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

Impact of HER2 Alterations on EGFR TKI Treatment Outcomes

Although gefitinib is not expected to inhibit HER2, before the discovery that TKIs exert efficient antitumor activities in patients with EGFR mutations, several studies evaluated the correlation between de novo HER2 overexpression/amplification and responsiveness to gefitinib in vitro and in vivo (Table 1). The preclinical data showed that HER2 overexpression increased the sensitivity of lung cancer cells to gefitinib.[50] This result was later validated in studies by Soh et al[51] and Cappuzzo et al,[52] in which HER2 FISH-positive patients (defined as HER2 high level of polysomy or gene amplification) who underwent gefitinib treatment had a higher objective response rate (ORR), time to progression (TTP), and progression-free survival (PFS) and a trend toward a longer OS after gefitinib treatment than patients who did not have HER2 amplification.[51,52] However, a study conducted in a Japanese cohort by Varella-Garcia et al[53] failed to show the different survival benefit in terms of HER2 FISH status, as did another cohort study by Tiseo et al.[54] In patients with HER2 overexpression, Cappuzzo et al[55] demonstrated that there was no difference in the TTP or OS compared with patients without HER2 overexpression. Of note, in these studies, the patients were not screened for EGFR mutations; thus, the additional benefit might be derived from the higher frequency of concurrent EGFR mutations in patients with HER2 amplification. For instance, Soh et al[51] showed that 43.8% of HER2 FISH-positive patients harbored EGFR-sensitive mutation in the HER2 FISH-positive group, whereas this was the case for only 19% of the FISH-negative patients.

Potential interactions between EGFR and HER2 have also been investigated. For EGFR-mutant lung cancers, the impact of the HER2 status on TKI susceptibility remains controversial. Preclinical studies have shown that HER2 overexpression did not confer resistance to TKIs, whereas HER2 knockdown elicited sensitivity to erlotinib in cell lines that harbored a concomitant EGFR-sensitive mutation.[56] On the contrary, subgroup analysis of EGFR mutations in the cohorts of the two studies mentioned above showed inconsistent results. Cappuzzo et al[52] showed that HER2 FISH-positive patients had a better ORR and disease control rate (DCR), yet Soh et al[51] have reported that HER2 FISH status did not have an impact on the ORR, PFS, or OS. Emerging evidence from a Japanese prospective cohort study has shown that concomitant HER2 overexpression may have a negative impact on the effects of EGFR-TKIs in NSCLC with an EGFR mutation,[57] which was consistent with the experimental data.[56] Therefore, there is still debate over the role of de novo HER2 overexpression/amplification in the response to TKIs in patients with EGFR-mutant NSCLC.

It is noteworthy to mention that the frequency of acquired HER2 amplification in patients who are resistant to EGFR-TKIs is dramatically higher (13%) than the frequency of de novo alterations (3%).[22]HER2 amplification is regarded as one of the bypass resistance mechanisms of EGFR-TKIs.[22] Thus, distinguishing de novo HER2 amplification from acquired HER2 amplification may provide a clinical benefit. In a phase II trial, analysis of paired pre- and post-treatment samples from patients resistant to EGFR-TKI revealed an increased HER2 IHC score.[58] Furthermore, a high level of HER2 overexpression might instigate tumor resistance. Preclinical data demonstrated that HER2 overexpression > 50-fold above baseline conferred resistance to erlotinib.[56]

Collectively, these data reveal a muddled scenario, indicating that the effects of HER2 amplification and HER2 overexpression on sensitivity and resistance to TKI drugs are intricate. This may be explained by differences in cell lines and the low incidence of HER2 aberrations, resulting in a small sample size with significant heterogeneity. Moreover, early studies enrolled patients who had not been screened for EGFR mutations. In addition, de novo and acquired HER2 pathway activation may play different roles during TKI treatment and so need to be evaluated separately.