Cancer Res Treat.  2021 Oct;53(4):973-982. 10.4143/crt.2020.798.

Pan-cancer Analysis of Tumor Mutational Burden and Homologous Recombination DNA Damage Repair Using Targeted Next-Generation Sequencing

• Wang HY
• Deng L
• Li YQ
• Zhang X
• Long YK
• Zhang X
• Feng YF
• He Y
• Tang T
• Yang XH
• Wang F

• KMID: 2521573
• DOI: http://doi.org/10.4143/crt.2020.798

Abstract

Purpose
Current variability in methods for tumor mutational burden (TMB) estimation and reporting demonstrates the urgent need for a homogeneous TMB assessment approach. Here, we compared TMB distributions in different cancer types using two customized targeted panels commonly used in clinical practice.
Materials and Methods
TMB spectra of 295- and 1021-gene panels in multiple cancer types were compared using targeted next-generation sequencing (NGS). The TMB distributions across a diverse cohort of 2,332 cancer cases were then investigated for their associations with clinical features. Treatment response data were collected for 222 patients who received immune-checkpoint inhibitors (ICIs) and their homologous recombination DNA damage repair (HR-DDR) and programmed death-ligand 1 (PD-L1) expression were additionally assessed and compared with the TMB and response rate.
Results
The median TMB between gene panels was similar despite a wide range in TMB values. The highest TMB was 8 and 10 in patients with squamous cell carcinoma and esophageal carcinoma according to the classification of histopathology and cancer types, respectively. Twenty-three out of 103 patients (22.3%) were HR-DDR‒positive and could benefit from ICI therapy; out of those 23 patients, seven patients had high TMB (p=0.004). Additionally, PD-L1 expression was not associated with TMB or treatment response among patients receiving ICIs.
Conclusion
Targeted NGS assays demonstrated the ability to evaluate TMB in pan-cancer samples as a tool to predict response to ICIs. In addition, TMB integrated with HR-DDR‒positive status could be a significant biomarker for predicting ICI response in patients.

Keyword

Tumor mutational burden; Homologous recombination DNA damage repair; Pan-cancer; Immunotherapy

Figure

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  Fig. 1 Flowchart illustrating the analytic workflow of the study comprising of TMB calculations from the 295- and 1021-customized sequencing panels. HR-DDR, homologous recombination DNA damage repair; NGS, next-generation sequencing; TMB, tumor mutational burden.

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  Fig. 2 The number of patients was calculated using the 295- and 1021-gene panels, and defined by cancer types (A) and pathological subtypes (B), respectively. SCC, squamous cell carcinoma. Unknown cancer types denote the sites of primary tumor were not available.

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  Fig. 3 TMB distributions across the different cancer types and pathological subtypes. Overview of the median TMB (log10-transformed) across different cancers (A) and pathological types (C). The comparison of TMB value (log10-transformed) defined by two different gene panels in cancers (B) and pathological types (D). SCC, squamous cell carcinoma; TMB, tumor mutational burden.

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  Fig. 4 The efficacy associated with TMB, HR-DDR mutation status PD-L1 expression among patients who received ICI treatment. DCB, durable clinical benefit; HR-DDR, homologous recombination DNA damage repair; ICIs, immunotherapy inhibitors; NDB, no durable benefit; PD-L1, programmed death ligand-1; TMB, tumor mutational burden.

Reference

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