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Tumor mutational burden and efficacy of chemotherapy in lung cancer

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Abstract

Purpose

TMB is one of the potent biomarkers of response to immune checkpoint blockade. The association between TMB and efficacy of chemotherapy in advanced lung cancer has not been comprehensively explored.

Methods

Ninety lung cancer patients receiving first-line chemotherapy with large panel next-generation sequencing data of pre-treatment tumor tissue were identified. The effect of TMB on PFS of chemotherapy were evaluated in univariate and multivariate analyses.

Results

The median TMB level of lung cancer patients enrolled in this study was 9.4 mutations/Mb, with TMB levels in smokers significantly higher than those in non-smokers. All patients were divided into high TMB and low TMB groups with the cutoff of the median TMB. The patients with low TMB had longer PFS of first-line chemotherapy (median PFS 9.77 vs 6.33 months, HR = 0.523, 95% CI 0.32–0.852, log-rank P = 0.009). Subgroup analysis showed that PFS of chemotherapy favored low TMB than high TMB among subgroups of male, age < 60, NSCLC, adenocarcinoma, stage IV, ECOG PS 0, driver mutation positive, TP53 wild type and patients not receiving bevacizumab. In multivariate analysis, PFS of chemotherapy remained significantly longer in low TMB group (HR = 0.554, p = 0.036). In those patients received immunotherapy upon unsatisfactory chemotherapy, PFS of immunotherapy was much longer in high TMB group (median PFS 32.88 vs 6.62 months, HR = 0.2426, 95% CI 0.06–0.977, log-rank P = 0.04).

Conclusions

TMB level of tumor tissue is a potent biomarker for efficacy of chemotherapy and immunotherapy in lung cancer. It may provide some clues for the decision of treatment strategy.

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Abbreviations

TMB:

Tumor mutational burden

NSCLC:

Non-small cell lung cancer

SCLC:

Small cell lung cancer

PFS:

Progression-free survival

mPFS:

Median progression-free survival.

OS:

Overall survival

HR:

Hazard ratio

CI:

Confidence interval

ECOG PS:

Eastern cooperative oncology group performance status

NGS:

Next-generation sequencing

SNV:

Single-nucleotide variant

KEGG:

The Kyoto encyclopedia of genes and genomes

NSCLC–NOS:

Non-small cell lung cancer–not otherwise specified

CR:

Complete response

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

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Funding

This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ2254400, 20DZ2261200), Bethune Charitable Foundation (BJ-RW2020017J), Shanghai Municipal Key Clinical Specialty (shslczdzk02201), and National Natural Science Foundation of China (82170088).

Author information

Author notes

  1. Juan Song, Yu Yan and Cuicui Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Juan Song, Yu Yan, Cuicui Chen, Jiamin Li, Ning Ding, Nuo Xu, Xin Zhang, Qunying Hong, Jian Zhou, Yuanlin Song, Lin Tong & Jie Hu

  2. Shanghai Respiratory Research Institute, Shanghai, 200032, China

    Juan Song, Yu Yan, Cuicui Chen, Jiamin Li, Ning Ding, Nuo Xu, Xin Zhang, Qunying Hong, Jian Zhou, Yuanlin Song, Lin Tong & Jie Hu

  3. Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, 200032, China

    Juan Song & Yuanlin Song

  4. Nanjing Geneseeq Technology Inc, Nanjing, 210032, Jiangsu, China

    Hairong Bao & Yang W. Shao

  5. School of Public Health, Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Yang W. Shao

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  1. Juan Song
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Contributions

JS: conceptualization; investigation; data curation; formal analysis; writing—original draft. YY: investigation; data curation; formal analysis; validation; writing—original draft. CC: investigation; data curation; formal analysis; validation; writing—original draft. JL: investigation; data curation; validation; writing—review and editing. ND: investigation; data curation; validation; writing—review and editing. JL: investigation; methodology; writing—review and editing. YZ: software; methodology; writing—review and editing. MY: investigation; writing—review and editing. CL: investigation; writing—review and editing. NX: formal analysis; methodology; writing—review and editing. HB: formal analysis; methodology; writing—review and editing. XZ: supervision; validation; writing—review and editing. QH: supervision; validation; writing—review and editing. JZ: methodology; funding acquisition; supervision; writing—review and editing. YS: supervision; methodology; funding acquisition; writing—review and editing. YWS: supervision; project administration; writing—review and editing. CB: supervision; funding acquisition; project administration; writing—review and editing. LT: conceptualization; investigation; data curation; formal analysis; review and editing; funding acquisition. JH: conceptualization; project administration; supervision; methodology; funding acquisition; writing—review and editing.

Corresponding authors

Correspondence to Lin Tong or Jie Hu.

Ethics declarations

Conflict of interest

Y. W. Shao and H. Bao are the shareholders or employees of Geneseeq Technology Inc. The other authors declare no conflicts of interest.

Research involving human participants and/or animals

This study was approved by the ethics committee of Zhongshan Hospital, Fudan University. The approval number was B2017-142R.

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All patients provided informed written consent.

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Cite this article

Song, J., Yan, Y., Chen, C. et al. Tumor mutational burden and efficacy of chemotherapy in lung cancer. Clin Transl Oncol 25, 173–184 (2023). https://doi.org/10.1007/s12094-022-02924-6

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