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Meta-Analysis
. 2017 Jun 20;8(25):41474-41486.
doi: 10.18632/oncotarget.17102.

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 X Soh  1 , Fahad J Siddiqui  2   3 , John C Allen  2 , Go Woon Kim  4 , Jae Cheol Lee  5 , Yasushi Yatabe  6 , Manabu Soda  7 , Hiroyuki Mano  7 , Ross A Soo  8   9 , Tan-Min Chin  8   9 , Hiromichi Ebi  10 , Seiji Yano  10 , Keitaro Matsuo  11 , Xiaomin Niu  12 , Shun Lu  12 , Kazutoshi Isobe  13 , Jih-Hsiang Lee  14 , James C Yang  15 , Mingchuan Zhao  16 , Caicun Zhou  16 , June-Koo Lee  17 , Se-Hoon Lee  18 , Ji Yun Lee  18 , Myung-Ju Ahn  18 , Tira J Tan  19 , Daniel S Tan  19 , Eng-Huat Tan  19 , S Tiong Ong  1   19   20   21 , Wan-Teck Lim  19
Affiliations
Meta-Analysis

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 X Soh et al. Oncotarget. .

Abstract

Background: 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) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue.

Results: In 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Materials and methods: 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase.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.

Conclusions: In 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.

Keywords: BIM; drug resistance; lung cancer; polymorphism; tyrosine kinase inhibitor.

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Conflict of interest statement

CONFLICTS OF INTEREST

We declare no relevant competing interests.

Figures

Figure 1
Figure 1. Flowchart of study identification, inclusion and exclusion
Studies identified from a PubMed and Embase search were filtered according to the exclusion and inclusion criteria listed in the Figure. In total, 10 studies were available for individual patient data (IPD) analysis.
Figure 2
Figure 2
Kaplan-Meier curves comparing progression-free survival (PFS) and overall survival (OS) on EGFR-TKIs between patients with and without the BIM deletion in the (A, B) whole cohort, (C, D) Korean cohort and (E, F) non-Korean cohort.
Figure 3
Figure 3. Cumulative meta-analysis of published and unpublished data of the association between the BIM deletion polymorphism and progression-free survival in EGFR-TKI-treated NSCLC patients
Estimates were adjusted for age, sex, smoking history, stage, ECOG status, histology, EGFR mutation and line of treatment. Zhong J et al. was omitted from this figure as both summary statistics and individual patient data (IPD) were not available. * indicates IPD was unavailable, † indicates summary HRs were calculated by the authors of this paper according to the methods described in the Methods section.
See this image and copyright information in PMC

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