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 Chemotherapy Outcomes

Some in vitro studies have demonstrated that NSCLC cell lines overexpressing HER2 can show intrinsic chemoresistance.[41–43] However, data from retrospective studies have shown that the influence of HER2 alterations on the efficacy of chemotherapy is debatable (Table 1). A study by Calikusu et al[44] evaluated 73 consecutive patients with advanced NSCLC who underwent cisplatin-based chemotherapies. This study revealed that patients with NSCLC who had high HER2 expression (IHC 1–3+) exhibited resistance to cisplatin-based regimens. However, this study did not take chemotherapy history into consideration. Moreover, some patients in the study received palliative radiotherapy, which may also have affected the results. In a study by Cappuzzo et al[45] in which all 190 patients received chemotherapy as first-line therapy, no difference in response rate was observed between patients who were HER2 positive and negative as per FISH analysis. Furthermore, data from cohort trials confirmed no relationship between the HER2 status and sensitivity to chemoradiotherapy. A phase II concurrent cisplatin-based chemoradiotherapy trial involving 68 patients with NSCLC showed that neither HER2 overexpression nor amplification was associated with the objective response to chemoradiotherapy.[46] In the Cancer and Leukemia Group B study,[47] 186 patients with unresectable stage-III NSCLC were treated with sequential chemotherapy followed by radiation therapy with or without concurrent chemotherapy. The results demonstrated that HER2 overexpression does not predict the response to chemotherapy.

Conversely, evidence of the impact of HER2 mutations on tumor chemosensitivity is limited. Li et al[48] retrospectively reviewed 106 cases of patients with NSCLC who received first-line pemetrexed and platinum-based chemotherapy. They concluded that patients who had a HER2 mutation had greater clinical benefit than HER2 wild-type patients. Interestingly, a study by Wang et al[49] showed that patients with HER2-mutant lung cancer had inferior outcomes compared with those with ALK/ROS1 rearrangements or EGFR mutations after pemetrexed-based chemotherapy, which is considered first-line therapy.