Prevalence Of High Tumor Mutational Burden And Association With Survival In Patients With Less Common Solid Tumors

Question What is the prevalence of high tumor mutational burden (TMB-H), defined as 10 or more mutations per megabase, and what is its association with overall survival among patients with 10 rare solid tumor types not treated with immunotherapy? Findings In this cohort study among 2589 patients, nearly 13% had TMB-H tumors. Overall survival among patients with TMB-H tumors did not differ from that observed among patients with non-TMB-H tumors when receiving nonimmunotherapy treatments. Meaning These findings suggest that TMB-H was not associated with overall survival in patients with these cancer types in the absence of immunotherapy.This cohort study examines tumor mutational burden in patients with uncommon cancers not receiving immunotherapy as a biomarker associated with overall survival.Importance Tumor mutational burden (TMB) is a potential biomarker associated with response to immune checkpoint inhibitor therapies. The prognostic value associated with TMB in the absence of immunotherapy is uncertain. Objective To assess the prevalence of high TMB (TMB-H) and its association with overall survival (OS) among patients not treated with immunotherapy with the same 10 tumor types from the KEYNOTE-158 study. Design, Setting, and Participants This retrospective cohort study evaluated the prognostic value of TMB-H, assessed by Foundation Medicine (FMI) and defined as at least 10 mutations/megabase (mut/Mb) in the absence of immunotherapy. Data were sourced from the deidentified Flatiron Health-FMI clinicogenomic database collected up to July 31, 2018. Eligible patients were aged 18 years or older with any of the following solid cancer types: anal, biliary, endometrial, cervical, vulvar, small cell lung, thyroid, salivary gland, mesothelioma, or neuroendocrine tumor. Patients with microsatellite instability-high tumors were excluded from primary analysis. For OS analysis, patients were excluded if immunotherapy started on the FMI report date or earlier or if patients died before January 1, 2012, and patients were censored if immunotherapy was started later than the FMI report date. Data were analyzed from November 2018 to February 2019. Main Outcomes and Measures Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level. Results Of 2589 eligible patients, 1671 (64.5%) were women, and the mean (SD) age was 63.7 (11.7) years. Median (interquartile range) TMB was 2.6 (1.7-6.1) mut/Mb, and 332 patients (12.8%) had TMB-H (>= 10 mut/Mb). Prevalence of TMB-H was highest among patients with small cell lung cancer (40.0%; 95% CI, 34.7%-45.6%) and neuroendocrine tumor (29.3%; 95% CI, 22.8%-36.6%) and lowest was among patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%) and thyroid cancer (2.7%; 95% CI, 1.2%-5.7%). Adjusted hazard ratio for OS of patients not treated with immunotherapy with TMB-H vs those without TMB-H was 0.94 (95% CI, 0.77-1.13). Comparable results were observed when including patients with high microsatellite instability tumors and calculating OS from first observed antineoplastic treatment date. Conclusions and Relevance These findings suggest that prevalence of TMB-H varies widely depending on tumor type and TMB-H does not appear to be a factor associated with OS among patients across these cancer types treated in the absence of immunotherapy.