title: Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival.
abstract: BACKGROUND
  There is limited Indian data on epidermal growth factor receptor (EGFR) gene activating mutations (AMs) prevalence and their clinicopathologic associations. The current study aimed to assess the relationship between EGFR AM and histologic subtypes and their impact on overall survival (OS) in a North Indian cohort.
  
  
  METHODS
  Retrospective analysis of nonsmall cell lung cancer patients who underwent EGFR mutation testing (n = 186) over 3 years period (2012-2014). EGFR mutations were tested using polymerase chain reaction amplification and direct sequencing. Patients were classified as EGFR AM, EGFR wild type (WT) or EGFR unknown (UKN). Histologically adenocarcinomas (ADC) were further categorized as per the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society-2011 classification.
  
  
  RESULTS
  Overall EGFR AM prevalence was 16.6%. The ratio of exon 19 deletions to exon 21 L858R mutations was 3.17:1. Female sex (P = 0.002), never smoking status (P = 0.002), metastatic disease (P = 0.032), and nonsolid subtype of ADC (P = 0.001) were associated with EGFR AM on univariate logistic regression analysis (LRA). On multivariate LRA, solid ADC was negatively associated with EGFR AM. Median OS was higher in patients with EGFR AM (750 days) as compared to EGFR-WT (459 days) or EGFR-UKN (291 days) for the overall population and in patients with Stage IV disease (750 days vs. 278 days for EGFR-WT, P = 0.024). On univariate Cox proportional hazard (CPH) analysis, smoking, poor performance status (Eastern Cooperative Oncology Group ≥ 2), EGFR-UKN status, and solid ADC were associated with worse OS while female sex and lepidic ADC had better OS. On multivariate CPH analysis, lepidic ADC (hazard ratio [HR] =0.12) and EGFR-WT/EGFR-UKN (HR = 2.39 and HR = 3.30 respectively) were independently associated with OS in separate analyses.
  
  
  CONCLUSIONS
  Histologic subtyping of ADC performed on small biopsies is independently associated with EGFR AM and with better OS. EGFR AM presence is a positive prognostic factor for OS.
authors.affiliation: Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Venkata Nagarjuna
authors.initials: VN
authors.lastname: Maturu
authors.affiliation: Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Navneet
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Amanjit
authors.initials: A
authors.lastname: Bal
authors.affiliation: Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Nalini
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Ashim
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
authors.forename: Digambar
authors.initials: D
authors.lastname: Behera
keywords: Adenocarcinoma; India; epidermal growth factor receptor; histology; mutations; overall survival