HER2 Test May Define Trastuzumab Benefit in Breast Cancer
NEW YORK (Reuters Health) – Breast cancer patients with low extracellular domains of human epidermal growth factor receptor 2 (HER2) are less likely to benefit from trastuzumab (Herceptin, Genentech), according to U.S. and Greek researchers.
As Dr. David L. Rimm explained in an email to Reuters Health, “Each patient that has breast cancer is tested for HER2 expression to see if they qualify for Herceptin therapy. Most labs use an antibody probe that recognizes the part of the molecule that is inside the cell (intracellular domain or ICD). Some labs use a molecule that recognizes the outside of the cell (extracellular domain, ECD), since that is where Herceptin binds to the target, but some studies have shown there is no difference.”
“Using a more careful measurement method, that uses fluorescence, we see that some patients (about 15%) express only the ICD and the ECD is gone (cleaved off),” he said. “We hypothesized that these patients would not benefit from Herceptin, since they had lost the drug binding site.”
As reported May 19 online in the Journal of the National Cancer Institute, Dr. Rimm, of Yale University School of Medicine, New Haven, Connecticut, and colleagues employed quantitative immunofluorescence in tissue microarrays to assess ICD and ECD expression in specimens from a cohort of 180 Greek breast cancer patients who had participated in a trial of adjuvant chemotherapy followed by trastuzumab.
In all, 15% of patients had discordant results for ICD and ECD expression. High ECD was significantly associated with longer disease-free survival, with a hazard ratio of 0.31. ICD status was not.
In patients with low ECD, there was no difference in disease-free survival by ICD status. However, when ICD was high, high ECD was associated with longer disease-free survival (HR 0.23).
“As new therapies like Kadcyla (trastuzumab emtansine, Genentech) become more popular and are used by themselves (without combination with chemotherapy), we believe it will be very important to not only measure HER2, but to measure the region of HER2 that binds to the drug,” Dr. Rimm continued.
He concluded, “We are also trying to determine if this domain-specific test will more accurately predict response to lapatinib (Tykerb, GlaxoSmithKline), a small molecule inhibitor that acts on the ICD. It may be that this drug is better for those patients that have lost the ECD.”
J Natl Cancer Inst 2015.
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