Last year, a groundbreaking international project found that a group of Japanese patients with advanced non-small cell lung cancer survived longer --and had a higher rate of side effects -- than U.S. patients with the same diagnosis,.when both groups were given two well-known drugs for the disease.
Now, a follow-up study suggests the reasons appear to lie in subtle variations in certain genes that govern how the body metabolizes chemotherapy drugs. David Gandara, M.D., a University of California, Davis researcher who led the recent Southwest Oncology Group study, presented the results Saturday, June 2, at the American Society of Clinical Oncology annual meeting.
The discovery that Japanese and U.S. patients, matched in age, gender and other respects, had differences in key metabolism-related genes is the latest result from a seven-year collaboration between the Southwest Oncology Group and two clinical trials groups in Japan. Gandara, who leads lung cancer trial efforts for the Southwest Oncology Group, is director of clinical research at the University of California, Davis, Cancer Center. The Southwest Oncology Group (SWOG) is the largest federally funded U.S. cancer trials network.
The recent SWOG study breaks new ground by exploring the possible role of ethnic patterns in the emerging science of pharmacogenomics, which promises to tailor drug regimens to a patient's genetic profile. "Nobody else in the world has ever done this, with a common arm looking at genetic differences among ethnic groups," Gandara says.
Researchers looked at DNA from 156 patients who received the chemotherapy drugs paclitaxel and carboplatin in a SWOG clinical trial and one conducted by the Japan Multicenter Trial Organization. In the trials, half the Japanese patients survived one year, while slightly more than one-third of U.S. patients did. The Japanese patients as a group survived longer despite the fact that a significant number of them had to be given a lower dose of paclitaxel and for a shorter time than the U.S. patients because of toxicity. The U.S. group was predominantly Caucasian; 2 percent were Asian-Americans.
To find clues to the differences, the scientists examined six genes in DNA samples from the patients. They found differences in four. In patients with certain variations in the CYP3A4 gene, it took 2.75 times longer for their lung cancer to progress than in patients without the variations. A variation in another gene, ERCC2, appeared to interfere with how well patients responded to treatment.
The differences in outcomes corresponded with the patients' genetic makeup, rather than their ethnicity per se, since. some individuals in each group possessed genetic variations not typical of their group. Thus, the study suggests therapies in the future need to be tailored to each individual based on analysis of his or her genetic makeup, not simply ethnicity.
The relatively small number of patients makes the results of the study far from conclusive: Gandara calls the study "hypothesis-generating." Next, he and other SWOG scientists are seeking funding to learn what genes may explain why Japanese and U.S. patients respond differently to EGFR inhibitors such as erlotinib, a relatively new targeted therapy that is another important class of drugs for lung cancer.
Institutions involved in the study include the Southwest Oncology Group (in addition to Gandara, members John Crowley, James Moon, Stephen K. Williamson, M.D., and Philip. C. Mack); the University of California, Davis, Cancer Center; the Japan Multinational Trial Organization; the University of Kansas, and the University of North Carolina.
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