title: Impact of Smoking and Brain Metastasis on Outcomes of Advanced EGFR Mutation Lung Adenocarcinoma Patients Treated with First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
abstract: OBJECTIVE
  This purpose of this study was to examine clinical-pathologic factors--particularly smoking and brain metastases--in EGFR mutation positive (M(+)) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI.
  
  
  METHODS
  A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M(+) ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival.
  
  
  RESULTS
  444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M(+.) Amongst never-smokers (n=468), EGFR M(+) were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson's chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival.
  
  
  CONCLUSIONS
  The high prevalence of EGFR M(+) in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Amit
authors.initials: A
authors.lastname: Jain
authors.affiliation: Clinical Trials & Epidemiological Sciences, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Cindy
authors.initials: C
authors.lastname: Lim
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Eugene MingJin
authors.initials: EM
authors.lastname: Gan
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: David Zhihao
authors.initials: DZ
authors.lastname: Ng
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Quan Sing
authors.initials: QS
authors.lastname: Ng
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Mei Kim
authors.initials: MK
authors.lastname: Ang
authors.affiliation: Department of Pathology, Academia, Level 7, Singapore General Hospital, Singapore, Singapore.
authors.forename: Angela
authors.initials: A
authors.lastname: Takano
authors.affiliation: Department of Pathology, Academia, Level 7, Singapore General Hospital, Singapore, Singapore.
authors.forename: Kian Sing
authors.initials: KS
authors.lastname: Chan
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Wu Meng
authors.initials: WM
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Chee Keong
authors.initials: CK
authors.lastname: Toh
authors.affiliation: Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore.
authors.forename: Chian Min
authors.initials: CM
authors.lastname: Loo
authors.affiliation: Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore.
authors.forename: Anne Ann Ling
authors.initials: AA
authors.lastname: Hsu
authors.affiliation: Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore.
authors.forename: Anantham
authors.initials: A
authors.lastname: Devanand
authors.affiliation: Department of Cardiothoracic Surgery, National Heart Centre Singapore, Singapore, Singapore.
authors.forename: Chong Hee
authors.initials: CH
authors.lastname: Lim
authors.affiliation: Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Heng Nung
authors.initials: HN
authors.lastname: Koong
authors.affiliation: Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Tina
authors.initials: T
authors.lastname: Koh
authors.affiliation: Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Kam Weng
authors.initials: KW
authors.lastname: Fong
authors.affiliation: Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Swee Peng
authors.initials: SP
authors.lastname: Yap
authors.affiliation: Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Su Woon
authors.initials: SW
authors.lastname: Kim
authors.affiliation: Clinical Pharmacology Laboratory, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.affiliation: Department of Pathology, Academia, Level 7, Singapore General Hospital, Singapore, Singapore.
authors.forename: Lynette
authors.initials: L
authors.lastname: Oon
authors.affiliation: Department of Pathology, Academia, Level 7, Singapore General Hospital, Singapore, Singapore.
authors.forename: Kiat Hon
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Wan Teck
authors.initials: WT
authors.lastname: Lim
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
authors.forename: Eng Huat
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; Cancer Therapeutics Research Laboratory, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore; Cancer Stem Cell Biology, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Daniel Shao Weng
authors.initials: DS
authors.lastname: Tan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003710:Demography; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D012018:Reflex / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors