Sholl, LynetteYeap, BeowIafrate, AnthonyHolmes-Tisch, A. J.Chou, Y.-P.Wu, Ming-TsangGoan, Y.-G.Su, LiBenedettini, E.Yu, J.Loda, MassimoJanne, PasiChristiani, DavidChirieac, Lucian2017-05-152009Sholl, L. M., B. Y. Yeap, A. J. Iafrate, A. J. Holmes-Tisch, Y.-P. Chou, M.-T. Wu, Y.-G. Goan, et al. 2009. “Lung Adenocarcinoma with EGFR Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers.” Cancer Research 69 (21) (October 13): 8341–8348. doi:10.1158/0008-5472.can-09-2477.0008-5472http://nrs.harvard.edu/urn-3:HUL.InstRepos:32679815In a subset of lung adenocarcinomas the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. We selected to study 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion-mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, low and high polysomy (100% v 54%, P=0.009). EGFR amplification occurred invariably on the mutated and not the wildtype allele (median mutated:wildtype ratios 14.0 v .33, P=0.003), was associated with solid histology (P=0.008), and advanced clinical stage (P=0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival 16 v 31 months, P=0.01) and when adjusted for stage (P=0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and demonstrate distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology.en-USJournal Article2017-05-1510.1158/0008-5472.CAN-09-2477