MOVING TO PRIME TIME: CYP2D6 Testing and Tamoxifen

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TenderIsOurMight
TenderIsOurMight Member Posts: 4,493
edited June 2014 in Hormonal Therapy - Before, During, and After
Moving to Prime Time!

Lovin Life recently generated a great thread on "CYP2D6 testing" and Tamoxifen. Its' importance bears license of redundancy.

I am posting below a brief article which confirms that oncology centers should soon be (and some apparently already are) offering testing to determine how you metabolize Tamoxifen individually through a simple blood test or (possibly) cheek swab. This test will help to ensure better insight (but not absolute, as there is none yet in BC) into your individual success with this important ER+ cancer fighting drug. This is exciting news to we patients as such clarion calls are made by researchers and physicians alike that CYP2D6 testing is available.

Please talk with your doctor about such testing. May I offer a collective thanks to Breast Cancer.org for allowing a forum where such insightful news may be widely exchanged and at a relatively fast clip. Good cheer to all while the Discussion Board goes down for tech updating and a note of appreciation to Tami and Melissa and coworkers for their generous efforts on our behalf.

Tender

Steroids. 2007 Jul 27

"New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer."

Author: Jordan VC.

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, United States.

Abstract:

"The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyltamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen."

Edit: 90% plus of women and men metabolize Tamoxifen just fine using individual CYP2D6 liver enzymes. The percentage of individuals not metabolizing Tamoxifen as effectively as once was thought varies between women and ethnicities and studies suggest this a small, yet significant when consider globally, minority of 7 to 10%. This posting is not to overly alarm us, but rather to disseminate information about relatively new testing which may help us in our fight against breast cancer and raise the bar for discussion with physicians about alternative hormones if necessary.
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  • thomcat
    thomcat Member Posts: 356
    edited September 2007
    I so appreciate this website. I saw a post regarding this test months ago and talked to my onco's NP. She had never heard of it. I will be asking AGAIN!

    Cathy
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  • DianeMarieWA
    DianeMarieWA Member Posts: 47
    edited September 2007
    Cathy,

    I am also very interested in this subject. After reading about this here a couple of months ago, I e-mailed my oncologist. She answered a couple of other questions I had but did not respond to my request for CYP2D6 testing. I am also going to request it AGAIN.
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  • VLJ
    VLJ Member Posts: 39
    edited September 2007

    I asked my onc about the test and he wasn't aware of it.  I sent a note to Lilly "ASK THE EXPERT" at JH and she stated that they are not doing the CYP2DF6 test and believed it was still in clinical trials.  Sounds like the CYP2D6 test is new, and as BC surviors, we need to push to have the test done.  I've been on tamoxifen over a year, and having a few problems and would hate to continue for 5-years, and find out that the tamoxifen did work.  I have appt in October with onc and will ask that the test be run.  

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  • wallycat
    wallycat Member Posts: 3,227
    edited September 2007

    I refused to go through DNA Direct because they expect you to order your own test and submit your own claim.  That doesn't bother me, but I have United health care....jack-a$$es.  I submitted a claim for my mastectomy camisoles in July and am STILL talking to 4 people a day trying to figure out why they won't cover it.  Idiots.  Plus now they are claiming it is for my husband.  I think they hire alcoholics.  Sorry....whew...that felt good to write.

    So, I checked Mayo clinic's website; my hospital is affiliated wtih the mayo labs and he ordered it through there.  That is a blood draw but they'll deal with my idiots at United health care!

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  • CaliforniaKate
    CaliforniaKate Member Posts: 258
    edited September 2007

    My onco was no help at all when I mentioned the CYP2DF6 test. Just said it was too new and insurance wouldn't cover it. I just went through DNA Direct because I didn't seem to have any other choice. Should get my results back in the next week or so. Since we put so much stock in the tamoxifen keeping our cancer away, I don't understand why the insurance companies don't want to pay for the test. I'm going to try submitting it myself, but not holding out a lot of hope. At least I'll learn my results.      Kate

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  • TenderIsOurMight
    TenderIsOurMight Member Posts: 4,493
    edited March 2008

    Many months and many excellent discussions on differing threads have occurred since entitling this thread. Perhaps it should have read: "Almost Moving To Prime Time: CYP2D6 Testing and Tamoxifen".

    I still believe in this test, and await with eagerness the clinical trials which hopefully will accrue on it. In the meantime, I came across this blurb on the American Society of Clinical Oncology cancer newsline this morning, and consider it appropriate to post.

    In the interim of completed studies, such remains a uniquely individual decision between each of us and our oncologist; no clear answer. I wish all walking this challenging path an embrace of support in their personal choice.

    "
     

    Genotype tied to success of breast cancer therapy with tamoxifen

     

    NEW YORK (Reuters Health) - Variants in genes CYP2D6 and CYP2C19 encoding P450 enzymes can predict therapy response or failure in patients with estrogen receptor-positive breast cancer treated with tamoxifen, according to German researchers.

    "The clinical importance of this finding," senior investigator Dr. Hiltrud Brauch told Reuters Health, "is that genotyping can identify patients likely to benefit from tamoxifen and, moreover, those in need for treatment alternatives -- a result that now calls for verification in large clinical trials."

    As reported in the November 20th issue of the Journal of Clinical Oncology, Dr. Brauch of the Institute of Clinical Pharmacology, Stuttgart and colleagues genotyped DNA from 206 patients receiving tamoxifen adjuvant monotherapy and 280 who were not.

    The team found that compared with carriers of functional alleles, patients in the tamoxifen group with CYP2D6 alleles *4, *5, *10, and *41 -- all associated with reduced formation of antiestrogenic metabolites -- had significantly more recurrences of breast cancer (hazard ratio, 2.24). They also had shorter relapse-free periods and lower event-free survival rates.

    In addition, patients with the CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical outcome (hazard ratio, 0.45) than carriers of the *1, *2, and *3 alleles.

    The finding, continued Dr. Brauch, "holds the potential to overcome the one-drug-fits-all concept and take current decisions on the choice of endocrine treatment to the level of germline polymorphisms. Due to their inherent nature, they are accessible to genotyping from blood and other diagnostic materials independent from disease stage."

    "Up-front genetic testing," she concluded, "will support this decision and thereby individualize drug treatment at the earliest stage for a maximum patient benefit."

    Tender

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  • Diana_B
    Diana_B Member Posts: 287
    edited December 2007

    Tender,



    Could you please explain the part about interaction with SSRIs in your original post? I don't understand.



    Is it suggesting that use of these drugs makes tamoxifen ineffective?



    And do you know if gabapentin falls in this category? I think it doesn't but I'm not sure.



    Thanks a lot,

    Darya

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  • TenderIsOurMight
    TenderIsOurMight Member Posts: 4,493
    edited March 2008

    Hello Darya,

    Fortunately for us, the newer chronic pain medicines, neuropathy medications and AEDs (antiepileptic drugs) do not appear to be either inducers or inhibitors of the CYP system. These include and include Gabapentin. Lamotrigine. Pregabalin. These drugs are increasingly used for neuropathy pain induced by chemotherapy, and I myself have used both Neurontin (Gabapentin) and Lyrica (Pregabilin). Not being metabolized through CYP450, you will not find Gabapentin on the below Flockhart chart of drugs metabolized by CYP, and hence Gabapentin-Tamoxifen interface should not be problematic.

    I hope you don't mind, yet for the sake of time and redundency, I will reference too the breastcancer.org thread listed under "hormones" entitled:Conversation: so what antidepressants CAN i take with tamoxifen? This has a lively back and forth on Tamoxifen and commonly used drugs in breast cancer.

    link:http://community.breastcancer.org/topic/78/conversation/695979?page=1#idx_23

    In this thread, BBS refers to a fairly involved, well known drug interaction table designed by Dr. Flockhart, who similutaneously is known for his research on Tamoxifen metabolism. The link to this table is here:http://medicine.iupui.edu/flockhart/table.htm. It takes time to learn to use it, but if you read, and re-read the definitions, I found I eventually came to understand how to look up two drugs in a handy way.

    Similarly BBS provided a helpful paper which reviews Tamoxifen and antidepressants, which is available here:

    Pharmacogenomics of Tamoxifen in a Nutshell-And Who Broke the Nutcracker?  

    http://jop.ascopubs.org/cgi/content/full/1/4/155

    Lastly, Mayo Laboratories has published an extensive paper on Tamoxifen and is available here: http://www.mayomedicallaboratories.com/media/articles/communique/mc2831-0107.pdf

    I bumped up this old thread not to pose a source of dismay for we women, but rather to let those who are interested in the Tamoxifen metabolism discussion know that new evidence on Tamoxifen's metabolism has just been published.

    Some day our gene signatures and use of drugs may be well spelled out, and a donation of blood DNA may offer great individual insight.

    Hope this helps you,

    Tender

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  • SueTacoma
    SueTacoma Member Posts: 69
    edited December 2007

    Tender,

    Thank you again for starting this thread.  The information here is important for us.  I got the 2D6 test result back.  My onc asked for the interpretation of the test result from the testing lab, and he told me to stay on Tamoxifen while waiting.

    Thanks.

    Sue

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  • corvette
    corvette Member Posts: 41
    edited December 2007

    I first heard of this test via the Lovin Life post.  She doesn't check in here often (nor do I) and I can't find my way around this new format so I don't know how to find her posts.  Search doesn't work for me.

    But I told my onc about this test and he said he never heard of it. I simply said 'well find out and call me.'

    You can't let these doctors get by with a 'I don't know about it.' Make them work for their money!

    Well he found out - I had the test - and I am an intermediate metabolizer which means I could have a toxic build up with the usual 20 mg dose and the dose has to be adjusted. That hasn't happened yet. I am still waiting.

    If you are a high metabolizer or poor you will reap no benefits from tamoxifen.

    I guess I am the first to start the ball rolling in my city.  I would like to thank Lovin Life but I am confused on this new format and can't find her posts or figured out how to PM her.  So thanks Lovin Life if you read this!!!

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  • Diana_B
    Diana_B Member Posts: 287
    edited December 2007

    Thanks, Tender. I read it slowly and think I got it more or less.



    I'm having a recurrence in spite of tamoxifen and so am curious as to why it was ineffective for me.

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  • san4850
    san4850 Member Posts: 117
    edited December 2007

    The CYP2D6 test is relatively new.  It was approved by the FDA around October 18, 2006 (not sure of the exact DAY, however).  When I met my onc. in January 2007 he suggested I take this test.  I never even heard about it, but when his nurse explained why they want to give it and what they're looking to find out, it made a lot of sense.  When I asked him how new the test was, and if my insurance would cover it, he didn't think I'd have a problem with my insurance because his nurse said they'll preauthorize it first, and even IF they didn't get authorization from my insurance (which they did), they'd still fight it.

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  • TenderIsOurMight
    TenderIsOurMight Member Posts: 4,493
    edited December 2009

     A little over two and a half years since my original post on this topic. Please note the expert authors and it's publication in JAMA (a peer reviewed journal).

     JAMA. 2009 Oct 7;302(13):1429-36.

    Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen.

    Schroth W, Goetz MP, Hamann U, Fasching PA, Schmidt M, Winter S, Fritz P, Simon W, Suman VJ, Ames MM, Safgren SL, Kuffel MJ, Ulmer HU, Boländer J, Strick R, Beckmann MW, Koelbl H, Weinshilboum RM, Ingle JN, Eichelbaum M, Schwab M, Brauch H.

    Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. hiltrud.brauch@ikp-stuttgart.de

    CONTEXT: The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme. OBJECTIVE: To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism. MAIN OUTCOME MEASURES: Time to recurrence, event-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51). CONCLUSION: Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

    Tender Smile

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  • AnnNYC
    AnnNYC Member Posts: 4,484
    edited December 2009

    Tender, thank you so much for posting this new study -- 1325 women with median 6.9 years of followup is pretty substantial!

    I know you and I have been on the same page about the importance of CYP2D6 testing for a long time!  I thank God my onc ordered this test for me at our first appointment in May 2007 -- I had no idea about it -- but it turned out I have TWO nonfunctional alleles, so she switched me from tamoxifen to AI as soon as the results came in.

    xox,

    Ann

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