Prognostic and Predictive Value of Blood Tumor Mutational Burden in Patients With Lung Cancer Treated With Docetaxel

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Background: Biomarkers for chemotherapy efficacy in non–small cell lung cancer (NSCLC) are lacking. This retrospective study assesses the association between blood-based tumor mutational burden (bTMB) and clinical benefit of chemotherapy. Methods: Clinical and targeted next-generation sequencing data from the OAK trial (training set; n=318) and POPLAR trial (validation set; n=106) in the docetaxel arm were analyzed. The cutoff value of bTMB for outcome prediction was determined based on a time-dependent receiver operating characteristic curve in the training set, and propensity score matching (PSM) was conducted. The primary outcome was overall survival (OS). Durable clinical benefit (DCB) was defined as OS lasting >12 months. Interaction between treatment and bTMB was assessed in the combined set. Results: A lower bTMB was observed in patients with DCB compared with no durable benefit, and in those with a partial response and stable disease compared with progressive disease. The optimized cutoff value of bTMB for predicting OS was 7 single-nucleotide variants per megabase. In the training set, a low bTMB was significantly associated with longer OS and progression-free survival (PFS). The prognostic value of bTMB was confirmed in the validation set and PSM set. The interaction between bTMB and treatment was significant for PFS (interaction P=.043) in the combined set. Mutations in KEAP1 were associated with high bTMB and a lack of benefit from chemotherapy. Conclusions: Low bTMB is associated with a survival advantage in patients with NSCLC treated with docetaxel, suggesting the prognostic and predictive potential of bTMB for determining chemotherapy efficacy.

Submitted August 19, 2019; accepted for publication December 2, 2019.

Author contributions: Literature search: Nie, J. Qian, Xu, Gu. Figures: Nie, J. Qian, Xu, Gu. Study design: Nie, J. Qian, Xu, Gu, Zhong, Han. Data collection: Nie, J. Qian, Xu, Gu, F.F. Qian, Lu, X.Y. Zhang, H.M. Wang, Yan, B. Zhang, S.Y. Wang, Hu, Li. Data analysis: Nie, J. Qian, Xu, Gu. Writing of manuscript: Nie, J. Qian, Xu, Gu, Zhong, Han. Review of manuscript: Zhong, Han.

Disclosures: Dr. Han has disclosed that he has received consultant fees from AstraZeneca and Roche Pharmaceutical Company and speaking fees from AstraZeneca Pharmaceutical Company and Lily Pharmaceutical Company. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This study was sponsored by Shanghai Municipal Human Resource and Social Security Bureau Talent Project (No. 052), National Natural Science Foundation of China (No. 81601988, 81602078, and 81502450), Science and Technology Commission of Shanghai Municipality, China (No. 18441904700), and Shanghai Chest Hospital Project of Collaborative Innovation (No. YJXT20190102).

Disclaimer: Datasets analyzed during the current study are available from the corresponding author on reasonable request.

Correspondence: Hua Zhong, MD, Shanghai Chest Hospital, Shanghai Jiao Tong University, Huaihai West Road No. 241, Shanghai 200030, China. Email: eddiedong8@hotmail.com; and Bao-Hui Han, MD, Shanghai Chest Hospital, Shanghai Jiao Tong University, Huaihai West Road No. 241, Shanghai 200030, China. Email: xkyyhan@gmail.com

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