Prevalence and molecular features of TMB-high and MSI-high breast cancer assessed by gene panel testing

Background Tumor mutational burden-high (TMB-H) and microsatellite instability-high (MSI-H) are useful biomarkers for immune checkpoint inhibitors (ICIs) across multiple cancer types. Nonetheless, their prevalence is low in breast cancer, and evidence remains scarce compared with that in other cancer types. Therefore, the TMB-H and MSI-H prevalence in breast cancer was assessed, and the mechanisms underlying these conditions were examined here using gene panel testing (GPT). Methods GPT was performed in primary invasive breast cancer cases to calculate tumor mutational burden (TMB) and microsatellite instability (MSI) and to determine the prevalence of TMB-H and MSI-H breast cancer. Gene mutation patterns and mismatch repair (MMR) protein expression were confirmed in patients with TMB-H. Single-base substitution (SBS) signature analysis was performed on samples with ≥ 50 mutations to estimate the mechanisms underlying TMB-H. Results The median TMB was 2.58 mut/Mb. TMB-H was detected in 2.6% (n = 6) of all cases (n = 234). MSI-H cases were identified in 1.3% (n = 3) of cases; all were included among the TMB-H cases. Among the three TMB-H/MSI-H cases, MLH1 mutations were detected in all; however, none were detected in the TMB-H/microsatellite instability-low (MSI-L) cases. SBS signature analysis was performed for three patients. The APOBEC and dMMR signatures were predominant in the TMB-H/MSI-H and TMB-H/MSI-L cases, respectively. Conclusion GPT detects TMB-H and MSI-H while enabling assessment of their underlying mechanisms, potentially supporting more accurate treatment selection, including ICIs, and prognosis prediction.