title: Impact of cigarette smoking on response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in lung adenocarcinoma with activating EGFR mutations.
abstract: OBJECTIVE
  The aim of this study is to evaluate the predictive impact of cigarette smoking on treatment outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma patients with activating EGFR mutations.
  
  
  METHODS
  We retrospectively analyzed 222 consecutive recurrent or unresectable lung adenocarcinoma patients who harbored activating EGFR mutations (exon 19 deletion or exon 21 L858R) and had received gefitinib or erlotinib. Detailed smoking histories were obtained from all patients according to a standard protocol.
  
  
  RESULTS
  Of 222 EGFR-mutated patients, 65.3% were never-smokers, 19.8% were smokers with < 30 pack-years, and 14.9% were smokers with ≥ 30 pack-years smoking dosage. The disease control rate (DCR) and objective response rate (ORR) of smokers with ≥ 30 pack-years were significantly lower than never-smokers and smokers with < 30 pack-years (DCR, 78.8% vs. 93.1%, p = 0.016; ORR, 45.5% vs. 62.4%, p = 0.020). Smokers with ≥ 30 pack-years showed significantly shorter PFS than never-smokers (6.4 vs. 11.8 months, p = 0.001) and smokers with < 30 pack-years (6.4 vs. 11.4 months, p = 0.033), as well as shorter overall survival from the time of metastatic diagnosis than never-smokers (33.6 vs. 46.2 months, p = 0.003). There was no survival difference between smokers with < 30 pack-year and never smokers. In the multivariate analysis adjusted for age, sex, performance status, initial stage, and line of EGFR-TKI, the presence of smoking dosage ≥ 30 pack-years was an independent predictive factor for the disease progression to EGFR-TKIs (hazard ratio, 1.87; 95% confidence interval, 1.15-3.05; p = 0.012).
  
  
  CONCLUSIONS
  Cigarette smoking dosage of ≥ 30 pack-years is an independent negative predictive factor of EGFR-TKI treatment outcome in lung adenocarcinoma patients with activating EGFR mutations.
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Min Hwan
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Byoung Chul
authors.initials: BC
authors.lastname: Cho
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Bae
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chang Young
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Dae Ryong
authors.initials: DR
authors.lastname: Kang
authors.affiliation: Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: kjhang@yuhs.ac.
authors.forename: Joo Hang
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020125:Mutation, Missense; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D012189:Retrospective Studies; D017384:Sequence Deletion; D012907:Smoking / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Cigarette smoking; EGFR mutation; EGFR-tyrosine kinase inhibitors; Lung adenocarcinoma; Prognosis; Response rate