Abstract P2-09-26: Frequency and mechanisms of elevated somatic mutation burden in metastatic breast cancer and response to immune checkpoint blockade

Abstract

Abstract Background: Immune checkpoint blockade (ICB) is effective in the treatment of various malignancies. Thus far, however, results in breast cancer have been mixed. Elevated tumor mutational load, and subsequent increased likelihood of forming immunogenic neoantigens, has been correlated with response to ICB. Mutational load observed in breast cancers varies widely. However, most studies have assessed mutational load using primary tumors. Few studies have explored the frequency of high mutational load, molecular mechanisms accounting for this phenomenon, and its potential impact on response to ICB in metastatic breast cancer (MBC). Methods: From 2011-2016, 124 patients (pts) with MBC of varying subtypes underwent research biopsy of their metastatic disease for whole genome, exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-OncoSeq). Those pts with elevated somatic mutation load were defined as having greater than 10 mutations per megabase of targeted sequencing and mutational signatures accounting for high mutation load were noted. Pts treated subsequently with ICB were followed to assess response. Results: Twelve MBC pts had high mutation load (10% of cohort). Eight pts had estrogen receptor (ER) positive MBC and 4 pts had metastatic triple negative breast cancer (TNBC). In 5 cases, a clear mutational signature accounting for high mutation load was evident. Two TNBC cases harbored an APOBEC mutational signature in addition to 1 TNBC and 2 ER positive tumors displaying a microsatellite instability signature (MSI-H). Among the tumors with MSI-H signature, 1 case was associated with a pathogenic germline alteration in MLH1. Two pts were subsequently treated with ICB on a clinical trial. One pt came off study after 3 months due to progressive brain metastases and another had partial response to therapy lasting 7 months. Conclusions: Elevated somatic mutation burden in MBC is observed in approximately 10% of pts, and is detected in both ER positive and TNBC. Since high mutation burden has been associated with increased likelihood of response to ICB, identification of this genomic feature could have important therapeutic implications for MBC pts. Citation Format: Cobain EF, Robinson DR, Wu Y-M, Lonigro R, Vats P, Rabban E, Kumar-Sinha C, Schott AF, Smerage JB, Morikawa A, Burness ML, Van Poznak CH, Griggs J, Wicha M, Hayes DF, Chinnaiyan AM. Frequency and mechanisms of elevated somatic mutation burden in metastatic breast cancer and response to immune checkpoint blockade [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-26.