DNA analysis helps explain why a common lung cancer drug therapy proved more effective, and more toxic, in Japanese vs. U.S. clinical trial participants
Last year, a groundbreaking international project led by UC Davis Cancer Center specialist David Gandara 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.
His follow-up study now suggests the reasons lie in subtle variations in certain genes that govern how the body metabolizes chemotherapy drugs. Gandara, a UC Davis Cancer Center physician and director of clinical research, presented his findings at the American Society of Clinical Oncology annual meeting in Chicago in June 2007.
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 leads lung cancer trial efforts for the Southwest Oncology Group, the largest federally funded U.S. cancer trials network.
Emerging science of pharmacogenomics
The UC Davis 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 said.
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 even though 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.
Specific genetic variations found
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, because 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 an 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 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.