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Exploratory cohort study and meta-analysis of BIM deletion polymorphism in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors

Authors Sun S, Yu H, Wang H, Zhao X, Zhao X, Wu X, Qiao J, Chang J, Wang J

Received 29 October 2016

Accepted for publication 23 February 2017

Published 3 April 2017 Volume 2017:10 Pages 1955—1967


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Dr Chiung-Kuei Huang

Si Sun,1,2 Hui Yu,1,2 Huijie Wang,1,2 Xinmin Zhao,1,2 Xintai Zhao,3 Xianghua Wu,1,2 Jie Qiao,1,2 Jianhua Chang,1,2 Jialei Wang1,2

1Department of Medical Oncology, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, 3Shanghai Shines Biomedical Co. Ltd., Shanghai, People’s Republic of China

Background: Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations might develop primary and secondary resistance to tyrosine kinase inhibitors (TKIs). The proapoptotic protein Bcl-2-like 11 (BIM) is a key modulator of apoptosis triggered by EGFR-TKIs. The recent studies have indicated that some patients with positive EGFR mutations were refractory to EGFR-TKIs if they harbored a BIM deletion polymorphism. The purpose of this study was to investigate whether BIM polymorphism predicts treatment efficacy of EGFR-TKIs in Chinese NSCLC patients.
Patients and methods: A cohort of advanced NSCLC patients with EGFR mutations and treated with EGFR-TKIs (gefitinib or erlotinib) were recruited. We drew peripheral blood to determinate BIM deletion status and then compared patients’ clinical outcomes according to the BIM deletion status. Additionally, we electronically searched eligible cohort studies and conducted a meta-analysis to pool event risk.
Results: The exploratory cohort study included 140 patients. Patients with and without the BIM deletion polymorphism had similar objective response rates (ORRs, 48.5 vs 63.0%, P=0.16), disease control rate (DCR, 93.9 vs 97.0%, P=0.60) and adverse reactions. Similar progression-free survival (PFS) and overall survival (OS) were noted in overall population (P=0.27 for PFS and P=0.61 for OS) and prespecified patient subgroups. The meta-analysis included 10 eligible cohort studies involving 1,317 NSCLC patients. It showed the positive BIM deletion was associated with shorter PFS (hazard ratio =1.45; P=0.02). Nonsignificant differences existed for ORR, DCR and OS.
Conclusion: The expanded meta-analysis results demonstrated the positive BIM deletion predicts shorter PFS in NSCLC patients after treatment with EGFR-TKIs while other clinical measures do not. A large multicenter well-designed cohort study involving other concurrent genetic alterations is warranted.

Keywords: BIM, EGFR, NSCLC, clinical outcome

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