title: Breast cancers with a BRCA1-like DNA copy number profile recur less often than expected after high-dose alkylating chemotherapy.
abstract: OBJECTIVE
  Breast cancers in carriers of inactivating mutations of the BRCA1 gene carry a specific DNA copy-number signature ("BRCA1-like"). This signature is shared with cancers that inactivate BRCA1 through other mechanisms. Because BRCA1 is important in repair of DNA double-strand breaks through error-free homologous recombination, patients with a BRCA1-like tumor may benefit from high-dose alkylating (HD) chemotherapy, which induces DNA double-strand breaks.
  
  
  METHODS
  We investigated a single institution cohort of high-risk patients that received tandem HD chemotherapy schedule comprising ifosfamide, epirubicin, and carboplatin or conventional chemotherapy. We classified copy-number profiles to be BRCA1-like or non-BRCA1-like and analyzed clinical associations and performed survival analysis with a treatment by biomarker interaction design.
  
  
  RESULTS
  BRCA1-like status associated with high-grade and triple-negative breast cancers. BRCA1-like cases benefitted from the HD compared with a conventional regimen on disease-free survival (DFS): [hazard ratio (HR), 0.05; 95% confidence interval (CI), 0.01-0.38; P = 0.003]; distant DFS (DDFS): (HR, 0.06; 95% CI, 0.01-0.43; P = 0.01); and overall survival (OS; HR, 0.15; 95% CI, 0.03-0.83; P = 0.03) after correction for prognostic factors. No such benefit was observed in the non-BRCA1-like cases on DFS (HR, 0.74; 95% CI, 0.38-1.46; P = 0.39), DDFS (HR, 0.79; 95% CI, 0.41-1.52; P = 0.47), and OS (HR, 0.93; 95% CI, 0.52-1.64; P = 0.79). The P values for interaction were 0.01 (DFS), 0.01 (DDFS), and 0.045 (OS).
  
  
  CONCLUSIONS
  BRCA1-like tumors recurred significantly less often after HD than conventional chemotherapy. BRCA1-like copy-number profile classification may be a predictive marker for HD alkylating chemotherapy.
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: Universitäts-Frauenklinik, University of Heidelberg, Heidelberg, Germany. National Center for Tumour Diseases, Heidelberg, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Marmé
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Aulmann
authors.affiliation: Institute of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Sinn
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Hendrik F
authors.initials: HF
authors.lastname: van Essen
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.affiliation: Universitäts-Frauenklinik, University of Heidelberg, Heidelberg, Germany. National Center for Tumour Diseases, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: Department of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands. s.linn@nki.nl.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein