Mutational analysis of K-RAS and EGFR implicates K-RAS as a resistance marker in the Southwest Oncology Group (SWOG) trial S0126 of bronchioalveolar carcinoma (BAC) patients (pts) treated with gefitinib

Abstract

7008 Background: S0126 was a phase II trial of the EGFR inhibitor gefitinib in BAC subtypes, a unique form of NSCLC adenocarcinoma. We reported that high levels of tumor p-MAPK correlated with poor overall survival in these pts, while EGFR levels were not predictive. We hypothesized that activation of the MAPK pathway, due to mutated K-RAS, would correlate with poor outcome to EGFR inhibitor therapy. Methods: DNA was extracted from pre-treatment tumor tissue of 66 pts. Exons 18, 19 & 21 in EGFR (64 pts) and codons 12 & 13 in K-RAS (63 pts) were examined by PCR/RFLP analyses with mutations identified by direct sequencing. Results: K-RAS mutations were found in 19 pts (30%), 17 who were current or former smokers. All were 12th codon point mutations. Of 17 pts with K-RAS mutations and measurable disease by RECIST or computer assisted image analysis (CAIA), 1 responded (6%). EGFR mutations were found in 12 pts (19%), with point mutations found at codons 719 (1) and 858 (9), and deletion mutations in exon 19 (2). All EGFR mutations were in former smokers, except a double-base change at codon 858 and one deletion. Both pts with EGFR deletions and 2/8 pts with codon 858 mutations responded [4/12 total; 4/8 with only EGFR mutations (50%)]. Four pts with K-RAS mutations also had EGFR codon 858 point mutations (6%), all were former smokers, and none responded. Transversion K-RAS mutations associated with smoking (G→T or G→C) were found in 9/17 smokers (53%), while both never-smokers had G→A transition mutations. All base change mutations in EGFR were transversions, with 81% found in pts with a history of smoking. Conclusions: These data show that 1) K-RAS transversion mutations are associated with smoking in this BAC cohort (exact p-value=0.006); 2) EGFR mutations in the absence of K-RAS mutations are associated with response to gefitinib (exact p-value=0.026); 3) K-RAS and EGFR mutations are relatively frequent in BAC, each found in smokers; and 4) Concomitant mutations in both genes are infrequent. These data suggest that further study of mutant K-RAS as a resistance marker for response to gefitinib is warranted. (Hope Fndtn, CA32102, CA38926, CA46441) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca