Dataset Information

Prevalence of High Tumor Mutational Burden and Association With Survival in Patients With Less Common Solid Tumors.

ABSTRACT:

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.

SUBMITTER: Shao C

PROVIDER: S-EPMC7596577 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing (WXS) or using commercially available sequencing panels.WXS and RNA-seq data of 33 solid cancer types from TCGA were analyzed to determine whether a robust immune checkpoint activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker for response to immune checkpoint blockade therapy.We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments.In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.