Background
Human epidermal growth factor receptor2(
HER2) positivity is well-studied in breast cancer, while much less defined in lung cancer. Although anti-HER2 monoclonal antibody such as trastuzumab has been proven effective in breast cancer and gastric cancer [
1,
2], the clinical trials [
3,
4] of lung cancer including patients treated with trastuzumab combined with chemotherapy failed to demonstrate benefit in survival in HER2 IHC positive patients. Besides that, pan-HER TKI dacomitinib also showed no response in patients with HER2 amplifications in a phase II trial [
5].
Apart from HER2 over-expression and amplification,
HER2 gene mutation is a distinct entity in lung carcinogenesis with an incidence of 4.8% among
EGFR wild-type lung adenocarcinoma resection samples [
6]. Drugs that target
HER2 gene mutations are currently being investigated. The National Comprehensive Cancer Network (NCCN) recommend trastuzumab or afatinib as potential therapy options for non-small cell lung cancers(NSCLC) patients with
HER2 mutations. Several phase I/II trials [
5,
7‐
9] is now investigating the efficacy of other irreversible pan-HER receptor family inhibitors, such as dacomitinib, neratinib and pyrotinib. Currently,
HER2 mutation is emerging as a promising druggable target, while the optimal choice of targeted therapy remains poorly defined.
Chemotherapy is still the standard first-line regimen for patients with advanced NSCLC who are improper for targeted therapy. Among them, pemetrexed-based regimen has showed superior efficacy with less side effects and was recommended preferentially for patients with adenocarcinomas [
10,
11].
ALK/
ROS1/
RET positive patients showed a superior progression free survival(PFS) after pemetrexed-based therapy than patients with
KRAS mutations [
12‐
16]. While the effects of
HER2 mutation on the outcomes of pemetrexed-based chemotherapy is still unknown in patients with advanced NSCLC.
Aim to investigate the efficacy of pemetrexed-based chemotherapy in patients with HER2-mutant lung adenocarcinomas, we conducted this retrospective study in Chinese patients with 1714 advanced NSCLC. In addition, we also observed the clinicopathologic and molecular features of HER2 mutations in patients with advanced NSCLC.
Discussion
As far as we know, this study is the first study to compare the efficacy of pemetrexed-based chemotherapy between HER2-mutant and groups of EGFR-mutant, ALK/ROS1-rearranged and KRAS-mutant lung adenocarcinoma. We found that patients with HER2-mutant lung cancers had a PFS of 5.1 months that was similar with KRAS-mutant (5.0 months, p = 0.971) lung cancers, and numerically shorter than EGFR-mutant (6.5 months, p = 0.247) and significantly shorter than ALK/ROS1-rearranged (9.2 months, p = 0.004) lung cancers, showing that HER2-mutant lung cancer patients may have poor outcomes with chemotherapy, which strengthen the importance of developing HER2-targeted drugs in this population. We also investigate the clinicopathologic features in patients with advanced HER2-mutant lung adenocarcinomas and found that HER2 mutations were more common in younger patients, females, non-smokers and adenocarcinomas.
Different from HER2 over-expression and amplification,
HER2 mutations was found to be a distinct entity in patients with NSCLC [
20].
HER2 mutations are found in about 1%–2% of NSCLC [
20‐
22]. In this study, the incidence of
HER2 mutations was 5.1% in
EGFR/
KRAS/
BRAF/
ALK/
ROS1 negative patients, indicating that
HER2 mutations will be enriched in the population without other driver gene mutations. Consistent with our study, a study from the Memorial Sloan Kettering Cancer Center (MSKCC) group [
23] showed that in a selected population with
EGFR/
KRAS/
ALK negative, the incidence of
HER2 mutations can reach up to 6%. In the early stage resection samples, our previous study [
6] showed that the presence of HER2 mutations was not correlated with gender, age, or smoking status. However, another retrospective study [
24] of resection samples obtained at Fudan University Shanghai Cancer Center found that the incidence of HER2 mutations can reach up to 5.94% in non-smoking patients with lung adenocarcinoma. Similarly, in biopsied samples from advanced NSCLC, our study showed that
HER2 mutations were more common in non-smokers and lung adenocarcinomas. But
HER2 mutations were also frequently detected in younger patients and females in our study. Furthermore, exon20 A775_G776insYVMA was the most frequently alteration.
In the era of targeted therapy, several oncogenic driver mutations were found not only could predict the efficacy of targeted therapy, but also associated with superior outcome of first line pemetrexed chemotherapy, such as
ALK,
ROS1 and
RET [
12‐
16]. Thus, we further investigate the association of
HER2 mutation with the efficacy of pemetrexed-based chemotherapy in patients with advanced lung adenocarcinomas. We found that patients with
HER2-mutant lung cancers had a PFS of 5.1 months. Similar to this study, in the EUHER2 study [
25] of patients with
HER2-mutant lung cancers, ORR and PFS with chemotherapy were 43.5% and 6 months in first-line and 10% and 4.3 months in second-line therapies. Our study also showed that
HER2-mutant lung cancers had a similar PFS of pemetrexed-based chemotherapy with
KRAS-mutant lung cancers (5.0 months), which was inferior compared with
EGFR-mutant(6.5 months) and
ALK/
ROS1-rearranged (9.2 months), indicating that
HER2 mutation might predict a poor efficacy of pemetrexed-based chemotherapy, just like
KRAS mutation. Although pemetrexed-based chemotherapy had the longest duration among chemotherapies(pemetrexed/taxane/gemcitabine/vinorelbine/etoposide±platinum) for patients with
HER2 mutations according to Eng et al’s study [
26] and Gow et al’s study [
27], outcomes of pemetrexed for
HER2 were poor compared to other oncogene subgroups,such as
ALK and
ROS1. Furthermore, we further divide
HER2 mutations into the exon20 A775_G776insYVMA group and the other variants group and it was the first time that we found that patients with YVMA insertion were associated with an inferior PFS (4.2 vs 7.2 months,
p = 0.085).
Currently, NCCN guideline recommend trastuzumab and afatinib as the targeted therapeutic options for patients with advanced
HER2-mutant NSCLC. While, in EUHER2 study [
25], afatinib showed a modest response of 18.2% and median PFS of 3.9 months even though this drug has showed response in all 3 assessable patients with
HER2-mutant adenocarcinoma in a preliminary study [
28]. Meanwhile, several other studies [
5,
7,
8] investigated the efficacy of other irreversible pan-HER receptor family inhibitors, dacomitinib, neratinib, or neratinib combining with mTOR inhibitors in advanced NSCLC patients harboring
HER2 mutations and showed a moderate response of 12%–21%. Although these ORR or PFS are much diminished compared with those of TKIs directed at other targets in NSCLC, HER2-targeted drugs is still promising. A phase II study recently investigated a novel EGFR/HER2 inhibitor, pyrotinib, in heavily pre-treated patients with
HER2-mutant adenocarcinomas and found a promising results with RR of 54.5%(6/11) and median PFS of 6.2 months [
9]. Large number cohort study is still needed to validate the efficacy of pyrotinib in this setting.
Our study does have several limitations. First, it was a retrospective study with limited patients number(
n = 25), while this study presented the real world nature in Chinese population. Second,
HER2 mutation testing was performed using the method of ARMS, thus some rare mutations might be missed in our population. Next generation sequencing (NGS), which allows for simultaneous testing for multiple mutations using one platform and one sample, is emerging as an important method for identification of gene mutations in NSCLC, but single-gene sequencing is still more widely used. Thirdly, a substantial part of the patients with
HER2 mutations also participant into the previous clinical trial of HER2-targeted drugs [
9], thus the overall survival might be heavily influenced by the subsequent therapy.