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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Veröffentlicht in:Breast cancer research : BCR Jg. 16; H. 3; S. R47
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 15.05.2014
BioMed Central Ltd
Schlagworte:
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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Zusammenfassung: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).
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ISSN:1465-542X
1465-5411
1465-542X
DOI:10.1186/bcr3655