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Integration of the Tumor Mutational Burden and Tumor Heterogeneity Identify an Immunological Subtype of Melanoma With Favorable Survival.

ABSTRACT: The tumor mutational burden (TMB) has been reported as a predictive marker of the response to immune checkpoint inhibition (ICI) therapy in previous melanoma clinical trials. However, the TMB alone is not sufficient to accurately predict immunotherapy benefit. Additional biomarkers are needed for better stratification of immunotherapy-sensitive patients. In the present study, mutation data and survival information of patients with melanoma were collected from several immunotherapy studies, and tumor heterogeneity was estimated using mutant-allele tumor heterogeneity (MATH). The benefit score was defined as the ratio between the TMB and tumor heterogeneity, and optimal critical values were selected to group patients and evaluate their response to ICI treatment. The benefit score significantly improved the performance of stratifying the overall survival of patients compared with the TMB alone as a predictor in two independent cohorts (p = 0.0068 vs. p = 0.1 and p = 0.045 vs. p = 0.13), in which patients were treated with Ipilimumab and Nivolumab, respectively. In another cohort of patients with melanoma receiving mixed ICI treatment, the benefit score was also positively associated with higher overall survival (p = 0.022) and outperformed the TMB alone, with a significance of p = 0.089. The benefit score showed a positive correlation with clonal TMB, a reported immunotherapy marker, and exceeded it in immunotherapy response prediction. Besides, a high benefit score was found to be associated with higher proportions of natural killer cells, lower proportions of M2 macrophages and elevated CD8 T cells, all of which favor ICI therapy. In summary, tumor heterogeneity combined with the TMB showed superior efficacy in predicting the response to ICI therapy. This might further help to delineate the mechanisms of immunotherapy in patients with melanoma.

SUBMITTER: Gao Y

PROVIDER: S-EPMC7661856 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Integration of the Tumor Mutational Burden and Tumor Heterogeneity Identify an Immunological Subtype of Melanoma With Favorable Survival.

Gao Yanmei Y Yang Chunhe C He Ning N Zhao Guodong G Wang Jianfei J Yang Yadong Y

Frontiers in oncology 20201030

The tumor mutational burden (TMB) has been reported as a predictive marker of the response to immune checkpoint inhibition (ICI) therapy in previous melanoma clinical trials. However, the TMB alone is not sufficient to accurately predict immunotherapy benefit. Additional biomarkers are needed for better stratification of immunotherapy-sensitive patients. In the present study, mutation data and survival information of patients with melanoma were collected from several immunotherapy studies, and t ...[more]

PMID: 33194669

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Project description:BackgroundHigh tumor mutational burden (TMB) is one of the widely researched predictive biomarkers of immune checkpoint inhibitors and has been shown to be closely related with response to immunotherapy in multiple cancer types. However, for patients who have failed conventional therapy and are about to undergo immunotherapy, there is no consensus recommendation on the timing of tumor sampling for TMB analysis, and the effects of different therapies on TMB have not been clarified. This retrospective observational study aimed to investigate the heterogeneity of TMB and genomic mutation under the treatment pressure.Patients and methodsWe retrospectively collected the available genomic and therapeutic information from 8051 samples across 15 tumor types (>50 samples/tumor) found in 30 published studies and investigated the distribution and heterogeneity of TMB under treatment across diverse cohorts.ResultsThis integrated analysis has shown anticancer treatments increased TMB. Significant effects of treatment on TMB were more frequently observed in tumor types with lower treatment-naïve TMB, including breast, prostate, and pediatric cancers. For different cancer therapies, chemotherapy was prone to be correlated with an increased TMB in most cancer types. Meanwhile, the fraction of the TMB-high category of breast, prostate, and bladder cancers and glioma increased significantly after chemotherapy. Several actionable genes including ERS1 and NF1 in breast cancer, as well as some prognostic markers including TERT in bladder cancer and IDH1 in glioma, were significantly changed in post-chemotherapy tumors compared to treatment-naïve tumors.ConclusionOur study reveals the heterogeneity of TMB under treatment across diverse cancer types and provides evidences that chemotherapy was associated with increases in TMB as well as the fraction of TMB-high category, suggesting that resampling tumor tissues for calculating post-chemotherapy TMB could be a better option for predicting the response to immunotherapy, especially for tumors with initially low TMB.

Dataset Information

Integration of the Tumor Mutational Burden and Tumor Heterogeneity Identify an Immunological Subtype of Melanoma With Favorable Survival.

Publications

Integration of the Tumor Mutational Burden and Tumor Heterogeneity Identify an Immunological Subtype of Melanoma With Favorable Survival.

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