA1 Protein - genetics BRCA2 Protein - genetics Breast cancer Cancer Research Carboplatin - therapeutic use Care and treatment Comparative Genomic Hybridization Cyclophosphamide - therapeutic use DNA Breaks, Double-Stranded DNA Repair - genetics Epirubicin - therapeutic use Female Fluorouracil - therapeutic use Homologous Recombination - genetics Humans Middle Aged Oncology Patient outcomes Receptor, ErbB-2 - metabolism Receptors, Estrogen - metabolism Receptors, Progesterone - metabolism Research Article Retrospective Studies Surgical Oncology Thiotepa - therapeutic use Treatment Outcome Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - pathology Breast Cancer Patient Sporadic Breast Cancer TP53 Mutation Array Comparative Genomic Hybridization Breast Cancer
ISSN:	1465-542X, 1465-5411, 1465-542X
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Shrnutí:	Introduction BRCA -mutated breast cancer cells lack the DNA-repair mechanism homologous recombination that is required for error-free DNA double-strand break (DSB) repair. Homologous recombination deficiency (HRD) may cause hypersensitivity to DNA DSB-inducing agents, such as bifunctional alkylating agents and platinum salts. HRD can be caused by BRCA mutations, and by other mechanisms. To identify HRD, studies have focused on triple-negative (TN) breast cancers as these resemble BRCA1 -mutated breast cancer closely and might also share this hypersensitivity. However, ways to identify HRD in non- BRCA -mutated, estrogen receptor (ER)-positive breast cancers have remained elusive. The current study provides evidence that genomic patterns resembling BRCA1- or BRCA2 -mutated breast cancers can identify breast cancer patients with TN as well as ER-positive, HER2-negative tumors that are sensitive to intensified, DSB-inducing chemotherapy. Methods Array comparative genomic hybridization (aCGH) was used to classify breast cancers. Patients with tumors with similar aCGH patterns as BRCA1 - and/or BRCA2 -mutated breast cancers were defined as having a BRCA-like CGH status, others as non-BCRA-like CGH . Stage-III patients (n = 249) had participated in a randomized controlled trial of adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus 5-fluorouracil-epirubicin-cyclophosphamide (FE 90 C) chemotherapy. Results Among patients with BRCA-like CGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE 90 C was observed regarding overall survival (adjusted hazard ratio 0.19, 95% CI: 0.08 to 0.48) that was not seen for patients with non-BRCA-like CGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) ( P = 0.004). Half of all BRCA-like CGH tumors were ER-positive. Conclusions Distinct aCGH patterns differentiated between HER2-negative patients with a markedly improved outcome after adjuvant treatment with an intensified DNA-DSB-inducing regimen (BRCA-like CGH patients) and those without benefit (non-BRCA-like CGH patients).
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-542X 1465-5411 1465-542X
DOI:	10.1186/bcr3655