Targeting HER2 Alterations in Non–Small-Cell Lung Cancer

A Comprehensive Review

Jing Zhao, MD; Yang Xia, MD, PhD


JCO Precis Oncol. 2020;4:411-425. 

In This Article

HER2 Alterations in NSCLC

Unlike other members of the erbB receptor tyrosine kinase family, HER2 is activated independently of ligand interactions. Instead, HER2 is activated by homodimerization or heterodimerization with other members of the erbB family, resulting in the phosphorylation of intracellular tyrosine residues. This causes the activation of downstream PI3K/AKT and MEK/ERK pathways that facilitate cell proliferation and migration.[8] NSCLC cells that harbor the G776insV_G/C mutation in the related ERBB2 tyrosine kinase show constitutive activation of the receptor.[9] Transgenic mice that express the HER2 mutation HER2YVMA in lung epithelium rapidly develop invasive adenosquamous carcinoma.[10] Furthermore, ERBB2 overexpression has been identified as an oncogenic driver in lung cancers by the Cancer Genome Atlas Research Network after molecular profiling of 230 resected lung adenocarcinomas.[11] Both in vitro and in vivo evidence have confirmed the role of HER2 as a driver in NSCLC.

Three types of HER2 alterations in NSCLC have been described: HER2 gene amplification, HER2 overexpression, and HER2 point mutations[12] (Table 1). The incidence of HER2 protein overexpression in patients with NSCLC is 2.4%-38%[12–15] and is more frequent in adenocarcinomas with well-differentiated histology.[16] Immunohistochemistry (IHC) is the most common tissue-based assay used to detect and quantify the amount of HER2 protein. A score of 2+ or 3+ has been defined as HER2 overexpression in most studies.[16] There have been conflicting findings regarding the impact of HER2 overexpression on the survival of patients with lung cancer.[16–18] However, two meta-analyses have demonstrated that HER2 overexpression in patients with lung cancer is associated with worse survival.[19,20] In a recent meta-analysis, which included 40 studies with 6,135 patients enrolled, the authors concluded that HER2 overexpression is a poor prognostic factor for lung cancer, especially for adenocarcinoma and early-stage NSCLC.[19]

For HER2 gene amplification, there are two scenarios: de novo HER2 gene amplification was present in 3% of patients who did not receive targeted therapies,[21] whereas acquired HER2 gene amplification was found in 13% of patients who showed disease progression after EGFR-TKI treatment, as one of the mechanisms responsible for the acquired EGFR-TKI resistance.[22] A commonly used assay to identify the HER2 gene copy number is the fluorescence in situ hybridization (FISH) assay. An average ratio of the HER2 gene copy number to centromeres of ≥ 2.0 represents HER2 gene amplification, which is also the standard used in breast cancer. Dual in situ hybridization is a more practical alternative to FISH in breast cancer[23] but remains experimental in NSCLC.[12] The prognostic value of HER2 amplification in lung cancer is ambiguous, although there have been anecdotal reports that the overall survival (OS) of patients with HER2 amplification is worse than for patients without such abberations.[18,24]

The first report of HER2 somatic mutations in NSCLC was published in 2004; 4% of the 120 samples showed mutations in the kinase domain of the protein. This finding defined a distinct molecular subset of NSCLC.[25] The incidence of HER2 mutations ranged between 2% and 4%;[26–28] they are more likely in females, never-smokers, and Asian ethnicity and were dependent on the adenocarcinoma subtype.[29] Reverse-transcription polymerase chain reaction (RT-PCR) is the most common assay used to detect HER2 mutations. The most common HER2 mutation occurs in exon 20: a duplication or insertion of the amino acids YVMA at codon 776 (YVMA 776–779 ins). This accounts for 80%-90% of all HER2 mutations.[17,26] Recently, some rare mutations located in the transmembrane domain and the juxtamembrane domain (G660D, R678Q, E693K, and Q709L) have been identified; these are distinct driver mutations that can be targeted.[30,31]

Previous studies have suggested that HER2 mutations tend to be mutually exclusive from aberrations in EGFR and ALK.[32–34] However, the application of NGS has allowed the parallel analysis of a number of DNA sequences in limited tumor material.[35] This technology has revealed more lung cancer cases with a mutation in HER2 along with other oncogenic drivers. Results from the European EUHER2 cohort, which contained 101 patients with HER2-mutant NSCLC, revealed concomitant EGFR mutations, ALK translocations, and ROS translocations in 5, 1, and 1 patient, respectively.[29] However, the prognostic value of HER2 mutations is unclear. Several studies have shown that overall survival was not significantly different between patients with wild-type and mutated HER2.[17,36] In addition, studies conducted by Pillai et al[37] and Ninomiya et al[38] demonstrated that a HER2 mutation was linked to worse survival compared with the HER2 wild-type patients; however, Gow et al[28] reported opposing results.