HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies

Abstract

Multiple oncogenic molecular alterations have been discovered that serve as potential drug targets in non-small cell lung cancer (NSCLC). While the pathogenic and pharmacological features of common targets in NSCLC have been widely investigated, those of uncommon targets are still needed to be clarified. Human epidermal growth factor receptor 2 (HER2, ERBB2)-altered tumors represent a highly heterogeneous group of diseases, which consists of three distinct situations including mutation, amplification and overexpression. Compared with breast and gastric cancer, previous studies have shown modest and variable results of anti-HER2 treatments in lung cancers with HER2 aberrations, thus effective therapies in these patients represent an unmet medical need. By far, encouraging efforts towards novel treatment strategies have been made to improve the clinical outcomes of these patients. In this review, we describe the biological and clinicopathological characteristics of HER2 alterations and systematically sum up recent studies on emerging therapies for this subset of patients.

NSCLC as the Paradigm of Precision Medicine at Its Finest: The Rise of New Druggable Molecular Targets for Advanced Disease

“…The presence of MET exon14 skipping mutation and MET amplification can be typically found in elderly female patients with non-smoking history and are more frequent in adenocarcinoma or sarcomatoid histology [ 39 , 137 , 138 , 139 ]. Similarly, HER2 aberrations, particularly HER2 mutations, are more frequent in never smoker women, affected by NSCLC of adenocarcinoma histology [ 140 , 141 , 142 , 143 ]. Taken together, KRAS mutations recur more often in smokers versus nonsmokers and in western patients [ 83 ].…”

Targeted therapy for lung cancer: Beyond EGFR and ALK

“…56 Reported HER2 overexpression ranges widely (from 2.5% to 35%) in NSCLC, probably because of the inconsistency among different methods of evaluation for positivity assessment. Mutations in HER2 are more frequent in women, nonsmokers, and patients with adenocarcinoma histology, 57 whereas HER2 gene amplification and protein overexpression have been related to male sex and cigarette smoking. 55 HER2 mutations can be detected either by reverse transcriptase-PCR or by NGS, but HER2 protein expression analysis should not be used as a surrogate marker for HER2 mutations.…”

Current treatments for non-small cell lung cancer

“…Mutations in the gene encoding human epidermal growth factor receptor 2 ( HER2 ) is the mutation of exon 20, and these mutations are found in 2%–4% of NSCLC patients, especially women, besides, the patients with HER2 mutations easily appear brain metastases ( 24 ). Activation of HER2 induces the phosphorylation of tyrosine residues, leading to the activation of downstream signaling pathways such as MEK/ERK and PI3K/AKT, which in turn increases the migration and proliferation of lung cancer cells ( 25 ).…”