Flawed studies informed recommendations against CYP2D6 testing for tamoxifen treatment, new study finds
A recent Mayo Clinic study has found that clinical recommendations discouraging the use of CYP2D6 genetic testing to advise tamoxifen treatment in women with breast cancer should be reconsidered because some of the studies the recommendations were based on had flawed methodology.
The article, published in the January issue of the Journal of the National Cancer Institute, found that some of the previous studies used as the basis for recommendations against CYP2D6 testing to guide tamoxifen therapy were prone to error. This previous work, which used tumor tissue instead of healthy tissue to determine the CYP2D6 genotype, found no link between the CYP2D6 genotype and tamoxifen effectiveness.
However, researchers Goetz et al. found that up to 45 percent of breast tumors showed genetic variations that affected the CYP2D6 gene profile in the tumor. This means that the use of DNA taken from tumor tissue to find out a patient’s CYP2D6 status lead to distortions of the patient’s true or inherited genotype. This, the researchers found, lead to an inability to predict concentrations of endoxifen, tamoxifen’s cancer-fighting active form.
CYP2D6 is one of the most important drug-metabolizing enzymes in the body and acts on roughly 25 percent of all drugs. Research has found that between 7 percent and 14 percent of the population has a slow-acting form of this enzyme, while 35 percent are carriers of completely non-functional variant.
Women with limited CYP2D6 activity have been shown to less efficiently metabolize tamoxifen into endoxifen, according to the Mayo Clinic. Research has shown that women with these variations benefit less from tamoxifen therapy, the Mayo Clinic says.
“The potential benefit of CYP2D6 testing is obvious but has been difficult to establish. One major reason appears to be the lack of analytical validity,” Matthew Goetz, M.D., an oncologist at the Mayo Clinic Cancer Center and senior author of the study, said in a Mayo Clinic news release. “We found that if you use tumor tissue to determine the CYP2D6 genotype a patient was born with, you are going to get it wrong a substantial portion of the time.”
The new research should prompt a careful review of the data needed to properly inform patients and clinicians about the value of CYP2D6 testing, the study authors conclude.
“It is sobering to consider that a decade of work by the oncology community has not produced a clear resolution of the value of CYP2D6 genotype for predicting tamoxifen efficacy,” says James Ingle, M.D., an oncologist at Mayo Clinic Cancer Center and co-author of the study.
“The potential impact of the delay in resolving this issue is quite large in that during this time over half a million women worldwide would have been expected to be poor metabolizers, and, if the relationship between CYP2D6 genotype and tamoxifen efficacy is correct, these women would have been given less than optimal adjuvant therapy had they received tamoxifen.”
Find out more about the study findings on the Mayo Clinic’s website. Genelex offers genetic testing options that cover a variety of CYP enzymes, including the CYP2D6 enzyme, and other non-CYP genetic indicators of drug response.