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  • #16
    Inability To Metabolize Tamoxifen

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    medicalnewstoday.com/articles/254491.php


    Breast cancer patients with a certain genetic liver enzyme alteration do not respond well to the hormone therapy tamoxifen as they have difficulty metabolizing the drug, leading to an increased risk of death and recurrence.


    The finding comes from a study carried out by researchers from the Mayo Clinic Cancer Center and the Austrian Breast and Colorectal Cancer Study Group, and was published in the journal Clinical Cancer Research


    They identified that women with alterations of the liver enzyme CYP2D6 can't metabolize the drug as well as those with normal enzyme activity, which can lead to severe complications.


    Lead author of the study, Matthew Goetz, M.D., said, "Our findings confirm that, in early breast cancer treated with tamoxifen, genetic alterations in CYP2D6 lead to a higher likelihood of recurrence and death."


    The study involved monitoring the recurrence of cancer and death among two groups of women who received different forms of breast cancer treatment. The first group included postmenopausal women with primary estrogen receptor-positive breast cancer who solely received tamoxifen therapy for five years, while the second group of women took tamoxifen for two years and then proceeded to take an aromatase inhibitor (which does not require the CYP2D6 enzyme) called anastrozole for three years.


    They found that women who had significant genetic alterations of CYP2D6 were 2.5 times more likely to develop the cancer again or die compared to women with normal CYP2D6 activity. The recurrence of the cancer and death was 1.7 times greater among women with intermediate levels of the enzyme.


    Surprisingly, the women who had genetic alterations of the enzyme but switched treatment after two years (from tamoxifen to anastrozole) did not have a greater risk of recurrence or death.



    Senior author James Ingle, M.D., of Mayo Clinic, said:


    "Switching from tamoxifen to an aromatase inhibitor may be one reason for the discrepant studies surrounding CYP2D6 and tamoxifen -- as information about whether a patient took an aromatase inhibitor after tamoxifen was not available in most of the prior studies."



    Around 6 percent of women in Europe and the U.S. have a genetic liver enzyme alteration which makes them unable to properly metabolize the drug tamoxifen. Blood tests are able to identify genetic variations of the enzyme CYP2D6 which can help determine what the best form of cancer treatment is.



    Michael Gnant, M.D., professor of surgery at the Medical University of Vienna, said:


    "The results of this successful high-level international research collaboration are an important step forward in our quest to individualize breast cancer treatment and provide tailored care to women with breast cancer."



    Some breast cancer medications only work for certain women and it is vital that doctors assess each woman completely before carrying out treatment. For example, a previous study indicated that women with who had low levels of a protein known as pERK in their cancer-associated fibroblasts do not respond well to tamoxifen either.


    The researchers believe women with decreased metabolism of CYP2D6 should switch from tamoxifen to an aromatase inhibitor after two years, while those who are unable to metabolize the drug should avoid tamoxifen completely.


    For tamoxifen to work it needs to be completely metabolized into it's most active form called endoxifen. Dr. Goetz is currently working with the National Cancer Institute to try and develop a way that endoxifen can be given to women without worrying about how tamoxifen is metabolized. This could potentially eliminate the problem for women with an alteration of CYP2D6.

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    • #17
      CYP2D6 Metabolism

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      clincancerres.aacrjournals.org/content/early/2012/12/04/1078-0432.CCR-12-2153.abstract?sid=1f63d0d8-dcc5-48f6-95ae-2c875a1d4659


      CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8


      1. * Corresponding Author:
      Matthew P Goetz, Oncology, Mayo Clinic, 200 First St. S.W., Rochester, MN, 55905, United States [email protected]



      Abstract




      Background: Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy. Methods: A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor positive breast cancer to tamoxifen for 5 years (Arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism. Findings: The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% CI: 1.05-5.73, p=0.04) and women with one poor allele (PM/IM or PM/EM: OR=1.67, 95% CI: 0.95-2.93, p=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3-5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards a higher likelihood of a disease event relative to EM/EM (OR= 2.40, 95% CI: 0.86-6.66, p=0.09) among women on Arm A but not among women on Arm B (OR= 0.28; 95% CI: 0.03-2.30). Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.


      Published OnlineFirst December 4, 2012; doi: 10.1158/1078-0432.CCR-12-2153

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      • #18
        The study on gyno used 10mg a day, I've also read, Heavy, that 20mg daily for three months will reduce gyno. I'm not even sure I have gyno as I've never used AAS, but my nipples have always been puffy. I can only get my hands on 40mg nolva, if I ran that ED for three months would that benefit me?

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