Tumor Mutational Burden in Breast Cancer: Current Evidence, Challenges, and Opportunities

SIMPLE SUMMARY: The tumor mutational burden (TMB) can be defined as the number of somatic mutations per megabase of the sequenced genome. It correlates with tumor neoantigen burden, T cell infiltration, and response to immune checkpoint inhibitors in many solid tumor types. In addition, TMB has been used as a biomarker of benefit to pembrolizumab in a tissue-agnostic manner; however, in breast cancer limited data exist regarding the true role of this biomarker in clinical practice. This review describes current knowledge about TMB in breast cancer and its potential role as a predictive biomarker of immunotherapy in the advanced setting. We also discuss the need for additional work to better understand how to integrate TMB in clinical practice, including the establishment of the best genomic tool to determine TMB, the ideal TMB cutoff, and the optimal immunotherapy regimen. ABSTRACT: Tumor mutational burden (TMB) correlates with tumor neoantigen burden, T cell infiltration, and response to immune checkpoint inhibitors in many solid tumor types. Based on data from the phase II KEYNOTE-158 study, the anti-PD-1 antibody pembrolizumab was granted approval for treating patients with advanced solid tumors and TMB ≥ 10 mutations per megabase. However, this trial did not include any patients with metastatic breast cancer; thus, several questions remain unanswered about the true role of TMB as a predictive biomarker of benefit to immune checkpoint inhibitor therapy in breast cancer. In this review, we will discuss the challenges and opportunities in establishing TMB as a predictive biomarker of benefit to immunotherapy in metastatic breast cancer.