Epidermal growth factor receptor mutations in lung cancers

Abstract

In 2004, two groups reported somatic mutations in the gene for the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC), which were highly correlated with the clinical response to the anticancer drug, gefitinib. Since then, a tremendous amount of knowledge has accumulated, and sheds light on significant oncological properties as well as the clinical relevance of this mutation, which could be applicable to other malignancies. The EGFR mutations are distributed throughout the kinase domain, but a deletion in exon 19 and the point mutation L858R in exon 21 account for approximately 90%, which confer a greater response to gefitinib treatment, compared with other types of EGFR mutations. These EGFR mutations in the tyrosine kinase domain are seldom acquired in cancers of the other organs and the mutations preferentially involve a subset of lung cancers, which are clinicopathologically characterized by female sex, non-smoking, adenocarcinoma histology and East Asian ethnicity. In Japan, the EGFR mutations are detected in approximately 30% of overall NSCLC and approximately 40% of surgically resected adenocarcinomas. The morphological features of adenocarcinomas harboring the mutations were reported to be frequent in those with bronchioloalveolar features, but it is suggested that the cellular lineage of the putative original cells of the cancers refines the subset more clearly. In the present study the current knowledge of EGFR mutations is reviewed, insights from which raise many further questions, and thus suggest new directions for future research.

Co-Activation of Epidermal Growth Factor Receptor and c-MET Defines a Distinct Subset of Lung Adenocarcinomas

“…7 Mutations of KRAS and EGFR lead to enhanced activation of similar signaling pathways, such as AKT and ERK, and they occur in a mutually exclusive manner. 5 Intriguingly, the EGFR mutation has reported associations with a bronchioloalveolar or papillary histological pattern, 8 with the expression of thyroid transcription factor-1, 9 and with micropapillary pattern, 10,11 an aggressive variant of papillary adenocarcinoma. 12,13 The KRAS mutation, on the other hand, is associated with mucinous histology.…”

Triage of Cytologic Direct Smears for Ancillary Studies: A Case-Based Illustration and Review

“…[3][4][5] The L858R point mutation and in-frame deletions in exon 19 represent the two most common clinically relevant mutations in EGFR. 6 The tyrosine kinase inhibitor, crizotinib, has been approved as targeted therapy for NSCLCs harboring ALK rearrangements. 7,8 Rearrangements involving ALK typically result in a fusion protein consisting of echinoderm microtubule-associated protein-like 4 (EML4) and ALK.…”

Good Response to Gefitinib in Lung Adenocarcinoma of Complex Epidermal Growth Factor Receptor (EGFR) Mutations with the Classical Mutation Pattern

“…Patients with both the del-19 and the L858R mutations have good responses to EGFR TKIs and these are termed "classical mutations" [11]. Patients with these mutations exhibit objective response rates in the range of 75%-95% [7-9, 14 -16].…”