Abstract

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

Highlights

  • Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are widely applied across numerous malignancies

  • Biomarker analysis of the KEYNOTE-086 study comprised of metastatic triple negative breast cancer (TNBC) patients treated with pembrolizumab monotherapy did show a positive association between high tumor mutational burden (TMB) (≥175 mutations per exome) and overall response rate, progression-free survival, and overall survival [14]

  • Deficient mismatch repair has been observed in multiple cancers and first demonstrated utility as a predictive biomarker for immunotherapy response in colorectal cancer [23]

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Summary

Immune Checkpoint Inhibition in Breast Cancer

Immune checkpoint inhibitors (ICIs) harness the ability of the immune system to recognize and destroy cancerous cells. They have demonstrated varied clinical success across a spectrum of solid organ malignancies. The FDA has approved pembrolizumab in two indications for the treatment of breast cancer based on results of phase III clinical trials combining it with standard of care chemotherapy in a subset of patients with TNBC [4,6]. The only predictive biomarker validated in phase III ICI trials in breast cancer is PD-L1 expression on tumor cells and surrounding cells as measured by immunohistochemistry (IHC). The results from the various assays could not be harmonized, suggesting different assays are identifying unique populations of patients [12]. This review focuses on the current landscape of both tumor-based and liquid-based potential biomarkers for ICI therapy

Tumor Cell Microenvironment Biomarkers
DNA Repair Pathways
Other Genomic Alterations
Immune Cell Microenvironment Biomarkers
Peripheral Blood Biomarkers
Circulating Tumor Biomarkers
Circulating Immune Cells Biomarkers
Gut Microbiome
Findings
Conclusions
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