Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors

I. Shou Chang, Shih Sheng Jiang, James Chih Hsin Yang, Wu Chou Su, Li Hsin Chien, Chin Fu Hsiao, Jih Hsiang Lee, Chih Yi Chen, Chung Hsing Chen, Gee Chen Chang, Zhaoming Wang, Fang Yi Lo, Kuan Yu Chen, Wen Chang Wang, Yuh Min Chen, Ming Shyan Huang, Ying Huang Tsai, Yu Chun Su, Wan Shan Hsieh, Wen Chi ShihShwn Huey Shieh, Tsung Ying Yang, Qing Lan, Nathaniel Rothman, Chien Jen Chen, Stephen J. Chanock, Pan Chyr Yang, Chao A. Hsiung

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Rationale: Patients with non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR) are relatively sensitive to EGFR-tyrosine kinase inhibitor (TKI) treatment and have longer progression-free survival (PFS) when treated with EGFR-TKI compared with platinum-based chemotherapy. However, many patientswith advanced NSCLCwho have mutated EGFR do not respond to first-line EGFR-TKI treatment and still have shorter PFS. Objectives: The aim of this study was to identify genetic variants associated with PFS among patients with lung adenocarcinoma who were treated with first-line EGFR-TKIs. Methods: A genome-wide association study on PFS was performed in never-smoking women diagnosed with lung adenocarcinoma and who were treated with first-line EGFR-TKIs (n = 128). Significant single-nucleotide polymorphisms (SNPs) were selected for follow-up association analysis (n = 198) and for replication assay in another independent cohort (n = 153). Measurements and Main Results: We identified SNPs at 4q12 associated with PFS at genome-wide significance (P,1028) andwith an estimated hazard ratio of more than 4. This association was also replicated in a larger but similar cohort and in an independent NSCLC cohort. Follow-up functional analyses showed that these SNPs were associated with the expression ofEGFR,whichencodes theTKI target, and with a nearby gene neuromedin-U, which encodes a G protein-coupled receptor ligand known to be involved in the progression of NSCLC. Considering these as possible prognostic biomarkers for the treatment of patients with late-stage lung cancer, we found that these SNPs were not associated with EGFR mutation status or with polymorphism of the Bcl2-interacting mediator of cell death gene. Conclusions: Genetic variants in 4q12 merit further investigation to assess their potential as pharmacogenomic predictors for and to understand the biology underlying its influence on PFS in patients treated with TKI therapy.

Original languageEnglish
Pages (from-to)663-673
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume195
Issue number5
DOIs
Publication statusPublished - Mar 1 2017
Externally publishedYes

Keywords

  • Genome-wide association study
  • Lung neoplasms
  • Molecular targeted therapy
  • Neversmokers
  • Single-nucleotide polymorphism

ASJC Scopus subject areas

  • Medicine(all)
  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Chang, I. S., Jiang, S. S., Yang, J. C. H., Su, W. C., Chien, L. H., Hsiao, C. F., Lee, J. H., Chen, C. Y., Chen, C. H., Chang, G. C., Wang, Z., Lo, F. Y., Chen, K. Y., Wang, W. C., Chen, Y. M., Huang, M. S., Tsai, Y. H., Su, Y. C., Hsieh, W. S., ... Hsiung, C. A. (2017). Genetic modifiers of progression-free survival in never-smoking lung adenocarcinoma patients treated with first-line tyrosine kinase inhibitors. American Journal of Respiratory and Critical Care Medicine, 195(5), 663-673. https://doi.org/10.1164/rccm.201602-0300OC