Single Genetic Assay Could Help Physicians Decide When to Switch Patients from Gleevec to Sutent

Newswise — Researchers have found that the same gene mutation responsible for a tepid response to Gleevec (imatinib) in treatment of gastrointestinal stromal tumors (GIST), bestows benefit when a newer targeted therapy, Sutent (sunitinib), is used.

They also discovered that a different GIST tumor mutation predicts the opposite - a better response to Gleevec than to Sutent.

This means, the researchers say, that a single genetic assay could potentially help physicians decide when to switch patients from Gleevec, the first-line treatment, to therapy with Sutent, which the FDA approved for second-line use for this cancer in January 2006.

Results were presented at the first meeting on the Molecular Diagnostics in Cancer Therapeutic Development, organized by the American Association for Cancer Research.

"This is a story about personalized medicine," said the lead researcher, Michael C. Heinrich, M.D., professor of medicine at Oregon Health and Science University. "Treatment isn't one-size-fits-all anymore. We can individualize therapy based on the types of mutations found in tumor cells.

"In the case of GIST, we now understand more about how the mutational status of a patient's tumor predicts response to different targeted therapies."

Gleevec revolutionized the care of GIST, a rare cancer resistant to chemotherapy when advanced. Gleevec blocks the abnormal tyrosine kinase enzyme that plays a role in both chronic myeloid leukemia (CML) and in GIST, for which the drug was approved for use in 2001, and 2002, respectively.

But not all patients respond equally well to Gleevec, and many become resistant. Follow-up studies have found that the various mutations present on the tyrosine kinase enzyme can predict the degree of Gleevec benefit, Heinrich said. For example, 85 percent of GIST patients have a mutation in their tumor cell's c-kit gene, which encodes a tyrosine kinase receptor, and the two-thirds of those patients whose mutation occurs in exon 11 of the molecule have the longest average response to Gleevec. But these tumors often mutate again, conferring resistance to Gleevec. The 10-15 percent of patients with a mutation in exon 9 don't respond as well to the drug, but are less likely to mutate again, and those with no mutations show the least benefit, he said.

Sutent, a more potent tyrosine kinase inhibitor with a wider range of action, demonstrated a survival turnaround for Gleevec-resistant patients in recent studies, so Heinrich and his research team looked to see whether c-kit exon position also predicted response to Sutent.

They examined primary and secondary mutations in tumor samples from 74 patients, and found "a striking relationship," Heinrich said. "Patients with tumors that are wild type or have an exon 9 mutation have a longer survival when treated with Sutent than do patients with an exon 11 mutation." he said. "We are trying to figure out why that is so, but we also found that 62 percent of tumors with exon 11 mutations mutated again, and that some of these secondary mutations respond to Sutent while others don't.

"These results suggest that patients with exon 11 mutations should stay on Gleevec for a longer period of time before switching to Sutent, Heinrich said, "and that the switch to Sutent could occur earlier when treating cancers with exon 9 mutations or no mutations."

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