A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer

Monika Graeser, Afshan McCarthy, Christopher J Lord, Kay Savage, Margaret Hills, Janine Salter, Nicholas Orr, Marina Parton, Ian E Smith, Jorge S Reis-Filho, Mitch Dowsett, Alan Ashworth, Nicholas C Turner

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Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

Original languageEnglish
Pages (from-to)6159-68
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number24
DOIs
Publication statusPublished - 15 Dec 2010

Keywords

  • Adult
  • Aged
  • Animals
  • Anthracyclines
  • Antineoplastic Combined Chemotherapy Protocols
  • Biomarkers, Pharmacological
  • Biopsy
  • Breast Neoplasms
  • Carcinoma, Ductal, Breast
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neoadjuvant Therapy
  • Prognosis
  • Rad51 Recombinase
  • Recombination, Genetic
  • Transplantation, Heterologous
  • Evaluation Studies
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Validation Studies

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  • Cite this

    Graeser, M., McCarthy, A., Lord, C. J., Savage, K., Hills, M., Salter, J., Orr, N., Parton, M., Smith, I. E., Reis-Filho, J. S., Dowsett, M., Ashworth, A., & Turner, N. C. (2010). A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clinical Cancer Research, 16(24), 6159-68. https://doi.org/10.1158/1078-0432.CCR-10-1027