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Genome sequencing identified HER-2 mutations as therapy targets
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SAN ANTONIO — The use of whole-genome sequencing has helped researchers to identify HER-2 mutations that would not have been identified using traditional HER-2 testing. These mutations may make the tumors susceptible to anti-HER-2 therapy, according to Ron Bose, MD, PhD, assistant professor in the division of oncology at the Washington University School of Medicine and the Siteman Cancer Center in St. Louis.
Bose presented the findings at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.
Ron Bose
“Using genome sequencing data, we identified 25 patients with a HER-2 mutation,” Bose said. “These particular mutations would be missed by current HER-2 testing.”
The hypothesis was that patients with HER-2 mutations would benefit from anti-HER-2 drugs.
“HER-2 mutations predominantly occur in patients who are HER-2–negative by conventional testing,” Bose said. “These mutations are found only in the breast cancer and are not inherited.”
The researchers used direct enzyme activity measurement, tissue culture experiments and tumor growth in mice to test 13 HER-2 mutations.
“The majority of HER-2 mutations are activating events that cause cancerous growth of cells in the lab, thus they are highly likely to drive the growth of these breast cancers,” Bose said.
He added that breast cancer cells with the HER-2 L755S mutation are resistant to lapatinib (Tykerb, GlaxoSmithKline). “However, their growth is blocked by neratinib (Puma),” Bose said.
The researchers tested the concentration of drug needed to inhibit cancer cell growth. “There was still resistance to lapatinib at 10,000 nmol/L of the drug,” Bose said.
Bose concluded that these results show how cancer genome sequencing can be directly applied to guide individual patient treatment.
“HER-2 mutations are a target for breast cancer treatment and gene sequencing is needed to identify these patients,” he said. “A multi-institutional, phase 2 clinical trial is opening to screen patients for HER-2 mutations and treat them with neratinib. If this trial is successful, we estimate that 4,000 women per year could benefit in the US, and, worldwide, that number could be five times as large.”
For more information:
Bose R. #S5-6. Presented at: the 2012 CTRC-AACR San Antonio Breast Cancer Symposium; Dec. 4-8, 2012; San Antonio.
Disclosure: Bose reports no relevant financial disclosures.