HER2 Mutations Identified as Treatment Targets in Patients With HER2-Negative Breast Cancer

Ron Bose, MD, PhD

Patients with breast cancer who do not exhibit amplifications of the HER2 gene may still have mutations of HER2 that drive the progression of their cancer, suggesting that these mutations could serve as therapeutic targets. The finding comes from research presented at the 2012 San Antonio Breast Cancer Symposium and concurrently published online in Cancer Discovery.

“The HER2 mutations have been picked up by many groups, but the role of them in the cancer was unknown,” said Ron Bose, MD, PhD, assistant professor in the Division of Oncology at Washington University School of Medicine and the Siteman Cancer Center in St. Louis, Missouri, and lead author of the study. “What we wanted to do is define the effect of these HER2 mutations and what implications they could have for patient treatment and patient outcomes.”

The researchers reviewed data from eight genome-sequencing studies that included nearly 1500 total patients. They identified 25 patients with somatic mutations of HER2, even though nearly all of these patients did not exhibit HER2 gene amplification.

Most of these patients would not have received HER2-targeted therapies because they would not normally be classified as having HER2-positive breast cancer, Bose explained. He said these mutations occur in about one to two percent of breast cancer cases, although there may be subgroups of patients in whom these mutations occur more frequently.

In their analysis, Bose et al observed that the HER2 mutations were clustered in two regions of the HER2 gene, with about 20% of patients exhibiting a cluster in the extracellular domain and 68% of patients exhibiting these mutations in the tyrosine kinase domain.

Overall, the researchers examined 13 HER2 mutations and tested the effect of targeted therapies on these mutations. Specifically, lapatinib (Tykerb) and neratinib, an investigational irreversible oral tyrosine kinase inhibitor, were tested on cell lines exhibiting the various identified HER2 mutations.

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Dr. Ron Bose on HER2 Gene Mutations in Breast Cancer

“Neratinib has been shown to be effective in a number of cases where we’re seeing drug resistance to gefitinib in lung cancer, and that was one of the reasons we were interested in it,” Bose said. “In the lab, we did a head-to-head comparison of three drugs: trastuzumab, lapatinib, and neratinib. Based on that head-to-head, neratinib was the most potent drug and showed the best activity, and that’s what we chose to take forward in our clinical trial.”

Bose et al measured the half maximal inhibitory concentration (IC50), or the amount of the drugs needed to inhibit tumor cell growth by half. The researchers found that for every cell line, less neratinib was needed to inhibit cell growth than lapatinib. Further, while some of the activating HER2 mutations that the researchers identified were resistant to lapatinib, all were sensitive to neratinib.

Based on the results of this study, a phase II clinical trial has been launched to assess the efficacy of neratinib given at a 240-mg dose once daily in patients with HER2-negative stage IV breast cancer.

Bose R, Kavuri SM, Searleman AC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancers. Cancer Res. 2012;72(24)(suppl 3): Abstract S5-6.