Lung adenocarcinomas usually show mutations in multiple genes encoding receptor tyrosine kinases. These include EGFR, ALK, ROS, MET, and RET. Some cases show mutations in the KRAS oncogene. EGFR gene mutations are frequently found in non-small cell lung carcinomas from East Asians than non-Asians (30% vs 8%), from women than from men (59% vs 26%), from never-smokers than ever-smokers (66% vs 22%), and in adenocarcinomas (non-mucinous lepidic or papillary predominant) vs other non-small cell lung cancers (49% vs 2%). (Ref: Rosai & Ackerman, 10th Ed., p 372). The two most commonly found EGFR mutations are: point mutation at codon 858 (L858R) and the in-frame deletions in exon 19. Together, they make up >90% of cases. These mutations are highly specific for lung adenocarcinoma and are associated with non-mucinous tumors with lepidic or papillary growth pattern, and TTF-1 positivity. Targeted Therapy: The presence of EGFR mutations predict the probability of response to an EGFR tyrosine kinase inhibitors, including Erlotinib (Tarceva), Afatinib (Gilotrif), and Gefitinib (Iressa). They can be used with or without chemotherapy as the first line of treatment in advanced non-small cell lung cancers with EGFR mutations. Eventually, many patients develop additional mutations in the EGFR gene and stop responding. One such mutation is T790M. These patients may respond to newer EGFR inhibitors such as Osimertinib (Tagrisso). The image shows lepidic predominant adenocarcinoma of lung.