Predictive Biomarkers for Immune Checkpoint Inhibitors in Metastatic Breast Cancer

Abstract

We examined a large dataset of female metastatic breast cancers (MBCs) profiled with comprehensive genomic profiling (CGP) to identify the prevalence and distribution of immunotherapy responsiveness-associated biomarkers. DNA was extracted from 3831 consecutive MBCs: 1237 (ER^pos /HER2^neg ), 1953 ER^neg /HER2^amp , and 641 triple-negative breast cancer (TNBC). CGP was performed using the FoundationOne^® or FoundationOne^® CDx NGS assay. Tumor mutational burden (TMB) and microsatellite instability (MSI) were determined in a subset of cases. PD-L1 expression in immunocytes in a subset of cases was determined by immunohistochemistry using the companion diagnostic VENTANA PD-L1 SP142 Assay. The median age of the cohort was 54 years (range 20-89). Genomic alterations (GAs)/tumor were similar (range: 5.9-7.3). Markers of potential immune checkpoint inhibitor (ICPI) benefit included: CD274 (PD-L1) amplification (1%-3%), BRAF GA (1%-4%), TMB of ≥10 mutations/Mb (8%-12%), MSI-high (0.1%-0.4%), PBRM1 GA (1%), and positive PD-L1 staining of immunocytes ranging from 13% in ER^pos /HER2^neg and 33% in ER^neg /HER2^amp to 47% in the TNBC group. Potential markers of ICPI resistance included inactivating STK11 GA (1%-2%) and MDM2 amplification (3%-6%). MTOR pathway targets were common with lowest frequency in TNBC. ERBB2 short variant mutations were most frequent ER^pos /HER2^neg and absent in TNBC. BRCA1/2 GA were least frequent in ER^neg /HER2^amp . The demonstrations of clinical benefit of immunotherapy in MBC support the need for development and utilization of biomarkers to guide the use of ICPIs for these patients. In addition to guiding therapy selection, CGP shows potential to identify GA linked to response and resistance to ICPI in MBC.

Keywords: PD-L1; biomarkers; comprehensive genomic profiling; immunotherapy; metastatic breast cancer; microsatellite instability; tumor mutational burden.