Soh, Sheila X; Siddiqui, Fahad J; Allen, John C; Kim, Go Woon; Lee, Jae Cheol; Yatabe, Yasushi; Soda, Manabu; Mano, Hiroyuki; Soo, Ross A; Chin, Tan-Min; Ebi, Hiromichi; Yano, Seiji; Matsuo, Keitaro; Niu, Xiaomin; Lu, Shun; Isobe, Kazutoshi; Lee, Jih-Hsiang; Yang, James C; Zhao, Mingchuan; Zhou, Caicun; Lee, June-Koo; Lee, Se-Hoon; Lee, Ji Yun; Ahn, Myung-Ju; Tan, Tira J; Tan, Daniel S; Tan, Eng-Huat; Ong, S Tiong; Lim, Wan-Teck
Oncotarget
2017Jun ; 8 ( 25 ) :41474-41486.
PMID : 28467813
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Soh, Sheila X -
Siddiqui, Fahad J -
Allen, John C -
Kim, Go Woon -
Lee, Jae Cheol -
Yatabe, Yasushi -
Soda, Manabu -
Mano, Hiroyuki -
Soo, Ross A -
Chin, Tan-Min -
Ebi, Hiromichi -
Yano, Seiji -
Matsuo, Keitaro -
Niu, Xiaomin -
Lu, Shun -
Isobe, Kazutoshi -
Lee, Jih-Hsiang -
Yang, James C -
Zhao, Mingchuan -
Zhou, Caicun -
Lee, June-Koo -
Lee, Se-Hoon -
Lee, Ji Yun -
Ahn, Myung-Ju -
Tan, Tira J -
Tan, Daniel S -
Tan, Eng-Huat -
Ong, S Tiong -
Lim, Wan-Teck -
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METHODS: 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase.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.
BIM; drug resistance; lung cancer; polymorphism; tyrosine kinase inhibitor
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