Assessment of blood tumor mutational burden as a potential biomarker for immunotherapy in patients with non-small cell lung cancer with use of a next-generation sequencing cancer gene panel
Open accessAbstract
IMPORTANCE: Tumor mutational burden (TMB), as measured by whole-exome sequencing (WES) or a cancer gene panel (CGP), is associated with immunotherapy responses. However, whether TMB estimated by circulating tumor DNA in blood (bTMB) is associated with clinical outcomes of immunotherapy remains to be explored. OBJECTIVES: To explore the optimal gene panel size and algorithm to design a CGP for TMB estimation, evaluate the panel reliability, and further validate the feasibility of bTMB as a clinical actionable biomarker for immunotherapy. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, a CGP named NCC-GP150 was designed and virtually validated using The Cancer Genome Atlas database. The correlation between bTMB estimated by NCC-GP150 and tissue TMB (tTMB) measured by WES was evaluated in matched blood and tissue samples from 48 patients with advanced NSCLC. An independent cohort of 50 patients with advanced NSCLC was used to identify the utility of bTMB estimated by NCC-GP150 in distinguishing patients who would benefit from anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) therapy. The study was performed from July 19, 2016, to April 20, 2018. MAIN OUTCOMES AND MEASURES: Assessment of the Spearman correlation coefficient between bTMB estimated by NCC-GP150 and tTMB calculated by WES. Evaluation of the association of bTMB level with progression-free survival and response to anti-PD-1 and anti-PD-L1 therapy. RESULTS: This study used 2 independent cohorts of patients with NSCLC (cohort 1: 48 patients; mean [SD] age, 60 [13] years; 15 [31.2%] female; cohort 2: 50 patients; mean [SD] age, 58 [8] years; 15 [30.0%] female). A CGP, including 150 genes, demonstrated stable correlations with WES for TMB estimation (median r2 = 0.91; interquartile range, 0.89-0.92), especially when synonymous mutations were included (median r2 = 0.92; interquartile range, 0.91-0.93), whereas TMB estimated by the NCC-GP150 panel found higher correlations with TMB estimated by WES than most of the randomly sampled 150-gene panels. Blood TMB estimated by NCC-GP150 correlated well with the matched tTMB calculated by WES (Spearman correlation = 0.62). In the anti-PD-1 and anti-PD-L1 treatment cohort, a bTMB of 6 or higher was associated with superior progression-free survival (hazard ratio, 0.39; 95% CI, 0.18-0.84; log-rank P = .01) and objective response rates (bTMB ≥6: 39.3%; 95% CI, 23.9%-56.5%; bTMB <6: 9.1%; 95% CI, 1.6%-25.9%; P = .02). CONCLUSIONS AND RELEVANCE: The findings suggest that established NCC-GP150 with an optimized gene panel size and algorithm is feasible for bTMB estimation, which may serve as a potential biomarker of clinical benefit in patients with NSCLC treated with anti-PD-1 and anti-PD-L1 agents.
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Limited biomarkers such as PD-L1 expression and tumor mutation load are clinically used to predict immunotherapy benefit.
“Currently, limited biomarkers, such as PD-L1 expression (88) and tumor mutation load (TMB) (89–91), are clinically used to predict the immunotherapy benefit.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [91]
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- Authors
- Wang, Z., Duan, J., Cai, S., Han, M., Dong, H., Zhao, J., Zhu, B., Wang, S., Zhuo, M., Sun, J., Wang, Q., Bai, H., Han, J., Tian, Y., Lu, J., Xu, T., Zhao, X., Wang, G., Cao, X., Li, F., Wang, D., Chen, Y., Bai, Y., Zhao, J., Zhao, Z., Zhang, Y., Xiong, L., He, J., Gao, S., & Wang, J.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- 3D Medicines, Inc. (China) (CN)
- Peking University Cancer Hospital (CN)
- Army Medical University (CN)
- Zhengzhou University (CN)
- Corresponding author
- Wang, Jie
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-05-01
- Volume
- 5
- Issue
- 5
- Pages
- 696
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6512308
- OpenAlex
- W2916508569
- Cited by
- 471
- References
- 23
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 36 · 2023: 72 · 2022: 82 · 2021: 129 · 2020: 87 · 2019: 34
- FWCI
- 35.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- JAMA Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- tumor mutational burden, circulating tumor DNA, non-small cell lung cancer, cancer gene panel, immunotherapy biomarkers, anti-PD-1 therapy, PD-L1 blockade, progression-free survival, panel design, synonymous mutations, liquid biopsy, immunotherapy response prediction, TIDE score, PD-L1 expression, tumor-infiltrating immune cells
- MeSH terms
- Circulating Tumor DNA, Antineoplastic Agents, Immunological, Aged, Carcinoma, Non-Small-Cell Lung, Female, Humans, Immunotherapy, Lung Neoplasms, Male, Middle Aged, Mutation, Biomarkers, Tumor, High-Throughput Nucleotide Sequencing, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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