Driver mutations determine survival in smokers and never-smokers with stage IIIB/IV lung adenocarcinomas

Cancer. 2012 Dec 1;118(23):5840-7. doi: 10.1002/cncr.27637. Epub 2012 May 17.


Background: The authors previously demonstrated that never-smokers with stage IIIB/IV nonsmall cell lung cancer (NSCLC) lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and sex. In this study, the authors hypothesized that smoking-dependent differences in the distribution of driver mutations may explain differences in prognosis between these subgroups.

Methods: In total, 293 never-smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for epidermal growth factor receptor (EGFR) mutations and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and rearrangements in anaplastic lymphoma kinase (ALK) between 2009 and 2010 were investigated. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan-Meier method. Group comparison was performed with log-rank tests and Cox proportional hazards methods.

Results: Although the overall incidence of these mutations was nearly identical (55% never-smokers vs 57% current/former smokers; P = .48), there were significant differences in the distribution of mutations between these groups for EGFR mutations (37% never-smokers vs 14% former/current smokers; P < .0001), KRAS mutations (4% never-smokers vs 43% former/current smokers; P < .0001), and ALK rearrangements (12% never-smokers vs 2% former/current smokers; P < .0001). Among never-smokers and former/current smokers, the prognosis differed significantly by genotype. Patients who had KRAS mutations had the poorest survival. Smoking status, however, had no influence on survival within each genotype.

Conclusions: Never-smokers and former/current smokers with lung adenocarcinomas were not homogeneous subgroups. Each was made up of individuals whose tumors had a unique distribution of driver mutations, which were associated with different prognoses, irrespective of smoking history.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Aged, 80 and over
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors / genetics*
  • Female
  • Gene Rearrangement*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Staging
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Smoking / adverse effects*
  • ras Proteins / genetics*


  • KRAS protein, human
  • Proto-Oncogene Proteins
  • ALK protein, human
  • Alk protein, rat
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins