From a series of studies documenting breast cancer genome sequencing, an analysis of data has confirmed that HER2 mutations may be ideal targets for breast cancer treatment.
Further, the majority of these mutations are activating mutations that drive breast cancer cell growth in tissue culture.
AdvertisementRon Bose, M.D., Ph.D., assistant professor in the division of oncology at the Washington University School of Medicine and the Siteman Cancer Center in St. Louis, Mo., presented these results at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held here Dec. 4-8. The data were also published in Cancer Discovery, a journal of the American Association for Cancer Research.
Bose and colleagues reviewed data from eight genome-sequencing studies that included nearly 1,500 patients. Twenty-five patients'' cancer had HER2 mutations, nearly all of which occurred in those who did not have HER2 gene amplification, the hallmark of HER2-positive breast cancer. Bose estimated that HER2 mutations occur in 1 percent to 2 percent of breast cancer cases, but there may be subgroups in which the frequency of this mutation is higher.
"Normally, patients with HER2 mutations would not qualify to receive drugs that target HER2, such as trastuzumab, because the HER2 gene amplification tests will come back as normal. This is because the current testing used to measure HER2 in breast cancer will not pick up HER2 mutations. DNA sequencing of HER2 is needed," Bose said. "It is possible that patients with cancers containing HER2 mutations will benefit from receiving the same drugs that are currently used to treat patients with HER2-positive breast cancer."
Analysis showed that HER2 mutations clustered in two regions of the HER2 gene. The researchers found one cluster in 20 percent of patients in the outside half of HER2, called the extracellular domain. Seventy percent of patients had mutations in the inside half of HER2, specifically in the tyrosine kinase domain. After testing 13 HER2 mutations, the researchers found a majority were activating mutations that were sensitive to the drugs lapatinib and trastuzumab. Two of the mutations, however, were resistant to lapatinib and sensitive to neratinib.
"The activating mutations are turning on HER2''s functioning and will probably result in abnormal, unregulated HER2 signaling, which is likely driving the cancer cell," Bose said. "These mutations were sensitive to HER2 tyrosine kinase inhibitors. Many were sensitive to lapatinib, an FDA-approved drug, and all were sensitive to neratinib, a drug in phase II clinical trials."
However, not all HER2 mutations were activating mutations. A few mutations appeared to be "silent events" occurring in the genome of the cancer. "Just because we see a mutation in the HER2 gene does not guarantee that every case is an activating mutation that is sensitive to drugs," Bose said. "The best way to find out is to test individual mutations in the laboratory."
Bose and his colleagues are now working on a multicenter, phase II clinical trial testing neratinib in patients who have HER2 mutations in their breast cancer.