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

Abstract

BackgroundNon-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 methodsA 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.ResultsThe 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.ConclusionThe 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.

BIM deletion polymorphism predicts poor response to EGFR-TKIs in nonsmall cell lung cancer

“…Therefore, the conclusions made by these meta-analyses should be interpreted cautiously. Since more original studies in this area have been published in recent 3 years, [ 17 – 20 , 23 , 24 ] we conducted this updated meta-analysis to obtain an objective and consistent conclusion. To the best of our knowledge, this updated meta-analysis collected the comprehensive literature and was more accurate as the heterogeneity in the analysis was low.…”

“…Some studies showed that NSCLC patients harboring BIM deletion polymorphism had inferior response to EGFR-TKIs than those with BIM wild after TKIs treatment, [ 11 – 20 ] while others argued that there was no difference in response to EGFR-TKIs in NSCLC patients with and without BIM deletion polymorphism. [ 21 – 24 ]…”

Prognostic Value of BIM Deletion in EGFR-Mutant NSCLC Patients Treated with EGFR-TKIs: A Meta-Analysis

“…For two studies, each reported two unrelated cohorts [21,23]. Finally, 20 datasets from 18 studies [18][19][20][21][22][23][35][36][37][38][39][40][41][42][43][44][45][46] exploring the association between BIM deletion polymorphism and EGFR-TKI efficacy in EGFR-mutant NSCLC patients were included in our meta-analysis (Figure 1).…”

Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

“…Others found that EGFR-mutant patients with and without the BIM deletion polymorphism had similar clinical outcomes in response to EGFR-TKI treatment (165)(166)(167)(168). Several meta-analyses have indicated that the BIM deletion polymorphism is associated with poor ORR (168)(169)(170)(171)(172), consistent with other studies demonstrating that the BIM deletion polymorphism is associated with shorter PFS in patients with NSCLC harboring EGFR mutations who received EGFR-TKIs (168)(169)(170)(171)(172)(173)(174)(175). Only one study showed no significant association between BIM status and the response to EGFR-TKIs (173).…”

“…Some studies have shown that EGFR-mutant NSCLC patients with the BIM deletion polymorphism had inferior EGFR-TKI efficacy compared to those with wild-type BIM ( 154 , 160 – 164 ). Others found that EGFR-mutant patients with and without the BIM deletion polymorphism had similar clinical outcomes in response to EGFR-TKI treatment ( 165 – 168 ). Several meta-analyses have indicated that the BIM deletion polymorphism is associated with poor ORR ( 168 – 172 ), consistent with other studies demonstrating that the BIM deletion polymorphism is associated with shorter PFS in patients with NSCLC harboring EGFR mutations who received EGFR-TKIs ( 168 – 175 ).…”