Ultra-high tumor mutation burden breast cancer: genomic profiling and real-world immunotherapy results.

Patients with metastatic breast cancer and tumor mutational burden (TMB) ≥10 mutations/megabase are eligible for immunotherapy, but clinical and genomic characteristics and outcomes of patients with ultra-high TMB (UHTMB) ≥20 mutations/megabase remain under-characterized. In this retrospective cohort and comparative effectiveness study we examined comprehensive genomic profiling assessed on tumors as part of routine care. Real-world time to next treatment (TTNT), and overall survival (rwOS) data were collected from the Flatiron Database. 45/2049 (2.2%) patients had UHTMB; patients with UHTMB were more likely to have estrogen receptor-positive disease (86.6% vs. 70.0%), lobular histology (40.0% vs. 14.5%), and PIK3CA mutation (81.8% vs. 37.9%) vs. patients with TMB ≤ 20. Patients with UHTMB who received immunotherapy had longer TTNT (4.9 vs. 2.6 months, hazard ratio (HR) = 0.49, 95% confidence interval (CI):0.26-0.91,p = 0.025) and longer rwOS (14.1 vs. 3.2 months, HR = 0.37, 95%CI:0.18-0.76,p = 0.007) than patients with TMB <10. Single agent immunotherapy is an important treatment option for patients with UHTMB.