Abstract 1776: Impact of homologous recombination deficiency (HRD) biomarkers on outcomes in triple-negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313)
Authors: Sharma Priyanka , Barlow William , Godwin Andrew K. , Pathak Harsh , Isakova Kamilla , Hartman Anne R. , Timms Kristen M. , Linden Hannah M. , Tripathy Debu , Hortobagyi Gabriel N. , Hayes Daniel F. 
Published: July 2017

Abstract
Introduction: There is a critical need to develop biomarkers of response and resistance to adjuvant chemotherapy for TNBC. In preliminary studies, homologous recombination deficiency (HRD)-causing alterations have been reported in TNBC patients. HRD may impact response to standard chemotherapy as well as investigational therapies, such as PARP inhibitors and platinum agents. We report on the prognostic impact of two such markers in a large cohort of early stage TNBC patients who were uniformly treated with adjuvant doxorubicin (A) and cyclophosphamide (C).
Aims: To investigate BRCA1 promoter methylation (PM) and HRD score as prognostic markers in TNBC patients treated with adjuvant AC on S9313.
Methods: SWOG protocol S9313 accrued 3,125 women with early stage breast cancer to two alternative dose schedules of AC with no difference in outcomes between the two arms (J Clin Oncol 2007). We identified 425 (14%) patients with centrally determined TNBC status for whom tissue was available. BRCA1 PM (methylation specific PCR) and HRD score (composite of loss of heterozygosity, telomeric allelic imbalance and large-scale state transitions, Myriad Genetics Inc.) were performed on genomic DNA isolated from pre-treatment FFPE breast tumor tissue. HRD was classified as positive if there was either a deleterious tumor(t) BRCA1 or BRCA2 mutation and/or a pre-defined HRD score &gt; 42. The markers were tested for prognostic effect on DFS and OS using a Cox regression model with adjustment for randomized treatment assignment.
Results: For 425 TNBC patients median age was 45 years (range 22-74) and at a median follow up of 10.2 years there are 166 DFS and 129 OS events (5 year DFS and OS = 74% and 82%, respectively; 10-year DFS and OS = 66% and 73%). BRCA1 PM was determined in 82% (348/425) and was detected in 32% of patients. Presence of BRCA1 PM was suggestive of better DFS, but not statistically significant (HR=0.74; 95% CI 0.50-1.08, p=0.12). HRD results were determined in 91% (379/425) and 67% were HRD positive (27% with tBRCA mutation and 40% tBRCA negative but HRD score &gt;42). HRD positive status was associated with a better DFS (HR = 0.69; 95% CI 0.49-0.96 (p=0.027)) and OS (HR= 0.67; 95% CI 0.47-0.97 (p=0.032)). High HRD score (≥42) in tBRCA negative patients (n=274) was also associated with better DFS (HR = 0.62; 95% CI 0.42-0.92). tBRCA status (positive versus negative) did not impact DFS (p = 0.78).
Conclusions: Two thirds of TNBC patients receiving adjuvant AC chemotherapy had tumor HRD positivity. HRD was associated with better DFS and OS, perhaps due to high responses to AC. HRD status has the potential to be used as a selection criterion to identify TNBC patients who receive significant benefit from anthracycline chemotherapy, and may also be of value in selecting patients suitable for treatment with other DNA damaging agents like platinum salts/PARP-inhibitors.
Citation Format: Priyanka Sharma, William Barlow, Andrew K. Godwin, Harsh Pathak, Kamilla Isakova, Anne R. Hartman, Kristen M. Timms, Hannah M. Linden, Debu Tripathy, Gabriel N. Hortobagyi, Daniel F. Hayes. Impact of homologous recombination deficiency (HRD) biomarkers on outcomes in triple-negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1776. doi:10.1158/1538-7445.AM2017-1776