Tamoxifen is a hormonal therapy medicine used to lower the risk of breast cancer coming back (recurrence) in women diagnosed with early-stage, hormone-receptor-positive breast cancer. Doctors call tamoxifen used in this way "adjuvant hormonal therapy."
The CYP2D6 enzyme helps tamoxifen work in the body by changing tamoxifen into a form that is more active. Because of genetic differences, people make different amounts of the CYP2D6 enzyme. The study reviewed here found that women diagnosed with early-stage, hormone-receptor-positive breast cancer who make very little or no CYP2D6 and were treated with tamoxifen didn't do as well as women with higher CYP2D6 levels. Other research has shown similar results.
The researchers looked at CYP2D6 levels in 1,580 women diagnosed with early-stage, hormone-receptor-positive breast cancer. All the women took tamoxifen as adjuvant hormonal therapy. The researchers identified three levels of CYP2D6 enzyme activity and production:
The researchers evaluated the medical histories of the women for 9 years after diagnosis, looking for differences in outcomes based on how much CYP2D6 the women produced. They found a number of differences, including a significant difference in the risk of recurrence:
Today, CYP2D6 gene testing isn't routinely done. Based on the results of this and other studies, CYP2D6 testing may help decide if tamoxifen is a good adjuvant hormonal therapy choice for a specific woman. For women with low levels of CYP2D6, an aromatase inhibitor might be a better hormonal therapy choice because aromatase inhibitors don't depend on the CYP2D6 enzyme.
The aromatase inhibitors are:
It may be some time before CYP2D6 testing is used to help guide hormonal therapy medicine choices. Still, you might want to talk to your doctor about this study if you're considering tamoxifen treatment or are already taking tamoxifen.
It's also important to know that some medicines can affect how the CYP2D6 enzyme functions and may reduce tamoxifen's effectiveness. These medicines include some antidepressants known as serotonin-specific reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Other commonly prescribed medicines such as Cardioquin (chemical name: quinidine), Benadryl (chemical name: diphenhydramine), and Tagamet (chemical name: cimetidine) can block CYP2D6 activity. Most doctors recommend avoiding any medicine that can affect CYP2D6 function while you're taking tamoxifen. If you have to take a medicine that may reduce CYP2D6 activity, you and your doctor should discuss hormonal therapy options that aren't affected by CYP2D6 activity.
Genetic variations in production of the enzyme that metabolizes tamoxifen have an impact on clinical outcomes, according to findings of a cohort study.
Breast cancer patients with polymorphisms reducing or eliminating CYP2D6 enzyme activity had 33% worse event-free survival (P=0.01) and 29% worse disease-free survival (P=0.02) after adjuvant tamoxifen compared with those who had the full-activity variant, Hiltrud Brauch, DPhil, of the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology in Stuttgart, Germany, and colleagues found.
However, overall survival did not depend on CYP2D6 genetics, they reported in the Oct. 7 issue of the Journal of the American Medical Association.
These findings provide "a powerful argument for refined endocrine treatment," Brauch's group wrote.
Women who metabolized tamoxifen well appeared to have outcomes that fit within the 95% confidence interval of those reported for aromatase inhibitors, and the difference between the poor- and good-metabolizers was greater than that seen between tamoxifen and anastrazole (Arimidex) in the ATAC trial (HR 2.12 unadjusted versus 1.31).
"Genotyping has the potential for identification of women who have the CYP2D6 poor metabolism phenotype and for whom the use of tamoxifen is associated with poor outcomes, thus indicating consideration of alternative forms of adjuvant endocrine therapy," the investigators speculated.
CYP2D6 is not a simple on/off gene, but rather a collection of approximately 100 genetic variants that manifest in distinct phenotypes: extensive (normal activity), intermediate (reduced activity), poor (no activity), and ultrarapid (high activity) metabolism.
However, their "clinical relevance has been questioned because of discrepant results and limited sample sizes," the researchers noted.
So, they aimed to resolve the issue with an adequately powered multicenter study. It included 1,580 women recommended to receive five years of adjuvant tamoxifen from a retrospective cohort of German women and the tamoxifen-only arm of a prospective clinical trial.
Together, 5.9% of the women had a poor tamoxifen-metabolism phenotype (CYP2D6*3, *4, or *5) and 48.1% had an intermediate metabolism phenotype (heterozygous for extensive plus the intermediate *10 or *41 alleles).
Adverse outcomes showed a "dose-dependent" increase with poorer tamoxifen-metabolizing enzyme activity. Compared with extensive metabolizers, those with reduced or absent activity had significantly shorter:
Recurrence rates at nine-years' follow-up were:
After full adjustment for tumor characteristics, the genetic variant-associated time to recurrence risk compared with CYP2D6 extensive metabolism was 90% worse for poor metabolizers (P=0.02) and 40% worse for the intermediate group (P=0.03).
The researchers cautioned that the study could not make direct comparison between tamoxifen-treated and nontreated or aromatase inhibitor-treated patients.
And they noted that the retrospective recruitment of patients might have led to less than optimal documentation of events, lack of data on use of CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors), and other factors that would have underestimated the gene-outcome effect.
This study was supported by the Robert Bosch Foundation and by National Institutes of Health grants and the Mayo Clinic Breast Cancer Specialized Program of Research Excellence.
Brauch reported receiving honoraria from AstraZeneca and, with a co-author, initiated scientific collaborations in 2009 with Roche Molecular Diagnostics and Siemens Healthcare Diagnostics Products. Several co-authors reported being named inventors on nonprovisional patent applications regarding tamoxifen and CYP2D6, though no royalties to date. One co-author also reported being named inventor on patent applications regarding prediction of chemotherapeutic response in breast cancer and molecular markers for breast cancer prognosis. Other conflicts of interest reported by co-authors were with Roche, Pfizer, sanofi aventis, AstraZeneca, DNADirect, Novartis, Essex, GlaxoSmithKline, Lilly, Amgen, Roche Molecular Diagnostics, and Siemens Healthcare Diagnostics Products.
Primary source: Journal of the American Medical Association Source reference: Schroth W, et al "Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen" JAMA 2009; 302: 1429-36.
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