title: Genomic patterns resembling BRCA1- and BRCA2-mutated breast cancers predict benefit of intensified carboplatin-based chemotherapy.
abstract: BACKGROUND
  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-likeCGH status, others as non-BCRA-likeCGH. 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 (FE90C) chemotherapy.
  
  
  RESULTS
  Among patients with BRCA-likeCGH tumors (81/249, 32%), a significant benefit of HD-CTC compared to FE90C 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-likeCGH tumors (adjusted hazard ratio 0.90, 95% CI: 0.53 to 1.54) (P = 0.004). Half of all BRCA-likeCGH 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-likeCGH patients) and those without benefit (non-BRCA-likeCGH patients).
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Vollebergh
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lips
authors.forename: Petra M
authors.initials: PM
authors.lastname: Nederlof
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Vd Vijver
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Rodenhuis
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D016190:Carboplatin / Q000627:therapeutic use*; D055028:Comparative Genomic Hybridization; D003520:Cyclophosphamide / Q000627:therapeutic use; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D015251:Epirubicin / Q000627:therapeutic use; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012189:Retrospective Studies; D013852:Thiotepa / Q000627:therapeutic use; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; 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; C551750:BRCA2 protein, human; C508053:ERBB2 protein, human