Abstract 2602: Clinical implication of mutation load in patients with HER2-positive refractory metastatic breast cancer
Authors: Park Yeon Hee , Park Kyunghee , Park Song Ee , Lee Eunjin , Kim Ji-Yeon , Ahn Jin Seok , Im Young-Hyuck , Jung Hun , Lee Chooghoon , Park Woong-Yang , Cristescu Razvan 
Published: August 2018

Abstract
Background and Purpose Studies have suggested that the antigenicity of tumor cell is highly correlated with response to immune checkpoint inhibitors. Checkpoint blockade has been found to be particularly effective in tumors with high tumor mutational burden (TMB) in certain indications such as melanoma and NSCLC, while cancers with lower TMB have been shown to be less responsive to checkpoint inhibitors. In HER2-positive metastatic breast cancer (MBC), TMB has potential to be a candidate prognostic or predictive marker for conventional treatments including HER2 targeting agents. This research was conducted to explore the clinical implication of somatic TMB in a well-defined HER2-positive MBC population who were previously treated but progressed.
Methods Forty-six patients with HER2-positive MBC who have progressed from more than two HER2-directed therapies were enrolled from 2007 to 2016. Whole exome sequencing was performed on FFPE tumor samples and matched normal tissue. Sequencing reads were aligned to reference human genome using BWA-MEM followed by standard pre-processing steps and GATK to generate analysis ready BAM files. MuTect suite was used to generate somatic single nucleotide variants (SNV) calls using default parameters by comparing BAM files from tumor and matched normal samples. TMB for a subject was defined as the sum of somatic non-synonymous SNVs that passed all the filters described.
Results Among 46 patients, 13 (28.3%) patients were determined to estrogen receptor (ER)-positive and 9 (19.6%) patients were determined to progesterone receptor (PR)-positive in immunohistochemistry (IHC) analysis. The median age 48 years (range: 29-68) and all (100%) patients were female. 20 patients (43.5%) were recurrent MBC compared to de novo (n = 26, 56.5%). 16 (34.6%) patients demonstrated more than 100 mutations (and defined as high TMB in this population). The median follow up of duration was 57.5 months (95% CI: 55.4 - 60.6). The median overall survival (OS) according to low or high TMB status (44.9 months vs. 85.8 months) was significantly different (p = 0.016). In a multivariate Cox regression analysis, TMB was the only independent prognostic factor for good OS when adjusted for age and recurrence (Hazard ratio = 0.32, 95% CI, 0.103 - 0.998, p = 0.049).
Conclusions Data implicated that high TMB can be a prognostic marker that predicts good OS outcomes with conventional HER2-directed treatments and chemotherapy. Furthermore, future trials using TMB as a stratification marker could identify the right population with potential to respond to immune checkpoint inhibitor after recurrence following HER2-directed treatments. To our knowledge this is the first report that tumor mutation burden (TMB) associate with response to standard of care therapy in HER2+ breast tumors.
Citation Format: Yeon Hee Park, Kyunghee Park, Song Ee Park, Eunjin Lee, Ji-Yeon Kim, Jin Seok Ahn, Young-Hyuck Im, Hun Jung, Chooghoon Lee, Woong-Yang Park, Razvan Cristescu. Clinical implication of mutation load in patients with HER2-positive refractory metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2602.