Will genetics soon guide drug treatment choices for the treatment of prostate cancer?
Avi Retter, MD, of the National Cancer Institute’s Medical Oncology Clinical Research Unit in Bethesda, Maryland, has been examining the ways in which an individual’s genetically determined metabolic predispositions predict response to drug therapies. Specifically, he and his colleagues are studying the relationship between mutations in genes that code for various cytochrome P450 (CYP450) enzymes and response to prostate cancer drugs. These enzymes, produced in the liver, catalyze the biochemical pathways through which many drugs are metabolized. In cancer chemotherapy, he said, a greater ability to metabolize drugs would presumably enhance response and improve survival while genetically determined deficiencies in metabolic enzyme production would lower the response rate.
Dr. Retter’s study looked at genes coding for the CYP2C19 enzyme, which plays an important role in the metabolism of thalidomide, a commonly used adjunct drug for prostate cancer. Thalidomide must be transformed into its active form through hepatic metabolism. The study involved 73 men with androgen-independent prostate cancer who received thalido-mide 200 mg daily plus the antineoplastic agent docetaxel (Taxotere®, Aventis) 30 mg/m2 for three of four weeks or docetaxel alone. Overall, those receiving combination therapy survived longer: median survival in the docetaxel/thalidomide arm was 25.9 months and 14.7 months for those who were taking docetaxel alone.
The primary investigation into the extent to which polymorphisms in the gene coding for CYP2C19 predicted survival, somewhat surprisingly, failed to detect significant differences. Comparing mean survival of men with genes for the wild-type CYP2C19 with those who had CYP2C19 mutations, Dr. Retter found no strong correlation between survival and genotype.
Median survival among 14 of 48 men with CYP2C19 mutations receiving thalidomide was 19 months; for the 34 men with the wild-type CYP2C19, it was 26 months. The difference was not statistically significant. Equally surprising was the observation that in the docetaxel monotherapy group, men who had the wild-type CYPC19 showed a trend toward improved survival over those with the mutation, even though the CYP2C19 enzyme is not thought to play a role in docetaxel metabolism.
Although the CYP2C19 genotype did not ultimately prove to be a good predictor of survival, Dr. Retter said that there are many other enzymes in the CYP450 pathways that are worthy of investigation.
“This is a step in the direction of choosing therapies based on genetic factors influencing drug metabolism. That is ultimately where we want to go with this.”