Somatic mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene are reportedly associated with sensitivity of lung cancers to gefitinib (Iressa), kinase inhibitor. In-frame deletions occur in exon 19, whereas point mutations occur frequently in codon 858 (exon 21). We found from sequencing the EGFR TK domain that 7 of 10 gefitinib-sensitive tumors had similar types of alterations; no mutations were found in eight gefitinib-refractory tumors (P ‫؍‬ 0.004). Five of seven tumors sensitive to erlotinib (Tarceva), a related kinase inhibitor for which the clinically relevant target is undocumented, had analogous somatic mutations, as opposed to none of 10 erlotinibrefractory tumors (P ‫؍‬ 0.003). Because most mutation-positive tumors were adenocarcinomas from patients who smoked <100 cigarettes in a lifetime (''never smokers''), we screened EGFR exons 2-28 in 15 adenocarcinomas resected from untreated never smokers. Seven tumors had TK domain mutations, in contrast to 4 of 81 non-small cell lung cancers resected from untreated former or current smokers (P ‫؍‬ 0.0001). Immunoblotting of lysates from cells transiently transfected with various EGFR constructs demonstrated that, compared to wild-type protein, an exon 19 deletion mutant induced diminished levels of phosphotyrosine, whereas the phosphorylation at tyrosine 1092 of an exon 21 point mutant was inhibited at 10-fold lower concentrations of drug. Collectively, these data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.

BackgroundSomatic mutations in the gene for the epidermal growth factor receptor (EGFR) are found in adenocarcinomas of the lung and are associated with sensitivity to the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, KRAS, and mutations in EGFR and KRAS appear to be mutually exclusive.Methods and FindingsWe sought to determine whether mutations in KRAS could be used to further enhance prediction of response to gefitinib or erlotinib. We screened 60 lung adenocarcinomas defined as sensitive or refractory to gefitinib or erlotinib for mutations in EGFR and KRAS. We show that mutations in KRAS are associated with a lack of sensitivity to either drug.ConclusionOur results suggest that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.

The accuracies of magnetic resonance (MR) imaging and computed tomography (CT) in determining tumor classification and assessing mediastinal node metastases were compared in a prospective cooperative study of 170 patients with non-small cell bronchogenic carcinoma. The sensitivity of CT in distinguishing T3-T4 tumors from T0-T2 tumors was 63%; specificity was 84%. These values for MR imaging were not significantly different (56% and 80%). With receiver operating characteristic (ROC) analysis, no difference existed between the accuracies of CT and MR imaging in diagnosis of bronchial involvement or chest wall invasion, but MR imaging was significantly more accurate than CT (P = .047) in diagnosis of mediastinal invasion. Lymph node sampling was performed in 155 patients (642 node stations). Cancerous nodes were found in 14% of stations in 21% of patients. There was no significant difference between the accuracies of CT and MR imaging in detecting mediastinal node metastases (N2 or N3); the sensitivities were 52% and 48%, respectively, and specificities were 69% and 64%. ROC analysis also showed no difference between CT and MR imaging.

Our data suggest that individuals in whom gefitinib is efficacious are more likely to have adenocarcinomas of the bronchioloalveolar subtype and to be never smokers. These observations may provide clues to mechanisms determining sensitivity to this agent and suggest that NSCLC has a different biology in patients who never smoked and those with bronchioloalveolar carcinoma.

Erlotinib is active in BAC and adenocarcinoma, mixed subtype, BAC. Testing for EGFR and KRAS mutations can predict RR and PFS after treatment with erlotinib in this histologically enriched subset of patients with non-small-cell lung cancer (NSCLC). These data suggest that histologic subtype and molecular characteristics should be reported in clinical trials in NSCLC using EGFR-directed therapy.