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German, American Team Confirms CYP2D6 Influence on Tamoxifen Response

NEW YORK (GenomeWeb News) – Variants in the cytochrome P450 2D6, or CYP2D6, gene affect outcomes in women treated with tamoxifen, according to a study by German and American researchers in today's issue of the Journal of the American Medical Association.

"CYP2D6 is one of the major enzymes involved in tamoxifen resistance," senior author Hiltrud Brauch, a researcher at the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology in Stuttgart, Germany, told GenomeWeb Daily News. "That is important for thousands of women worldwide."

Brauch and her colleagues used a retrospective approach to look at tamoxifen treatment outcomes in about 1,300 women with early-stage, estrogen receptor positive breast cancer. They found that women with CYP2D6 variants associated with poor or intermediate enzyme activity had higher recurrence rates and worse event- and disease-free survival than those carrying versions of the enzyme with normal activity.

Past research suggests tamoxifen, which is used to treat hormone receptor-positive breast cancer, is converted to two of its active metabolites — 4-hydroxytamoxifen and endoxifen metabolites. CYP2D6 is thought to be particularly important for producing endoxifen, Brauch explained.

Based on previous studies suggesting CYP2D6 genetics impact tamoxifen treatment response, the US Food and Drug Administration has considered changes to tamoxifen labeling that would include information about CYP2D6 genotyping.

Nevertheless, Brauch says, "There has never been a statistically-powered study to link the genotype to the outcome."

To explore this in more detail, she and colleagues genotyped CYP2D6 in stored tissue or blood samples from 1,325 individuals with stage I to stage II breast cancer who had been treated in Germany or the US between 1986 and 2005.

The women, most of whom were post-menopausal, all had hormone receptor positive tumors that had not metastasized. Each had been treated with adjuvant tamoxifen therapy but not chemotherapy.

Overall, the team identified 609 women carrying versions of CYP2D6 believed to have normal enzymatic activity, along with 637 individuals with intermediate variants that reduced the enzyme's activity and 79 individuals with poor metabolism variants that severely decrease the enzyme's activity.

Based on follow-up data available for a median time of 6.3 years, the researchers then looked at which variants influenced patient outcomes, if any.

Indeed, they found that cancer recurrence was higher in women carrying the "poor metabolism" versions of CYP2D6. Whereas the recurrence rate was about 15 percent in those with normal CYP2D6 metabolism and almost 21 percent in those with intermediate CYP2D6 variants, it jumped to 29 percent in the poor metabolism group.

The poor metabolism group also had worse event- and disease-free survival, though the team did not see differences in overall survival based on CYP2D6 genotype.

That may be because overall survival includes non-cancer related deaths, Brauch explained, which may mask differences in breast cancer-related death.

"Overall survival was not significantly associated, but a median follow-up of 6.3 years prevents this study from being conclusive because of the limited number of deaths or more common non-breast cancer deaths," Brauch and co-authors noted.

The findings suggest women who have poorer metabolizing CYP2D6 variants may be good candidates for an alternative breast cancer therapy, such as treatment with aromatase inhibitors, rather than tamoxifen, Brauch noted.

She and her team plan to do prospective studies looking at how tamoxifen metabolite levels vary in individuals with respect to their CYP2D6 genotype.

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