Genome sequencing identifies HER2 gene mutations as ideal for targeted therapy

Analyzing data from a series of studies that documented breast cancer genome sequencing has confirmed that HER2 gene 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.

Data was reviewed from eight genome-sequencing studies that included nearly 1,500 patients. HER2 mutations occurred in 25 patients, nearly all of whom did not have HER2 gene amplification, which is the hallmark of HER2-positive breast cancer. HER2 mutations are estimated to occur in 1% to 2% of breast cancer cases, though subgroups may have a higher frequency of this mutation.

“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,” said Ron Bose, MD, PhD, of Washington University School of Medicine and Siteman Cancer Center in St. Louis, Missouri. “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.”

The HER2 mutations clustered in two regions of the HER2 gene. One cluster, which occurred in 20% of patients, was in the outside half of HER2, known as the extracellular domain. The other cluster involved mutations in the tyrosine kinase domain, which is in the inside half of HER2, and it occurred in 70% of the patients. After the researchers tested 13 HER2 mutations, a majority were found to be activating mutations that were sensitive to lapatinib and trastuzumab. However, two of the mutations were resistant to lapatinib, yet 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.

This analysis was presented at the San Antonio Breast Cancer Symposium, held December 4-8, 2012, and published in Cancer Discovery (2012; doi:10.1158/2159-8290.CD-12-0349).

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