Apr. 7, 2013 Researchers using a tool called BEAMing technology, which can detect cancer-driving gene mutations in patients' blood samples, were able to identify oncogenic mutations associated with distinct responses to therapies used to treat patients with gastrointestinal stromal tumors (GIST), according to a researcher who presented the data at the AACR Annual Meeting 2013, held in Washington D.C., April 6-10.
Data from a subanalysis of the phase III GIST-Regorafenib In Progressive Disease (GRID) trial indicated that this blood-based screening technology may provide physicians with a real-time, comprehensive picture of a patient's tumor mutations, according to George D. Demetri, M.D., director of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School in Boston, Mass.
"Our results show that it is possible to sum the total of all of the heterogeneity in a cancer and get a clear picture of the entire tumor burden, using a simple blood sample," Demetri said.
In this era of targeted cancer therapies, the goal is to focus cancer treatments on a specific molecular target. However, as researchers discover more about cancers and their heterogeneity, they are finding many patients have anywhere from one to dozens of different mutations in their tumors.
"It is a real issue that when you do a biopsy on one tumor, and then biopsy a different tumor in that same patient a few inches away or on the other side of the body, you may get a different answer when you do the molecular analysis," Demetri said. "With this blood test, you get a robust summary statement about all the different mutations present across the different tumors in the body. I believe this testing technology has promise to become a standard part of care in the next five to 10 years."
Data from the main analysis of the phase III GRID study showed that the molecularly targeted drug regorafenib significantly improved progression-free survival compared with placebo for patients with GIST. The researchers hope these results will ultimately lead to the drug's approval by the U.S. Food and Drug Administration (FDA), according to Demetri. The drug is intended to treat patients with advanced GIST whose disease has failed to be controlled by the only two other FDA-approved therapies for GIST, imatinib and sunitinib (Sutent).
Demetri and colleagues conducted an exploratory analysis on patients in the GRID study to assess GIST genotypes. They isolated DNA from archival tumor tissue, which was then analyzed for mutations in two genes, KIT and PDGFRA, which generate the cancer-driving proteins that are the targets of imatinib, sunitinib and regorafenib. The researchers believed that primary mutations would be detectable using traditional analysis, but that those mutations that developed after treatment with imatinib and sunitinib would not be detectable. They then took blood samples drawn at study entry after failure of both imatinib and sunitinib, and analyzed them for mutations via BEAMing technology.
Mutations in the KIT gene were detected in 60 percent of the blood samples compared with 65 percent of the tumor tissue samples. However, when focusing their analysis on secondary KIT mutations, which are the mutations that drive resistance to targeted therapies like imatinib and sunitinib, the researchers found mutations in 48 percent of blood samples compared with only 12 percent of tissue samples. In addition, nearly half of blood samples in which secondary KIT mutations were found harbored multiple secondary mutations.
Importantly, regorafenib was clinically active compared with placebo in patients with secondary KIT mutations.
According to Demetri, the results show a clear association between the presence of different cancer-driving gene mutations in patients' blood samples and clinical outcomes.
"By using this technology, we hope to develop the most rational drug combinations and better tests to match patients with the most effective therapies going forward," Demetri said.
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