Tamoxifen Breakdown Gene CYP2D6 - Is the Plot Thickening?

Kevin Knopf, MD Health Guide
  • I wrote about CYP2D6, which refers to a gene that codes for a biologic molecule involved in the breakdown of tamoxifen, about a year ago.  Since then it has not become standard of care to order this on patients taking tamoxifen, but my desire to do so has increased.  Routine testing is not yet recommended, according to those in the know.


    We refer to women who have two normal copies of this gene as having the "wild-type," which means normal type for the breakdown of tamoxifen.  "Heterozygous" means one copy of the normal gene and one copy of a variant gene.  The "wild type" group of women have the best response to tamoxifen - they don't metabolize tamoxifen to an inactive substance as quickly.

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    A recent article by Dr. Punglia of the Harvard Oncology Programs looked back at the BIG 1-98 trial of tamoxifen vs. letrozole as curative therapy for postmenopausal breast cancer. 


    Using a mathematical model Dr. Punglia questioned whether women with the "wild type" of CYP2D6 would be better off taking tamoxifen than the aromatase inhibitor, where current thinking has been to use an aromatase inhibitor when feasible in postmenopausal women.


    This is early work, and an accompanying commentary questions whether anything should be changed - often mathematical models can predict things incorrectly, and the metabolic pathway is probably not completely understood.  Mathematical models can be informative, but the model itself can be flawed, or the data inputs to the model can be only partially correct or incorrect.  Rarely does clinical practice change based on a mathematical model.


    Still, I wonder at this point whether I should be testing some of my younger patients for CYP2D6 and if they were heterozygous whether they should be placed on an aromatase inhibitor rather than tamoxifen.  This is not yet a standard - but I do avoid certain medicines in combination with tamoxifen, such as prozac and paxil (often used to treat hot flashes).


    Perhaps there will be more information presented at the American Society of Clinical Oncology meeting at the end of May.  And of course we also look forward to interesting research developments in breast cancer at this meeting. Stay tuned.


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Published On: May 12, 2008