CYP2D6 test?

KathyL624 · May 2016

I talk to my oncologist (at Sloane Kettering) today about the CYP2D6 enzyme issue. She said they do not do tests for it. Is this common? I don't understand why they wouldn't want to make sure that I can metabolize tamoxifen.

wallycat · May 2016

Some doctors don't accept that the pathway makes a difference. Are you post menopause? estrogen positive? If that is the case, they may start you with an aromatase inhibitor, which doesn't use that pathway. If they plan to put you on tamoxifen, you may want to ask them why they won't run it. It is covered by insurance (I'm pretty sure). Have they talked to you about your plan of care?

Best to you.

Lisey · July 2016

The more I research the more I realize how important knowing your metabolic rate for your own body is on pathways. Kailos offers a test of 20 different pathways for only $150, so I went ahead and did it. There is a thread (just search for Kailos) and you'll find it... all on the CYP2D6 enzyme. I strongly recommend reading over there as there's a wealth of knowledge.

Also do a google for pharmacogenetics, and see that customized dosage and understanding your own bodie's genes is going to be really important in the future.

voraciousreader · July 2016

To date, there is no evidence that validates the hypothesis. That said, that doesn't mean that there will hopefully, one day soon, be clear evidence that will validate the need for such testing. Furthermore, I think this testing is, presently, more advantageous to the companies that perform these tests than they are to the individuals. I think that's why these tests are relatively inexpensive. These biotech companies are still in the data collection gathering mode.

voraciousreader · July 2016

lisey....just want to add that the DH has an extremely rare genetic metabolic disorder and we work very closely with world class medical genetic and endocrinology departments. The DH lacks an enzyme that breaks down fats. Finding a treatment, that is, to find another pathway into the mitochondria took a decade of research. I really wish that understanding how metabolism works was easier. It just isn't. Collecting data and coming up with with these general ideas about how pathways work based on our genetics is not that simple. Again, I am impressed with the direction of where medical research is heading, but we are just not there yet, once we have that knowledge.

_______________At the most recent San Antonio Breast Cancer Symposium, the CYP2D6 issue with respect to Tamoxifen was discussed:

"The anti-hormone therapy tamoxifen can reduce breast cancer recurrence by about half in women with hormone-sensitive breast cancer. But it works better in some women than others. Researchers are not sure why.

"We do know that some tumors are inherently resistant to tamoxifen because of tumor genetic changes," says Daniel L. Hertz, Pharm.D., Ph.D., an assistant professor in the University of Michigan College of Pharmacy and member of the U-M Comprehensive Cancer Center.

"These tumor have found pathways to overcome anti-estrogen treatment. But we also believe some patients may be less likely to benefit from tamoxifen or endocrine therapy because of their genetics," Hertz says.

One theory is that in some patients, tamoxifen is not activated to the more potent estrogen inhibitor endoxifen. Patients with low levels of endoxifen may have worse outcomes on tamoxifen.

A meta-analysis by the International Tamoxifen Pharmacogenetics Consortium points to genetic variants. Researchers found patients.....

https://www.sciencedaily.com/releases/2015/12/1512...

Lisey · July 2016

Hey Voracious, I totally agree we are in the baby steps of this new world of pharmcogenetics. I plan on having my endoxifen levels checked to see where they are at quarterly, just to make sure Tamoxifen is doing it's job... I also here there are clinical trials for an endoxifen medicine, hopefully that produces good outcomes. In any case, I still think it's important to know your own metabolism rates as most drugs use certain pathways, not just for Tamox, but for all drugs. I consider a good insurance policy.. I do wish they'd just do this type of testing like the newborn screening so we just know from the start. But science will keep getting more exact and stronger...
I hope to benefit from it, but if only this damn cancer occurred a decade in the future... sigh.

BarredOwl · July 2016

I understand why people might be interested in this type of testing at the individual level. However, I note that clinical consensus guidelines from the NCCN (Version 2.2016), which are population-based, currently do not recommend routine CYP2D6 testing for the purpose of selecting adjuvant endocrine therapy. The NCCN guidelines state (Version 2.2016):

"The cytochrome P-450 (CYP450) enzyme, CYP2D6, is involved in the conversion of tamoxifen to endoxifen. Over 100 allelic variants of CYP2D6 have been reported in the literature.(378) Individuals with wild-type CYP2D6 alleles are classified as extensive metabolizers of tamoxifen. Those with one or two variant alleles with either reduced or no activity are designated as intermediate metabolizers and poor metabolizers, respectively. A large retrospective study of 1325 patients found that time to disease recurrence was significantly shortened in poor metabolizers of tamoxifen.(379) However, the BIG 1-98 trial reported on the outcome based on CYP2D6 genotype in a subset of postmenopausal patients with endocrine-responsive, early invasive breast cancer.(380) The study found no correlation between CYP2D6 allelic status and disease outcome or between CYP2D6 allelic status and tamoxifen-related adverse effects.(380) A genetic analysis of the ATAC trial found no association between CYP2D6 genotype and clinical outcomes.(381) Given the limited and conflicting evidence at this time,(382) the NCCN Breast Cancer Panel does not recommend CYP2D6 testing as a tool to determine the optimal adjuvant endocrine strategy. This recommendation is consistent with the ASCO Guidelines.(383) When prescribing a selective serotonin reuptake inhibitor (SSRI), it is reasonable to avoid potent and intermediate CYP2D6 inhibiting agents, particularly paroxetine and fluoxetine, if an appropriate alternative exists."

This more recent 2016 review from Hertz and Rae summarizes some of the major conflicting clinical studies in the area, and outstanding clinical validation questions:

Hertz and Rae (2016): http://www.futuremedicine.com/doi/pdf/10.2217/pgs-2016-0059

This is an on-going area of research, and the scientific literature is extensive and at times contentious, in view of the conflicting studies. Some patients may reasonably choose to await further data, while some remain interested in testing, which might not to be covered by insurance in view of the position taken by current local guidelines (see e.g., this long thread):

https://community.breastcancer.org/forum/73/topics/798301?page=1#post_3359098

BarredOwl

voraciousreader · July 2016

lisey....many newborn metabolic screening tests were invented by the DH's physicians. Yep! And the folks who promote equal testing across the United States are friends of mine. Check out the website,Savebabies.org. The foundation was started many years ago because parents with children who were born in some states that didn't provide comprehensive testing had lost their children or had children who had profound disabilities due to genetic metabolic diseases. These mavericks recognized the need for early intervention of genetic metabolic disorders.

Now, you might be wondering why I hesitate as does the NCCN hesitate to make these metabolic tests mandatory.M ake no mistake, we CAN AND DO make many newborn metabolic disorder screening tests mandatory. That said, some tests will provide false positives, while others might be positively positive, but patient might never become symptomatic. And, as what recently happened to my newborn grandson, discharged from the hospital on the 3rd morning following birth, he had to be retested because the results were neither positive nor negative. And what really confounds physicians and researchers, is that two people can be missing the same amount of enzymes and one person could be profoundly affected while the second person is fine. Likewise, some people like the DH might be born with just enough enzymes to complete the metabolic process, but at adulthood, become symptomatic because the body requires more enzymes....the researchers and clinicians had hoped, way back in the 1990s, when they figured out the human genome, that treatments would soon follow. And what happened? Sadly, not much. The more they learned how elegant our genes were, the more they realized how little they knew. Junk DNA was recently found to not be such junk.

Without a doubt, metabolic pathways are extremely important. However, until there is consensus on how we should use that info and it is written into guidelines, I will yield to the judgment of my team of oncology specialists.

And the DH? For patients like himself and for a few other rare genetic metabolic diseases, the researchers are finding treatments. Sadly, not fast enough for many babies.

BTW...Eric Topol, MD has written in his book that tests like the CYP2D6 are beginning to be used clinically. In fact, some cardiac clinicians are using the Cyp2D6 test to measure whether the drug Plavix is effective for their patients. Unfortunately, truly individualized medicine is still in its infancy.

There is a reason why most pharmacogenomic testing hasn't been endorsed yet by the experts in each specialty. The reason? We still lack evidence of clinical outcomes. I know this for a fact. The DH is in an ongoing clinical trial for his disorder for more than a decade! The treatment? It is helping some, like him, more than others despite all having the SAME metabolic genetic disorder.

Make no mistake, we are mandating more genetic screening, especially for newborns, but it will be a decade or more before we get better clinical outcomes based on these genetic metabolic tests.

voraciousreader · July 2016

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC387259...

For those interested in learning about newborn metabolic screening.....

CYP2D6 test?

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