Liquid Biopsies to Evaluate Immunogenicity of Gynecological/Breast Tumors: On the Way to Blood-Based Biomarkers for Immunotherapies

Abstract

<b><i>Background:</i></b> Despite the assumption of breast cancer (BC) as a cold, non-immunogenic tumor, immune checkpoint inhibitor (ICI) therapy is favorable for a subgroup of patients. Immunohistochemical assessment of the programmed cell death ligand 1 (PD-L1) is the only approved companion diagnostic for anti-PD-L1 therapy in metastatic triple-negative BC; however, challenges regarding the standardization of PD-L1 scoring in tumor tissue still remain. Consequently, to select patients most likely to respond to ICI, blood-based biomarkers are urgently needed. <b><i>Summary and Key Messages:</i></b> Liquid biopsy, comprising circulating immune cells, circulating tumor cells and extracellular vesicles, as well as their surface proteins, is of high potential, and these analytes were already shown to be molecular correlates or regulators of the evasion from antitumoral immune reaction. Liquid biopsy, also enabling the evaluation of tumor mutational burden (TMB), microsatellite instability, and the T-cell receptor repertoire, allows serial sampling for monitoring purposes and reflects intra-tumoral heterogeneity which qualifies as marker for immunogenicity. Only a very few studies have already elucidated the potential of these analytes as biomarkers under ICI therapy. Nonetheless, the topic is of growing interest and has high relevance for the future. However, for clinical implementation, these multifarious analytes first need to pass robust standardization and validation procedures.

Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis

“…Breast cancer immunotherapy based on immune checkpoint inhibitors is currently effective for some TNBCs. These patients with TNBC usually show a high TMB and specific characteristics of immune cell infiltration (21,22). In this study, to further explore the immunogenicity of TNBC, i) we investigated differences in immune cell infiltration between high and low tumor mutation loads, differences in key pathways, and correlation to the prognosis of TNBC; ii) we analyzed the difference in immune cell infiltration between the wild and mutation group; iii) In order to identify biomarkers related to the prognosis of TNBC, we screened and identified a prognostic gene related to TNBC, the key mutation gene FAT3.…”

Tumour mutation burden and infiltrating immune cell subtypes influenced the breast cancer prognosis

“…With these advances in research, TMB and infiltrating immune cells have emerged as potential prognostic biomarkers for tumour treatment selection. Previous studies have shown that ICIs are effective in some triple-negative breast cancer patients, who typically present with high TMB and specific immune cell infiltration ( 27 - 29 ). It is therefore essential to explore the role played by TMB in all types of breast cancer and its relation to clinical prognosis.…”

Classification and immune invasion analysis of breast cancer based on m6A genes

“…Further analysis showed that a higher m6A score was positively associated with mutations in TMB and had a poorer prognosis. Immunotherapy based on immune checkpoint inhibitors has some efficacy in TNBC, and these patients often show higher TMB and immune cell infiltration (28)(29)(30). In addition, we observed a strong correlation between the m6A score and PD-L1, a predictor of the immune response, suggesting that the m6A gene may influence the efficacy of immunotherapy and that this score could be used in clinical practice to assist in the formulation of treatment plans.…”