Missense HER2 Mutations May Not Respond to Targeted Therapies

Not all HER2 genes are capable of causing cancer growth or spread, and thus may also fail to predict response to anticancer drugs that target the gene, according to a recent study published in the Proceedings of the National Academy of Sciences.

Roughly 5% of breast cancers contain HER2 missense mutations, which primarily occur in the absence of HER2 gene amplification. Unlike most HER2 genes, missense mutations do not cause an overproduction of proteins and, as a result, classify as negative for HER2 by FISH or immunohistochemistry assays.

To determine if these HER2 missense mutations could be targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers, researchers from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center individually placed 7 missense mutations found in human breast cancers into normal and cancerous human breast cells that do not produce excessive amounts of the HER2 protein or have any baseline HER2 mutations.

Using genome editing, researchers found that the majority of HER2 missense mutations did not impart detectable oncogenic changes. However, 1 HER2 missense mutation, HER2 V777L, increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro.

The V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. None of the missense mutations increased the formation or spread of tumors in mice.

According to study authors, these results suggest that HER2 missense mutations are functionally distinct and require additional oncogenic input to impart cancerous phenotypes. By themselves, HER2 missense mutations may not be reliable predictors of response to HER2-targeted therapies; however, this hypothesis is currently being tested in genomically driven clinical trials, says study author Ben Ho Park, MD, PhD, a scientist at Sidney Kimmel Comprehensive Cancer Center.

“Knowledge of HER2 missense mutations, as opposed to HER2 amplification or overexpression, is relatively new,” Park noted. “Studies are ongoing to see if therapies like Herceptin work for breast cancers that have these mutations, but this is not the standard of care.”

HER2-positive patients are often treated with targeted agents, such as trastuzumab (Herceptin), pertuzumab (Perjeta), T-DM1 (Kadcyla) or lapatinib (Tykerb). However, since the HER2 missense mutations are usually found in patients with breast cancer who are HER2-negative, it is unclear how these targeted drugs might work in patients with rare mutations, said Ho.

It is estimated that 1 in 5 breast cancers contain amplification of the HER2 gene. This amplification abnormally carbon copies and overproduces the whole gene several times within the genome, resulting in too much HER2 protein in cancer cells. Missense mutations differ from standard HER2 genes, as they swap a single DNA nucleotide for another. These mutations are rare; however, it is estimated that of the 210,000 new annual breast cancer cases in the United States, 10,000 may have a HER2 missense mutation.

Earlier studies have shown that one of the HER2 missense mutations, known as L755S, could cause resistance to the HER2¬-targeted lapatinib (Tykerb) treatments when the mutated gene was overexpressed. However, Park and colleagues found no signs of lapatinib resistance in their experimental cell lines when that mutated gene was active at normal levels.

These results are clinically important, the researchers note, because patients with breast cancer who carry this mutation at normally expressed levels could still be sensitive to lapatinib treatment.

Clinical trials to test HER2-targeted agents on cancers with HER2 missense mutations are ongoing, said Park. Looking at the genetics of tumors that do and do not respond to these therapies, “would aid our thinking about how to best target those mutations,” he added.

Zabranskya DJ, Yankaskasb CL, Cochran RL. HER2 missense mutations have distinct effects on oncogenic signaling and migration. Proc Natl Acad Sci. 2015;112(45):E6205—E6214.