CYP2D6 Test and Tamoxifen

I had my cyp tested and I came out as intermediate. No one here knew how to interpret the results.  My se were horrific and getting worse after 1 1/2 yrs.  I just couldn't stay on it and so even though I have osteoporosis I have gone on arimidex.  The woman in the NY Times article also had debilitating se and I think she was between poor and intermediate.  I realize the popular thought of the day is if you have se then it's working but a number of women who are normal metabolizers have few se.  There may be a clearance issue going on as some of us may be slow as well as incomplete metabolizers creating a buildup.

According to the genelex site, intermediate metabolizers may need their dosage reduced not increased.  I believe this as I eliminated a deep dark depression from tamoxifen by splitting my dosage in half and taking half twice a day indicating a possible metabolism problem.

I think intermediate lies somewhere between normal metabolizing and none to very little. It makes sense to me that there would be a reduction of dosage.  And it makes sense to me that our risk of recurrence is more than normal and less than the PM.

Some oncs don't think this is reliable.  I have no idea how my oncs think but if I were to put their knowledge up against some of the finest minds of the Mayo clinic who's focus was on this issue alone rather than the upteen dozen cancers our oncs have to deal with, I think I'll follow the researchers of the Mayo Clinic.  But I also think there is more to be learned.

Best of luck to you

jan

Mayo Clinic Rochester Minnesota is doing the test.

I am postmenopausal so no ovarian suppression needed. My oncologist;s office drew the blood for the test and sent it to Bio reference Laboratories who I think is in California. I have had a very difficult time getting a contact number for this lab to request an itemizes bill so I can argue with the insurance company. You can order the test yourself from htpp://dnadirect.com for $300. My oncologist never indicated to me that there was a possibility that the insurance wouldn't cover it. Since I am an interemdiate metabolizer the oncologist is leaving it up to me if I wish to contniue with it or not.

Mayo Clinic in Scottsdale also gives this test.  I didn't even know about this test until my onc. told me he was going to give it to me, so I didn't have a choice.  I figured he knows what he's doing.  My younger sis was also diagnosed 21 months after me, and she mentioned this test to her onc, and her onc. doesn't believe this test is legit, so she didn't have to take the test.

Well I got my test back and I came up as an intermediate metabolizer with a *41 variant. So I have one functional allele and one with decreased function. The reason we did this test was to decide if I should stay on Tam or move to an AI after I have my hyster/ooph.  He seems to think that being an intermediate metabolizer is find and wants me to remain on the Tam after surgery.  Why are there always so many decisions?  I don't know if being an intermediate metabolizer is good or not.  I haven't had a period since I started taking Tam, but my night hot flashes which were intense for a couple of months have stopped. I don't know how any of you feel, but since the moment of diagnosis, nothing has been black and white, not even what kind of surgery to have, so many things to think about with such huge consequences.

I think the thought behind increasing the Tamoxifen dose in intermediate metabolizers is the following: 

 Tamoxifen itself is not the biologically active form of the helpful drug, hence it is called a Prodrug. Tamoxifen must be broken down into various metabolites, one of which is felt to be the active form (their may be others) called Endoxifen.

Let's say an intermediate metabolizer of Tamoxifen (one who carries half-active gene, half-inactive gene status) takes a 20 mg Tamoxifen pill. It's felt that their gene status allows a variable amount of change from the prodrug Tamoxifen to the active endoxifen, say hypothetically, 70%. Pharmacologic principles apply in all drugs too, not just gene status effects. If the amount of available Tamoxifen is increased by taking 40 mg of Tamoxifen, then there is more Tamoxifen (called a substrate here) available for the intermediate or somewhat slow gene proteins to pharmacologically act on to metabolize the extra Tamoxifen to Endoxifen. In this way, the result should be more active drug (i.e., the drug that does the business on enabling blockage of estrogen receptors) and hopefully brings the intermediate metabolizers status up, maybe as much as a regular metabolize. This is how I look at it all at least. Perhaps there's a pharmacologist who might way in. Note that this does not comment on known inhibitors of CYP2D6 genes, such as Paxil, which results in limiting/blocking the conversion of Tamoxifen, a prodrug, to it's active metabolic or workable form, one being endoxifen.

I took a look at the healthanddna site, phoenix. Their recommendation of reduced drug need in CYP2D6 intermediate metabolizers does not apply in a PRO-drug state (one which needs further metabolism to the active, second drug). That is where an error is introduced in their statement that intermediate metabolizers need less: it truly depends on the individual drug involved and in the case of the prodrug Tamoxifen, the opposite is more true. Such is reflected by your two doctors suggesting more of Tamoxifen rather than less. Side effects, too, should be proportional to the amount of active drug in the system, not the prodrug. So an intermediate metabolizer on 40 mg Tam might well have the same side effects of a full metabolizer on 20 mg Tamoxifen. I believe there are ongoing clinical studies on this issue, and certainly hope so.

I hope this helps some. It's a complicated subject where more facts are needed and hopefully coming. It's good for us to discuss it.

Best,

Tender 

Soon, tests of endoxifen, the active metabolite of tamoxifen, will be available. I went to Dana Farber, specifically because my oncologist didn't know what to do about the test, and I'm pre/peri-menopausal.

I saw an oncologist at Dana Farber, and he said the ability to test for endoxifen--to really know if you make the active metabolite, should be available by June at Dana Farber.

Momofbraj, can you ask your oncologist if they can test for endoxifen, not just the genes?

Kira 

Kira-please keep us posted about this test for endoxifen-thanks! I have never heard of it. This is all so new, I don't think most oncologists know about this.

I think the test they have now is accurate for determining your genetic makeup relative to the CYP2D6 pathway of metabolism. What they don't know is if that is the only pathway we use to metabolize tamoxifen and if there are other metabolites (if that is the right word) that are just as important a endoxifen in preventing recurrence. So while the test is accurate genetically, they don't know if it is accurate predictor of how well tamox works for any given individual. Those studies still need to be done.

I would be very wary of increasing the dosage.  First of all, it was the higher doses in teh bad old days that caused so many cases of endometrial cancer.  Since going down to 20 mg, the incidence of endometrial cancer has gone down significantly.  Second, there is some thought that even 20 mg is overmedicating.  They haven't studied lower doses.  

Here is a December 2008 article from researchers-clinicians at the Mayo Clinic. It talks about bypassing the CYP2D6 issue by direct use of endoxifen (also as a means to lower SE's of Tamoxifen). It also discusses how endoxifen is felt to be the active SERM or estrogen receptor modulator. 

CYP2D6 and Tamoxifen:  Using Pharmacogenomics to Rediscover an Old Drug

http://discoverysedge.mayo.edu/de08-4-gen-goetz/

Tender 

I think the below article provides good information on the status of  CYP2D6 genotyping with tamoxifen therapy.

http://clincancerres.aacrjournals.org/cgi/reprint/15/1/15

Tamoxifen is converterd to atleast two known active metabolites 4-hydroxy tamoxifen and endoxifen. Both are equipotent in binding to estrogen receptors and suppressing tumor progression. The plasma levels of endoxifen are ten fold higher than that of 4-hydroxy tamoxifen and hence is considered to be more important. CYP2D6 plays an important role in the formation of endoxifen and poor metabolizers were found to have lower levels. Similarly, coadministration of CYP2D6 inhibitors like Paxil results in reduced levels of endoxifen. On the other hand, extensive metabolizers make more endoxifen and also have more side effects. Out of the six studies that investigated the association between Cyp2d6 genotype and tamoxifen therapy, three confirmed the hypothesis that there is a definitive relationship.

However, there are no studies linking endoxifen levels to the clinical outcome after tamoxifen therapy. A plasma concentration effect relationship study will provide more details. Since endoxifen is not the only active metabolite and there may be others in addition to 4-hydroxy tamoxifen, more data needs to be generated to provide confirmatory evidence for recommendation of CYP2D6 genotyping. This has also lead to development of endoxifen as a new drug by researchers at Mayo clinic.

As a result, not all oncologists are recommending this test and are probably waiting until FDA puts it in the label.