The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non–small cell lung cancer

Authors

  • Mingchuan Zhao PhD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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    • The first two authors contributed equally to this work.

  • Yishi Zhang MD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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    • The first two authors contributed equally to this work.

  • Weijing Cai PhD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Jiayu Li PhD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Fei Zhou MD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Ningning Cheng PhD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Ruixin Ren MD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Chao Zhao,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Xuefei Li PhD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Shengxiang Ren MD,

    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
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  • Caicun Zhou MD, PhD,

    Corresponding author
    1. Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
    • Corresponding author: Caicun Zhou, MD PhD, Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, 507 Zheng Min Road, Shanghai, 200433 China; Fax: (011) 86-21-55660346; caicunzhoudr@163.com

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  • Fred R. Hirsch MD, PhD

    1. Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado
    2. Department of Pathology, University of Colorado Cancer Center, Aurora, Colorado
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  • We thank Genosaber, Amoy Diagnostics Company, Ltd., and AstraZeneca for technical support.

Abstract

BACKGROUND

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of patients with advanced non–small cell lung cancer (NSCLC) who have EGFR mutations. Recent studies have indicated that some patients with positive mutations were refractory to EGFR TKIs if they harbored a B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (Bim) deletion polymorphism. The objective of the current work was to retrospectively study the Bim deletion polymorphism in Chinese patients with NSCLC and its correlation with the efficacy of EGFR TKIs.

METHODS

Distribution of the Bim polymorphism was detected using polymerase chain reaction analysis and direct sequencing of DNA from peripheral neutrophils in samples from 352 patients with NSCLC. Of the 352 patients, 166 who received TKI therapy and had an activating mutation identified were involved in further analysis. Progression-free survival (PFS) was the primary endpoint of the subsequent analyses, and the incidence of the Bim polymorphism and its relation to clinical benefit from EGFR TKIs also were investigated.

RESULTS

In total, 45 of 352 patient samples (12.8%) had the Bim deletion polymorphism, which was distributed randomly with regard to various clinical characteristics. In patients with EGFR mutations who received treatment with TKIs, the median PFS and the median objective response rate were 4.7 months and 25%, respectively, for those with the Bim deletion polymorphism versus 11 months (P = .003) and 66% (P = .001), respectively, for those with wild-type Bim. Cox regression analysis identified Bim status (P = .016) and sex (P = .002) as independent factors predicting clinical benefit from EGFR TKIs in patients with EGFR-mutated NSCLC.

CONCLUSIONS

The incidence of the Bim deletion polymorphism was approximately 13% in this study, and it was associated with a poor clinical response to EGFR TKIs in patients who had NSCLC with EGFR mutations. Cancer 2014;120:2299–2307. © 2014 American Cancer Society.

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