Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung

Abstract

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.