Some Rare HER2 Mutations May Not Be Capable of Causing Breast Cancer Growth
Results of a new laboratory study by Johns Hopkins Kimmel Cancer Center researchers suggest that some rare “missense” mutations in the HER2 gene are apparently not—on their own—capable of causing breast cancer growth or spread. In a related finding, the research team said such mutations, which are found in about 5% of breast cancers, might also fail to predict response to anticancer drugs that target the HER2 gene, unlike the more common alterations of the gene that amplify or overexpress it. These findings were published by Zabransky et al in the Proceedings of the National Academy of Sciences.
Cancer experts estimate that one in five breast cancers contains amplification of the HER2 gene. These so-called HER2-positive tumors can be detected in breast cancer tissue samples, and anticancer drugs have been designed to seek them out. “Missense” mutations, on the other hand, swap a single DNA nucleotide for another. Because these rare mutations cause no overproduction of proteins, laboratory models that scan for signs of excess protein production often overlook them. According to Kimmel Cancer Center scientist Ben Ho Park, MD, PhD, about 5% of breast cancers contain HER2 missense mutations.
After other scientific reports identified these missense mutations, Dr. Park and his colleagues were drawn to study “whether cancers that carry the missense mutations were susceptible to the same drugs as HER2-positive breast cancers.”
Study Findings and Details
For the study, the research team individually placed seven missense mutations found in human breast cancers into normal and cancerous human breast cells that do not produce excessive amounts of HER2 protein or have any baseline HER2 mutations. They identified one HER2 missense mutation that increased HER2 activity, but only in cases where the mutation was partnered with a mutation in another cancer-related gene.
None of the missense mutations increased the formation or spread of tumors in mice.
Dr. Park, Professor of Oncology at the Johns Hopkins University School of Medicine, said that although missense mutations are rare, further study of them is important, given that 210,000 new cases of breast cancer are diagnosed each year in the United States alone, which means more than 10,000 cases annually that may have a HER2 missense mutation.
HER2-positive patients are often treated with HER2-targeted drugs, such as trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), or lapatinib (Tykerb). However, since the HER2 missense mutations are usually found in HER2-negative breast cancer patients, Dr. Park says it is unclear how HER2-targeted drugs might work in patients with the rare mutations.
“Knowledge of HER2 missense mutations, as opposed to HER2 amplification or overexpression, is relatively new,” Dr. Park noted. “Studies are ongoing to see if therapies like trastuzumab work for breast cancers that have these mutations, but this is not the standard of care.”
Earlier studies, Dr. Park said, have shown that one of the HER2 missense mutations, dubbed L755S, could cause resistance to the HER2-positive–targeted lapatinib treatments when the mutated gene was overexpressed. But Dr. 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 noted, because it could mean that breast cancer patients who carry this mutation at normally expressed levels could still be sensitive to lapatinib treatment.
Clinical trials to test HER2-targeted drugs on cancers with HER2 missense mutations are ongoing, Dr. Park said. Looking at the genetics of tumors that respond and don't respond to these therapies, Dr. Park suggested, “would aid our thinking about how to best target those mutations.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
