Abstract 3542: Frequency of homologous recombination-related gene mutations in breast cancer and their correlation with tumor mutation burden
Authors: Lan Haitao , Bu Qing , Zhuang Li , Ren Shuang , Yan Xuexin , Li Ye , Yu Qian , Shi Xiaoliang , Zhao Juan , Guo Honglin , Zhao Liang 
Published: September 2020

Abstract
Background:
Breast cancer is the most common malignancy in women worldwide and important therapeutic progress has been achieved over the past decade. The identification of new biomarkers in breast cancer is urgently needed to stratify populations who may benefit from new personalized therapies. Defects in the homologous recombination DNA damage repair (HR-DDR) pathway sensitizes tumors to therapeutics that target this pathway, such as (PARP) inhibitors. The aim of our study was to determine the prevalence of HR-DDR pathogenic mutations and their correlation with tumor mutation burden (TMB).
Materials and Methods:
Formalin-fixed, paraffin-embedded (FFPE) and matched blood samples of 328 Chinese breast cancer patients were collected for 450 cancer gene next-generation sequencing (NGS) targeted panel assay. Genomic alterations (GAs), including single base substitution, short and long insertion/deletions, copy number variations, gene fusions, and rearrangements, and TMB values were assessed with a mean coverage of 1000X. Samples with at least 1 GA in the HR pathway genes (ARID1A, ATM, ATR, ATRX, AURKA, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L/M, MRE11A, NBN, PALB2, RAD50/1/1B/1C/1D/2, RAD54B/L, or WRN) were identified as HR-DDR deficient (HRD).
Results:
Our cohort included 326 females and 2 males with a median age of 49 years old. Molecular subtypes included HR+ (49%, n=161), HER-2+ (32.6%, n=107), and triple-negative breast cancer (TNBC) (18.2%, n=60). HR-DDR mutations were detected in 38.1% (125/328) of patients, and more than one mutation was found in 23 patients. The most commonly mutated genes included BRCA2 (7.31%), ARID1A (6.4%), BRCA1 (5.48%), AURKA (2.4%), and RAD50 (2.1%). No mutations were identified in genes of CHEK1, FANCE/F/G/L, MRE11A, RAD51/1B/1D, or RAD54L. HRD variations were enriched in 47.3% of stage IV cases, and only in 13.6% of cases at earlier stages (p&lt;0.01). HRD mutations were not significantly associated with molecular subtypes, including HR+ (38.5%, n=62), HER-2+ (37.4%, n=40), and TNBC (38.3%, n=23). HRD cases had a higher median TMB than non-HRD cases (5.4 vs 3 muts/Mb, respectively, P &lt;0.01). HRD-related germline mutations were found in 11.9% (39/328) of patients, and HR+ patients seemed to harbor more HRD-related germline mutations. BRCA1/2 mutations were the most frequent germline mutations (BRCA1, n=8; BRCA2, n=13). One patient had 2 germline mutations (BRCA2/FANCA).
Conclusions:
Our study revealed that HR-DDR mutations occurred in 38.1% of Chinese breast cancer patients, and BRCA2 was the most commonly mutated gene. HR-DDR mutations were associated with a higher TMB value, indicating a potential strategy for immunotherapy in Chinese breast cancer patients. The role of HRD-directed therapies, including poly-ADP ribose polymerase inhibitors and newer agents such as ATR inhibitors, needs to be explored.
Citation Format: Haitao Lan, Qing Bu, Li Zhuang, Shuang Ren, Xuexin Yan, Ye Li, Qian Yu, Xiaoliang Shi, Juan Zhao, Honglin Guo, Liang Zhao. Frequency of homologous recombination-related gene mutations in breast cancer and their correlation with tumor mutation burden [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3542.