5242

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in Non Small Cell Lung Cancer (NSCLC) of Never-smokers whereas HER2 mutations are rare. We have analyzed EGFR (exons 18 to 21), HER2 (exons 19 and 20) and expression of the two products of the CDKN2a gene, p16ink4a and p14arf, in 116 NSCLC of patients with detailed smoking history. Data on TP53 and KRAS mutations have been reported previously (Le Calvez et al. Cancer Res: 2005 65:5076-5083). EGFR mutations were detected in 20/116 tumors (17 %) whereas 5 tumors contained HER2 mutations (4.3%). No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from Never-smokers and 32% from Former-smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among Never-smokers, 11/16 tumors with EGFR mutation also had TP53 mutation, in contrast with 2/17 tumors without EGFR mutation (p=0.0008). Expression of p14arf, but not p16ink4a, was more frequently down-regulated in Never-smokers (62.5%) than Ever-smokers (35%) (p=0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14arf expression. These observations suggest that functional inactivation of the p14arf/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA