Abstract
Background: 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. Recently three DNA-based measures (LOH, Abkevich et al.; TAI, Birkbak et al; LST, Popova et al.) have been developed and shown to be highly associated with BRCA1/2 mutation status and sensitivity to platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline and cyclophosphamide, with or without a taxane. This study assesses the association of LOH, TAI, LST and the sum of these measures, the HRD Score, with response to standard neoadjuvant chemotherapy in patients with TNBC.
Methods: Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutation positive hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline-based neoadjuvant chemotherapy at Stanford University Medical Center or Cedars-Sinai Medical Center under IRB approved protocols. Measures of LOH, TAI, LST were obtained; tumor BRCA1/2 mutation analysis was conducted; and BRCA1 promoter methylation status was determined. Response was categorized by the residual cancer burden (RCB) score with responders defined as RCB 0 or 1, and non-responders as RCB 2 or 3. Data were also analyzed using the outcome of pathologic complete response (RCB 0). BRCA1/2 deficiency was defined as either BRCA1/2 germline or somatic mutant, or BRCA1 methylated with loss of the second allele in the tumor confirmed by LOH at the affected gene. Associations of LOH, TAI, LST, HRD Score, BRCA1/2 deficiency and mutation status with response to neoadjuvant therapy were evaluated with univariate logistic regression models.
Results: All three metrics showed significant association with response (LOH: p=0.0018; TAI: p=0.0057; LST: p=0.0043) and pCR (LOH: p=0.0061; TAI: p=0.0044; LST: p=0.047). The sum of the scores, HRD Score, was also significantly associated with response (p=0.0021) and pCR (0.011). Neither BRCA1/2 mutation status (p=0.78 and p=0.31 respectively) nor BRCA1/2 deficiency (p=0.12 and p=0.34 respectively) were significantly associated with response or pCR in this cohort. When the analysis was restricted to BRCA1/2 intact samples (n=29) all scores were still significantly associated with pCR (LOH: p=0.019; TAI: p=0.0046; LST: p=0.013; HRD: p=0.0067), while only the sum was significant for response (p=0.042).
Conclusions:All three measures of HR deficiency, LOH, TAI and LST and the sum of these three metrics, the HRD Score, are 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, though we have yet to examine cohorts of patients treated with non-anthracycline-containing standard chemotherapy regimens, such as docetaxel and cyclophosphamide. The HRD Score could be used clinically to identify patients with increased sensitivity to DNA damaging therapeutics.
Citation Format: Melinda L Telli, William Audeh, Kirstin C Jensen, Shikha Bose, Kirsten Timms, Alexander Gutin, Victor Abkevich, Jerry Lanchbury, Chris Neff, Elisha Hughes, Zaina Sangale, Joshua Jones, Richard Wenstrup, Anne-Renee Hartman, Pei-Jen Chang, Shaveta Vinayak, James M Ford. Homologous recombination deficiency (HRD) score predicts response to standard neoadjuvant chemotherapy in patients with triple negative or BRCA1/2 mutation-associated breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-06-01.
Volume 75, Issue 9 Supplement
