Prevalence and mutational determinants of high tumor mutation burden in breast cancer

BackgroundHigh tumor mutation burden (TMB) has been associated with benefit to immunotherapy in multiple tumor types. However, the prevalence of hypermutated breast cancer is not well described. The aim of this study is to evaluate frequency, mutational patterns, and genomic profile of hypermutated breast cancer.\n\nPatients and MethodsWe used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients samples that underwent whole exome sequencing or gene panel sequencing. Samples were classified as having high TMB if they had [≥]10 mutations per megabase (mut/Mb). An additional 8 patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among patients with high TMB, the mutational patterns, and genomic profile were determined. A subset of patients was treated with regimens containing PD-1 inhibitors.\n\nResultsThe median TMB was 2.63 mut/Mb. Median TMB significantly varied according to tumor subtype (HR-/HER2-> HER2+ > HR+/HER2-, p primary, p 2.2x10-16). Hypermutated tumors were found in 198 patients (5%), with an enrichment in metastatic versus primary tumors (8.4% versus 2.9%, p = 6.5 x 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer--including two with a dominant APOBEC activity signature and one with a dominant MMRd signature--treated with pembrolizumab-based therapies derived an objective and durable response to therapy.\n\nConclusionHypermutation occurs in 5% of all breast cancers, with an enrichment in metastatic tumors. Different mutational signatures are present in this population, with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.\n\nKey MessageHigh tumor mutation burden is found in 5% of all breast cancers and is more common in metastatic tumors. While different mutational signatures are present in hypermutated tumors, APOBEC activity is the most common dominant process. Preliminary data suggest that those tumors are more likely to benefit from PD-1 inhibitors.