A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

Sheila Soh ,Kazutoshi Isobe,Manabu Soda,Jae Cheol Lee,Seiji Yano,Hiromichi Ebi,Ji Yun Lee,Hiroyuki Mano,Caicun Zhou,Yasushi Yatabe,Xiaomin Niu,John C Allen,Go Woon Kim,Ross A Soo,S Tiong Ong,Keitaro Matsuo,Jake June-Koo Lee ,Daniel Shao-Weng Tan ,Fahad Javaid Siddiqui ,Tan Min Chin ,Ming Zhao ,Eng Huat Tan ,Jih Hsiang Lee ,Se‐Hoon Lee ,Myung Ju Ahn ,James Chih‐Hsin Yang ,Shun Lü ,Tira Jing Ying Tan ,Wan–Teck Lim

doi:10.18632/oncotarget.17102

Abstract

BackgroundA germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue.ResultsIn an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06–2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251–2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603–4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063–1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS.Materials and Methods10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS.ConclusionsIn selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.

Highlights

While sensitizing mutations in the Epidermal Growth Factor Receptor (EGFR) gene predict very high response rates among patients with non-small cell lung cancer (NSCLC) [1,2,3], up to 30% of such patients fail to experience optimum responses [4, 5]
In selected populations, the BIM deletion is a significant predictor of shorter progressionfree survival (PFS) and Overall survival (OS) on EGFR-Tyrosine Kinase Inhibitor (TKI)
We excluded patients if they were not treated with TKIs, the treatment period was < 2 weeks, or BIM deletion status was unknown

Summary

Introduction

While sensitizing mutations in the EGFR gene predict very high response rates among patients with NSCLC [1,2,3], up to 30% of such patients fail to experience optimum responses [4, 5]. Recent data from the European Tarceva (EURTAC) trial demonstrated poorer outcomes in EGFR-mutant NSCLC patients with low BIM expression, further supporting the importance of intact apoptotic machinery in such populations [21]. Together, these studies highlight BIM function as a critical factor in determining patient responses to cancer therapies. A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC).

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Conclusion