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OHSU Researchers Uncover Prognostic Role For Her-2 Fragment; Investigating PGx Possibilities

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In research with implications for one of the best-known examples of personalized therapy, Oregon Health and Science University Cancer Institute Investigators have identified a prognostic use for a fragment of the Her-2 protein, publishing their results in the Jan. 15 issue of Clinical Cancer Research.

Pathologists typically search for the whole Her-2 protein on the surface of tumor biopsies using DakoCytomation's Herceptest to determine whether specific patients will react favorably to the cancer drug Herceptin. "This is the intracellular portion of that protein," Edward Keenan, an author of the study told Pharmacogenomics Reporter this week. Keenan is a professor of physiology and pharmacology, as well as the associate dean for medical education at the OHSU School of Medicine. "There is a truncated version of the full-length receptor known as P95Her-2 that is present in about a third of the full-length Her-2 P185-positive tumors, and the presence of this protein is associated with a much earlier recurrence of metastasis," said Keenan.

The presence of P95Her-2 can predict the risk of breast-cancer recurrence independent of other factors, based on the researchers' study of 483 biopsy samples from hospitals in the United States and Spain from all stages of the disease, Keenan said. "Another way to say this is if a patient's tumor is P185 positive, and they don't have this protein — the P95 truncated version — they actually are not at increased risk of recurrence, as might be thought relative to their P185 status," he said.

Additionally, the fragment is twice as likely to be present in the tumors of patients with positive lymph nodes, versus those that are node negative, Keenan said.

The detection of P95 might prove to be a valuable tool in guiding treatment of certain breast cancers, but nobody knows how that might work yet, said Keenan. "It's where we're going to go with this work: What does the presence of the truncated protein mean relative to whether or not the patient will respond to Herceptin or not? And we don't know the answer to that," he said. "I'd love to know."

The group has a "very good" antibody for P95, but in order to make the test practical for the clinic, the laboratory method needs to be developed beyond its current Northern blot assay to an immunocytochemical process, which is "going to be quite challenging," he said.

Ideally, patients would first be tested for the full-length Her-2, and a P95 test would follow, said Keenan. "Not every tumor needs to be evaluated … that's only going to be about 30 percent of the total number of patients," he said. "Cleavage of the full-length [protein] seems to be associated with activation of the intracellular signaling portion of the protein — the tyrosine kinase activity," he added. That activity is often the target of anti-cancer drugs.

The researchers have not had contact with any diagnostic or pharmaceutical companies regarding the clinical utility of the test, said Keenan.

The work was conducted in the laboratory of Gail Clinton, a professor of biochemistry and molecular biology at the OHSU School of Medicine, in collaboration with Keenan and Jose Baselga at the Medical Oncology Service of Vall d'Hebron University Hospital in Barcelona, Spain.

— Chris Womack ([email protected])

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