Abstract
Background Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable in EGFR-mutant non-small-cell lung cancer (NSCLC) patients. A germline 2903 bp deletion polymorphism of Bcl-2-like protein 11 (BIM) causes reduced expression of proapoptotic BH3-only BIM protein and blocks TKI-induced apoptosis of tumor cells. Yet the association between the deletion polymorphism and response to EGFR-TKI treatment remains inconsistent among clinical observations. Thus, we performed the present meta-analysis. Methods Eligible studies were identified by searching PubMed, Embase, and ClinicalTrials.gov databases prior to March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) of progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) and 95% CIs of objective response rate (ORR) and disease control rate (DCR) were calculated by using a random effects model. Sensitivity, metaregression, and publication bias analyses were also performed. Results A total of 20 datasets (3003 EGFR-mutant NSCLC patients receiving EGFR-TKIs from 18 studies) were included. There were 475 (15.8%) patients having the 2903-bp intron deletion of BIM and 2528 (84.2%) wild-type patients. BIM deletion predicted significantly shorter PFS (HR = 1.35, 95% CI: 1.10-1.64, P = 0.003) and a tendency toward an unfavorable OS (HR = 1.22, 95% CI: 0.99-1.50, P = 0.068). Patients with deletion polymorphism had lower ORR (OR = 0.60, 95% CI: 0.42-0.85, P = 0.004) and DCR (OR = 0.59, 95% CI: 0.38-0.90, P = 0.014) compared with those without deletion. Conclusion BIM deletion polymorphism may confer resistance to EGFR-TKIs and can be used as a biomarker to predict treatment response to EGFR-TKIs in EGFR-mutant NSCLC patients from Asian populations.
Highlights
Lung cancer is the most prevalent malignant tumor with the highest mortality worldwide, which accounts for 11.6% of newly diagnosed cancers and 18.4% of cancer-related deaths in 2018 [1]
20 datasets from 18 studies [18–23, 35–46] exploring the association between BIM deletion polymorphism and Epidermal growth factor receptor (EGFR)-TKI efficacy in EGFR-mutant non-small-cell lung cancer (NSCLC) patients were included in our meta-analysis (Figure 1)
Our analysis indicated that BIM deletion was related to a shorter overall survival (OS), but the association was not significant (HR = 1:22, 95% confidence intervals (CIs): 0.99-1.50, P = 0:068, Figure 3)
Summary
Lung cancer is the most prevalent malignant tumor with the highest mortality worldwide, which accounts for 11.6% of newly diagnosed cancers and 18.4% of cancer-related deaths in 2018 [1]. Molecular targeted therapy has shown great potentials in improving survivals, response, and quality of life and reducing adverse events and is recommended as the first-line therapy for advanced NSCLC with driven gene mutations according to National Comprehensive Cancer Network (NCCN) guidelines For those negative for driven gene mutations, chemoimmunotherapy or immune checkpoint inhibitors (ICIs) are currently the first-line treatment according to programmed cell death ligand 1 (PD-L1) score on tumor tissue. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable in EGFRmutant non-small-cell lung cancer (NSCLC) patients. BIM deletion polymorphism may confer resistance to EGFR-TKIs and can be used as a biomarker to predict treatment response to EGFR-TKIs in EGFR-mutant NSCLC patients from Asian populations
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