title: A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer.
abstract: OBJECTIVE
  To assess the prevalence of defective homologous recombination (HR)-based DNA repair in sporadic primary breast cancers, examine the clincopathologic features that correlate with defective HR and the relationship with neoadjuvant chemotherapy response.
  
  
  METHODS
  We examined a cohort of 68 patients with sporadic primary breast cancer who received neoadjuvant anthracylcine-based chemotherapy, with core biopsies taken 24 hours after the first cycle of chemotherapy. We assessed RAD51 focus formation, a marker of HR competence, by immunofluorescence in postchemotherapy biopsies along with geminin as a marker of proliferative cells. We assessed the RAD51 score as the proportion of proliferative cells with RAD51 foci.
  
  
  RESULTS
  A low RAD51 score was present in 26% of cases (15/57, 95% CI: 15%-40%). Low RAD51 score correlated with high histologic grade (P = 0.031) and high baseline Ki67 (P = 0.005). Low RAD51 score was more frequent in triple-negative breast cancers than in ER- and/or HER2-positive breast cancer (67% vs. 19% respectively; P = 0.0036). Low RAD51 score was strongly predictive of pathologic complete response (pathCR) to chemotherapy, with 33% low RAD51 score cancers achieving pathCR compared with 3% of other cancers (P = 0.011).
  
  
  CONCLUSIONS
  Our results suggest that defective HR, as indicated by low RAD51 score, may be one of the factors that underlie sensitivity to anthracycline-based chemotherapy. Defective HR is frequent in triple-negative breast cancer, but it is also present in a subset of other subtypes, identifying breast cancers that may benefit from therapies that target defective HR such as PARP inhibitors.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Academic Department of Biochemistry, and Breast Unit, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Monika
authors.initials: M
authors.lastname: Graeser
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Kay
authors.initials: K
authors.lastname: Savage
authors.forename: Margaret
authors.initials: M
authors.lastname: Hills
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Nicholas
authors.initials: N
authors.lastname: Orr
authors.forename: Marina
authors.initials: M
authors.lastname: Parton
authors.forename: Ian E
authors.initials: IE
authors.lastname: Smith
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D001706:Biopsy; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D011379:Prognosis; D051135:Rad51 Recombinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous
chemical_list: D018943:Anthracyclines; D054316:Biomarkers, Pharmacological; D051135:Rad51 Recombinase
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