Distinct Epidermal Growth Factor Receptor and KRAS Mutation Patterns in Non–Small Cell Lung Cancer Patients with Different Tobacco Exposure and Clinicopathologic Features

Abstract

Purpose:This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non^small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features. Experimental Design: Mutational profile of exons 18 to 21of EGFR and codons12,13, and 61of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11EBV-associated lymphoepithelioma-like carcinomas (LELC). Results: EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and welldifferentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001).Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor. Conclusion: This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.

Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib

“…There have been several reports of an inverse correlation between smoking exposure and EGFR mutation rate Pham et al, 2006;Sugio et al, 2006;Tam et al, 2006;Toyooka et al, 2006). In line with these studies, our data show that smoking status, unlike EGFR mutation status, is not an independent prognostic factor.…”

Effectiveness of erlotinib treatment in advanced KRAS mutation-negative lung adenocarcinoma patients: Results of a multicenter observational cohort study (MOTIVATE)

“…As KRAS mutation is found mainly in smokers [6,33], the negative prognostic value of KRAS mutation may be related to the poor performance status associated with smoking [34]. In our study, no significant difference was observed in survival when stratified according to smoking status in the entire patient population.…”

Molecular pathology of lung cancer: key to personalized medicine

“…196 Santis et al 209 observed a similar Molecular pathology of lung cancer pattern. In a study including 121 adenocarcinomas from African-American patients, KRAS mutations were compared with data from Caucasian patients (n ¼ 476).…”

“…15 In addition to the previously mentioned mutations, even rarer primary mutations, such as D761Y, G719C, and E709A mutations, have also been shown to be insensitive to EGFR TKIs, and even more so when co-occurring with other genetic alterations. 196 Primary TKI resistance may also be mediated by the presence of other genetic alterations that affect signaling downstream from EGFR, such as mutation of KRAS, PIK3CA, and loss of PTEN expression. [197][198][199] Mutations in KRAS, which are frequently found in adenocarcinomas with wildtype EGFR, are a mechanism of primary resistance to gefitinib and erlotinib.…”