One mutation in a gastrointestinal stromal tumor predicts a poor response to imatinib and a strong response to sunitinib, whereas a different mutation in the same gene predicts a strong response to imatinib, according to a presentation at the American Association for Cancer Research’s first meeting on Molecular Diagnostics in Cancer Therapeutic Development.

The impact of different mutations in the same gene means that a single genetic assay could potentially help physicians decide when to switch patients from one targeted therapeutic agent to the other.

“This is a story about personalized medicine,” said lead researcher, Michael C. Heinrich, MD, 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 gastrointestinal stromal tumor (GIST), we now understand more about how the mutational status of a patient’s tumor predicts response to different targeted therapies.”

Imatinib revolutionized care of GIST. The agent blocks the abnormal tyrosine kinase enzyme that plays a role in both chronic myeloid leukemia and in GIST. However, not all patients respond to imatinib and some may become resistant to it. Follow-up studies have found that various mutations present on the tyrosine kinase enzyme can predict the degree of benefit with imatinib.

For example, 85 percent of patients have a mutation in the c-kit gene, which encodes a tyrosine kinase receptor, and the two thirds of those patients whose mutation occurs in exon 11 have the longest average response to imatinib. However, tumor cells often mutate again, conferring resistance to imatinib.

The 10 to 15 percent of patients with a mutation in exon 9 of the receptor gene do not respond as well to the drug, but the tumors are less likely to mutate again. Furthermore, Heinrich said, tumors with no mutations show the least benefit.

Sunitinib, a more potent tyrosine kinase inhibitor with a wider range of action, demonstrated a survival turnaround for imatinib-resistant patients in recent studies, so Heinrich and his research team examined whether c-kit exon position also predicted response to the newer agent.

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 sunitinib than do patients with an exon 11 mutation. 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 sunitinib while others do not.

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