Imatinib mesylate is not likely to be effective for patients with high grade renal cell carcinoma
Dec 22, 2005 - 5:03:38 AM
Mayo Clinic Cancer Center investigators report that imatinib mesylate (GleevecTM), the drug used to treat patients with gastrointestinal stromal cancers (GISTs), is not likely to be effective for patients with high grade renal cell carcinoma -- the most aggressive kidney cancer. Results of the study are published in the January issue of The Journal of Urology.
"While this finding does not seem like good news for patients with kidney cancer," says Bradley Leibovich, M.D., Mayo Clinic urologist and lead investigator of the study, "it does help us to narrow down the treatment options among the new targeted therapy drugs and would seem to indicate that resources for investigating potential new kidney cancer therapies may be better utilized on other options."
The American Cancer Society reports that kidney cancer is diagnosed in over 36,000 people in the United States each year and kills more than 12,000 annually. Mayo researchers are looking for better ways to treat this and other cancers, and to alleviate the uncertainty that accompanies a cancer diagnosis by finding better ways to individualize treatment plans.
This study's purpose was to determine the frequency of KIT (a receptor kinase tyrosine) expression and mutation in aggressive kidney tumors. The goal was to be able to recommend imatinib as a viable treatment option for patients who may not be adequately treated by surgery alone. KIT is a cell-surface molecule involved in the production of blood cells, pigmentation and gametes (male and female sex cells). Mutations of KIT have been linked to several types of cancer, and KIT expression is often measured as an indicator of certain cancers. KIT expression also appears to be related to the effectiveness of imatinib for treatment of patients with GISTs, as reported in The New England Journal of Medicine in 2002.
KIT is expressed normally in kidneys and also frequently in oncocytomas and chromophobe kidney tumors, which are usually effectively cured by surgery -- not requiring additional therapy. Wanting to verify results found a 2004 study published in The Journal of Clinical Pathology, and another the same year in The Journal of Urology that reported frequent KIT expression in these tumor types, Dr. Leibovich's team investigated sarcomatoid and high-grade kidney tumors. Since these tumors are aggressive and may recur after surgical removal, treatment after surgery with new targeted drug therapies would potentially benefit patients.
Using positive immunohistochemical staining, the researchers found no evidence to support those previous findings and reported only about 4.5 percent of the tumors showed KIT expression. "Imatinib only would have had the potential to be helpful to that small percentage of patients that we found to have a KIT-positive tumor," says primary author Shomik Sengupta, M.D. "And even then it would only work if they also had specific mutations that would respond to the drug."
Drs. Leibovich and Sengupta and their fellow researchers believe the misconception that mere detection of KIT predicts tumor responsiveness was born of the successful treatment of GISTs with imatinib. They say that it is not simply KIT expression, but rather cancerous KIT mutations that result in the GISTs success as well as the failures in other tumors. "Tumors that express KIT but lack KIT mutations may not respond to imatinib, and other researchers have shown that recently for adenoid and small cell lung cancers," says Dr. Leibovich. "Because we rarely found KIT expression and no KIT mutations, we cannot justify imatinib therapy." They also cited differences in staining protocols as reasons the other studies obtained different results.
This study reviewed records of all patients undergoing partial or radical nephrectomy between 1970 and 2002. The records were obtained from the Mayo Clinic Nephrectomy Registry, which includes over 5,000 patients. A total of 194 patients with nuclear grade 4 (highly aggressive) tumors were part of the final study analysis. An additional 50 had been identified, but insufficient tissue was available for analysis.
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