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Across nearly 4,000 breast cancers, one in twenty carried ten or more mutations per megabase, more often in triple-negative and metastatic tumours, and mostly because of APOBEC enzyme activity or mismatch repair failure.
3,969 primary or metastatic breast cancer samples from six public genomic studies with exome or panel sequencing were classified as high TMB at 10 or more mutations per megabase; eight Dana-Farber patients were added. Median TMB was 2.63 mut/Mb and varied by subtype (HR-negative/HER2-negative above HER2-positive above HR-positive/HER2-negative) and sample type (metastatic above primary). Hypermutated tumours were found in 198 patients (5%), enriched in metastatic versus primary disease (8.4% versus 2.9%). APOBEC activity (59.2%) and mismatch repair deficiency (36.4%) were the commonest mutational processes; three hypermutated patients treated with pembrolizumab-based therapy had objective durable responses.
TMB-high is uncommon but not negligible in TNBC, rises at relapse, and the tumour-agnostic pembrolizumab indication makes it worth measuring on a metastatic biopsy.
Shares Nancy U. Lin, TMB-high (tumour mutational burden >= 10 mutations per megabase), Sara M. Tolaney, Tumour mutational burden (TMB).
Shares TMB-high (tumour mutational burden >= 10 mutations per megabase), Mutational signature, Tumour mutational burden (TMB).
Shares Nancy U. Lin, Dana-Farber Brigham Cancer Center, Triple-negative breast cancer (TNBC).
Shares Nancy U. Lin, Sara M. Tolaney, Dana-Farber Brigham Cancer Center, Triple-negative breast cancer (TNBC).
Shares Tumour mutational burden testing, Tumour mutational burden (TMB), Triple-negative breast cancer (TNBC).
Shares Mutational signature, Tumour mutational burden (TMB).
Shares Nancy U. Lin, Dana-Farber Brigham Cancer Center, Triple-negative breast cancer (TNBC).