title: Poorer prognosis in Taiwanese female ever smokers with stage IV lung adenocarcinoma who were readministered a tyrosine kinase inhibitor.
abstract: BACKGROUND
  Readministering a second epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with acquired resistance to an initial EGFR TKI is a common treatment strategy. However, the prognostic factors for the second EGFR TKI are still uncertain.
  
  
  METHODS
  In this retrospective study, we enrolled patients with stage IV lung adenocarcinoma diagnosed between June 2009 and October 2013 at two university-affiliated hospitals in Taiwan. Basic characteristics including age, sex, smoking status, performance status, EGFR mutation status, tumor response, and progression-free survival (PFS) of the second EGFR TKI (PFS2) were recorded.
  
  
  RESULTS
  A total of 72 patients with stage IV adenocarcinoma with susceptible EGFR gene mutations who had been treated with a second EGFR TKI were enrolled. Survival analysis using the Kaplan-Meier method and log-rank test showed a significant difference in PFS2 when classifying the patients according to smoking history and sex (P=0.0179). When stratifying the patients by sex, a significant difference was found in PFS2 between ever smokers and never smokers in the female (1.87 vs 4.87 months, P=0.0081) but not in the male (2.83 vs 2.9 months, P=0.9605) patients. A reduced multivariate model developed using the backward variable selection method showed that only ever smoking remained an independent poor prognostic factor for PFS2, and that sex and ever smoking remained independent poor prognostic factors for PFS2 in the female patients (hazard ratio [HR] =3.386, 95% confidence interval [CI]: 1.015-11.298, P=0.0473).
  
  
  CONCLUSIONS
  This study is the first to demonstrate that female ever smokers have a poorer PFS if they have acquired resistance to an initial EGFR TKI and receive a second EGFR TKI. Further large-scale studies are urgently needed to elucidate the mechanism.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Yang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Ju
authors.initials: MJ
authors.lastname: Tsai
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jen-Yu
authors.initials: JY
authors.lastname: Hung
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ying-Ming
authors.initials: YM
authors.lastname: Tsai
authors.affiliation: Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jui-Ying
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Chest Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shah-Hwa
authors.initials: SH
authors.lastname: Chou
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ta-Chih
authors.initials: TC
authors.lastname: Liu
authors.affiliation: Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Mei-Chiou
authors.initials: MC
authors.lastname: Shen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Geriatric Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Respiratory Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Inn-Wen
authors.initials: IW
authors.lastname: Chong
keywords: adenocarcinoma; epidermal growth factor receptor tyrosine kinase inhibitor; erlotinib; gefitinib; lung cancer; smoker