The presence of activating mutations in the tyrosine kinase domain of the human epidermal growth factor receptor (EGFR/HER/erbB) in nonsmall cell lung cancer (NSCLC) correlates with a clinical phenotype of adenocarcinoma in never or light smokers, and renders the tumor exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs) . The introduction of targeted drugs for the treatment of NSCLC with EGFRdirected smallmolecule TKIs and monoclonal antibodies 4 has led u0126
to a significant but relatively small overall improvement in clinical outcome of unselected patients with advanced
disease. EGFR mutations and increased EGFR copy number by fluorescence in situ hybridization (FISH) are Compound Libraries predictive biomarkers that identify patients who are most sensitive to TKIs 5,6. HER2 kinase domain mutations are rare in NSCLC, and are found in approximately 4% of lung adenocarcinomas with a similar phenotype as tumors with EGFR mutations 79. In 229 patients with adenocarcinoma of the lung, with a little or no smoking history, we identified a HER2 mutation in the tumor tissue of five patients (2%), which is 0fold rarer than the frequency of EGFR mutations in the same cohort of patients 0. In other cohorts with potentially differing phenotypic selection criteria, the HER2 mutation rate was even lower: in tumors from 80 patients analyzed within the NCI’s Lung Cancer Mutation Consortium High Throughput Screening
(LCMC) a HER2 mutation was found in only three cases (%) compared to 98 cases with an EGFR mutation. In 552 samples analyzed at Massachusetts General Hospital, only one patient with a HER2 mutation was identified 2. The HER2 mutations found in clinical samples so far are all in exon 20. Afatinib is a potent, irreversible ErbB family blocker with preclinical activity in Ba/F cells expressing an artificial HER2 mutant and in a human lung cancer cell line Screening Libraries with an insertional mutation at codon 776 . We determined the tumor genomic status of the EGFR and HER2 genes in non or light smokers with lung adenocarcinoma by denaturing gradient gel electrophoresis (DGGE)/DNA sequencing of NSCLC tumor tissue or increased copy number of the EGFR gene, as determined by FISH analysis. HER2 FISH was not required