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, Fahad J. Siddiqui, John C. Allen, Go Woon Kim, Jae Cheol Lee, Yasushi Yatabe, Manabu Soda, Hiroyuki Mano, Ross A. Soo, Tan-Min Chin, Hiromichi Ebi, Seiji Yano, Keitaro Matsuo, Xiaomin Niu, Shun Lu, Kazutoshi Isobe, Jih-Hsiang Lee, James C. Yang, Mingchuan Zhao, Caicun Zhou, June-Koo Lee, Se-Hoon Lee, Ji Yun Lee, Myung-Ju Ahn, Tira J. Tan, Daniel S. Tan, Eng-Huat Tan, S. Tiong Ong and Wan-Teck Lim _

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Oncotarget. 2017; 8:41474-41486. https://doi.org/10.18632/oncotarget.17102

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Sheila X. Soh1,*, Fahad J. Siddiqui2,3,*, John C. Allen2, Go Woon Kim4, Jae Cheol Lee5, Yasushi Yatabe6, Manabu Soda7, Hiroyuki Mano7, Ross A. Soo8,9, Tan-Min Chin8,9, Hiromichi Ebi10, Seiji Yano10, Keitaro Matsuo11, Xiaomin Niu12, Shun Lu12, Kazutoshi Isobe13, Jih-Hsiang Lee14, James C. Yang15, Mingchuan Zhao16, Caicun Zhou16, June-Koo Lee17, Se-Hoon Lee18, Ji Yun Lee18, Myung-Ju Ahn18, Tira J. Tan19, Daniel S. Tan19, Eng-Huat Tan19, S. Tiong Ong1,19,20,21 and Wan-Teck Lim19

1Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore

2Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore

3Centre for Global Child Health, Sick Kids Hospital, Toronto, Canada

4Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea

5Department of Oncology, Asan Medical Center, University of Ulsan, Seoul, Republic of Korea

6Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan

7Department of Cellular Signaling, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

8Department of Haematology-Oncology, National University Cancer Institute, Singapore

9Cancer Science Institute, National University of Singapore, Singapore

10Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

11Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan

12Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China

13Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan

14Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

15Department of Oncology, Graduate Institute of Oncology and Cancer Research Centre, National Taiwan University Hospital, Taipei, Taiwan

16Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China

17Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea

18Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

19Division of Medical Oncology, National Cancer Centre, Singapore

20Department of Haematology, Singapore General Hospital, Singapore

21Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

*These authors contributed equally to this work

Correspondence to:

Wan-Teck Lim, email: [email protected]

S. Tiong Ong, email: [email protected]

Keywords: BIM, polymorphism, tyrosine kinase inhibitor, lung cancer, drug resistance

Received: February 21, 2017     Accepted: March 30, 2017     Published: April 13, 2017


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.

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