Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer

Abstract

Purpose

Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer.

Methods

Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ≥ 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index.

Results

HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52–11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65–160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%).

Conclusions

HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.

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Funding

This study was funded by Susan G. Komen for the Cure, Breast Cancer Research Foundation, Stanford Cancer Institute, Myriad Genetics.

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Correspondence to Melinda L. Telli.

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Conflict of interest

Zaina Sangale, Rebecca Peterson, Kirsten Timms, Alexander Gutin, Joshua Jones, Chris Neff, Elisha Hughes, Richard Wenstrup, and Victor Abkevich are employed by and own stock in Myriad Genetics. Anne-Renee Hartman is employed and receives stock from GRAIL. Shaveta Vinayak has received travel funds and sits on the advisory board at Tesaro.

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Telli, M.L., Hellyer, J., Audeh, W. et al. Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer. Breast Cancer Res Treat 168, 625–630 (2018). https://doi.org/10.1007/s10549-017-4624-7

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Keywords

  • Triple-negative breast cancer
  • Homologous recombination DNA repair
  • HRD assay
  • Neoadjuvant chemotherapy
  • BRCA1
  • BRCA2