The 2006 finding that Japanese patients tolerated a chemotherapy regimen for advanced non-small cell lung cancer better and survived longer than peers in the USA may be due to variations in genes that control body metabolism of chemotherapeutic drugs, according to a presentation at the 2007 annual meeting of the American Society of Clinical Oncology.

David Gandara, MD, the University of California, Davis researcher who led the recent Southwest Oncology Group study, presented the results for Japanese and American patients who were matched in age, gender, and other factors: Genetic analysis showed there were differences in key metabolism-related genes.

The discovery 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 finding marks new ground in exploring the possible role of ethnic patterns with 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 U.S. clinical trial and in 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 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, as 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 scientists are seeking funding to learn what genes may explain why Japanese and U.S. patients respond differently to epidermal growth factor receptor (EGFR) inhibitors such as erlotinib, a relatively new targeted therapy that is another important class of drugs for lung cancer.