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

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.

Comprehensive Genomic Profiling of Taiwanese Breast Cancer Using a Novel Targeted Sequencing Panel

“…Another study using pan-cancer samples from 8 KEYNOTE studies further augments the clinical validity and applicability of TSO500 by showing its Youden index of 10.17 mutations/Mb corresponds to the cut-off value by the standard FoundationOne CDx [44]. It must be noted that advanced breast cancers were under-represented in the KEYNOTE-158, the study the FDA's approval came from [50]. Thus, the decision for the use of ICI for advanced breast cancers should be based on programmed death-ligand one (PD-L1) expression rst; TMB-high status evaluation to identify more patients who might bene t from ICI therapy should be used only for cases without a positive PD-L1 testing [46][47].…”

Significance of Multi-Cancer Genome Profiling Testing for Breast Cancer: A Retrospective Analysis of 3326 Cases from Japan’s National Database

“…There was a significant difference in frequency between MSI-High and TMB-High. It has been reported that patients with TMB ≥ 14 mut/mb have a higher response rate than patients with TMB ≥ 9 and < 14 mut/Mb [ 26 ]. Since the overall response rate of ICIs for BC is reported to be 7.1% [ 27 , 28 ], setting the TMB-High cutoff value above 10 mut/Mb might be more appropriate.…”

Molecular pathology in breast disease: diagnostic, prognostic, and therapeutic tools

“…Mutations in the ERS1 gene which codes ER occur in 20–40% of metastatic ER-positive luminal breast cancer and less often in early forms (1–2%) and can be detected via NGS sequencing [ 43 , 49 , 56 , 57 ]. Endocrine resistance, which has been attributed to ESR1 mutations in ER-positive breast cancer, can be tailored by alternative combination therapy with aromatase inhibitors and CDK4/6 inhibitors [ 43 , 49 , 56 – 58 ].…”

“…Mutations in the ERS1 gene which codes ER occur in 20–40% of metastatic ER-positive luminal breast cancer and less often in early forms (1–2%) and can be detected via NGS sequencing [ 43 , 49 , 56 , 57 ]. Endocrine resistance, which has been attributed to ESR1 mutations in ER-positive breast cancer, can be tailored by alternative combination therapy with aromatase inhibitors and CDK4/6 inhibitors [ 43 , 49 , 56 – 58 ]. For the detection of ESR1 mutation, it is probably more adequate to perform the test in liquid biopsy if available than on paraffin embedded tissues, which was endorsed by recent clinical guidelines as well [ 10 ].…”