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GEN News Highlights : Oct 7, 2009

Genetic Variations in Cytochrome Enzyme Impacts Effectiveness of Tamoxifen

Study in JAMA details about 100 gene variants that present as four distinct phenotypes.

An international team of scientists has found that natural variations in breast cancer patients’ cytochrome P450 2D6 enzyme can significantly influences whether supplementary tamoxifen therapy prevents their cancers from returning.

The researchers’ studies showed that patients with CYP2D6 variations associated with poor metabolism of tamoxifen into its active metabolites were almost twice as likely to have their breast cancer recur as those with CYP2D6 enzyme variants that exhibit normal levels of metabolism.

The research is published in the October 7 issue of JAMA in a paper titled "Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen."

There are about 100 CYP2D6 gene variants identified that present as four distinct phenotypes—extensive (noramal activity), intermediate (reduced activity), poor (no activity), and ultrarapid (high activity) metabolism—points out lead researcher, Werner Schroth, D.Phil, at the Dr. Margarete Fischer-Bosche-Institute of Clinical Pharmacology in Stuttgart, Germany. “Thus it can be speculated that genotype-related differences in the formation of active metabolites influence therapeutic response to tamoxifen.”
 
To investigate this relationship, the researchers genotyped tumor tissue DNA for variations in CYP2D6 associated with reduced or absent enzyme activity in 1,325 breast cancer patients taking adjuvant tamoxifen therapy. On the basis of this genotyping, the women were classified as having either extensive (609 individuals), heterozygous extensive/intermediate (637 women), or poor (79) metabolism.

The researchers found clear evidence that breast cancer was more likely to return in patients with reduced or absent CYP2D6 function. “At nine years of follow-up, the recurrence rates were 14.9 percent for extensive metabolizers, 20.9 percent for heterozygous extensive/intermediate metabolizers, and 29 percent for poor metabolizers,” Dr. Schroth continues. Although patients with decreased CYP2D6 activity had worse event-free survival and disease-free survival, there was no significant difference in overall survival.