Two treatment strategies to target EGFR have been developed: monoclonal antibodies directed against the extracellular ligand-binding domain of the EGFR (e.g., cetuximab)^1,2 and ³ and small molecule TK inhibitors (TKIs) (e.g., gefitinib and erlotinib).^4,5,6 and ⁷ Initial clinical trials reported objective responses to EGFR TKIs in 10% to 27% of unselected NSCLC patients after failure of chemotherapy. Several clinical features were found to be associated with increased response rate to EGFR TKIs including female gender, never smokers, Asian ethnicity, and adenocarcinoma histology. Several groups of investigators independently identified somatic mutations in the exons 18 to 21 of the TK domain of EGFR in responders to TKI therapies.^8,9 and ¹⁰ These mutations occur in approximately 10% of Western and up to 50% of Asian patients. The most common are in-frame deletions in exon 19 (45%), followed by a point mutation (CTG to CGG) in exon 21 at nucleotide 2573 which results in substitution of leucine by arginine at codon 858 (L858R) (41%). Other less common mutations which are associated with sensitivity to EGFR TKIs include G719 mutations in exon 18 and the L861 mutations in exon 21. In recent prospective clinical trials of gefitinib or erlotinib, response rates of EGFR-mutated cases ranged from 65% to 90%. In most studies, patients with EGFR mutations and a response to erlotinib showed a longer progression-free survival and a trend towards improved overall survival.

The correlation between morphology and EGFR mutations is still controversial but indicates that the histologic subtype of NSCLC should be explicitly reported in pathology reports. Initial studies indicated that EGFR mutations are most frequently observed in bronchioloalveolar
carcinomas (BAC).^11,12,13 and ¹⁴ However, studies that applied strict 2004 WHO definition of BAC failed to demonstrate this association. Subsequently, several reports showed that mixed subtype of invasive adenocarcinoma with a BAC component were commonly associated with EGFR mutations, although other studies did not confirm this correlation. More recent studies found a link between papillary differentiation and EGFR mutations.^15,16 In our experience, there is a large overlap in histologic growth patterns between different adenocarcinomas with a different mutational profile. EGFR mutations are extremely rare in large cell carcinomas, small cell carcinomas, and large cell neuroendocrine carcinomas.

Genetic mutations in the gene encoding proteins involved in the EGFR signaling cascade (KRAS, HER2, BRAF, PI3K, LKB1, SHP2) seem to exist as mutually exclusive somatic mutations, with the possible exception of those in PI3K.¹⁷ KRAS mutations are predictor of failure of EGFR TKI therapy. They occur most often in adenocarcinomas of smokers and are adverse prognostic factor.^18,19 and ²⁰ Mucinous differentiation in mixed subtypes of adenocarcinomas and mucinous type of BAC strongly correlates with KRAS mutations.^21,22 HER2 mutations are very similar to EGFR mutations, affecting adenocarcinomas with BAC morphology in women, never smokers and may predict sensitivity to other targeted therapies.²³ It has been reported that mutation of the BRAF gene occurs in about 1% to 3% of lung adenocarcinomas.²³ Because of the low incidence, it is not clear how patients with BRAF mutation respond to EGFR-TKIs. Animal models and early clinical
trials demonstrated that tumors harboring BRAF mutation (V600E) showed regression induced by a specific MEK inhibitor, CI-104045.^24,25