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

Associations of HER2 Gene Amplification and Mutation and HER2 Protein Overexpression in Lung Cancer

The molecular associations of HER2 gene amplification and mutation and HER2 protein overexpression in lung cancer are controversial. In breast cancer, HER2 overexpression often occurs along with HER2 amplification. For example, a HER2 protein overexpression score of 3+ measured using IHC is equal to a HER2 amplification score assessed by FISH, but a HER2 overexpression level of 2+ measured using IHC must be confirmed by FISH.[7] However, this correlation could not be confirmed in NSCLC. In an analysis by Nakamura et al[16] in 50 surgically removed NSCLC specimens, HER2 overexpression was detected in 26% of the cases, whereas HER2 amplification was only detected in 2%. No significant correlation was observed between an increase in gene copy number and protein overexpression. Hirsch et al[13] investigated 51 NSCLC tumors and found that only 12% of the specimens had corresponding IHC- and FISH-positive results. However, 14% of specimens with a score of 2+/3+ as determined by IHC had negative results when measured by the FISH test, whereas 21% of the samples with 9 or more gene copies had a score of 0 or 1+ by IHC. Conversely, in an evaluation by Yoshizawa et al[12] of 243 lung adenocarcinoma specimens, HER2 overexpression (IHC 2+ and 3+) and HER2 gene amplification were significantly associated. Furthermore, other studies reported a higher incidence of overlap between IHC 3+ staining and HER2 amplification.[13,15,39,40]

There are several possible explanations for these conflicting results. First, overexpression of HER2 can be the consequence of different mechanisms that do not involve upregulation at the transcriptional level, such as polysomy of chromosome 17. Another reason for the conflicting results may be alterations in transcriptional or post-transcriptional regulation mechanisms.[16] Finally, differences in the criteria defining overexpression and the methods used may also affect the results.

A limited number of studies have demonstrated that mutations in the HER2 gene are associated with increased levels of HER2 amplification. Suzuki et al[17] showed that higher HER2 expression levels were coupled with HER2 mutations in approximately half of 46 tumor samples. Yoshizawa at al[12] found that 2 of 6 cases with HER2 mutation also had HER2 amplification, on the basis of their investigation of a total of 243 lung adenocarcinoma specimens. In contrast, numerous studies demonstrated a negative association between HER2 mutations and amplification. A study by Li et al[21] showed that no patients had tumors with both a HER2 mutation and HER2 amplification, similar to Arcila et al.[26] Although conflicting results exist, NSCLC cases that harbor a mutation and amplification in HER2 are rare.

Overall, the unclear associations between HER2 protein overexpression, HER2 gene amplification, and HER2 gene mutations highlight that the role of HER2 alterations in lung cancer is still unclear. Therefore, it might be necessary to reconsider the diagnostic value of HER2 alterations in NSCLC.