CYP2D6 ability to metabolize tamoxifen and recurrence

Hi all:

The article posted by Lisey mentioned:

Saladores (2015): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4308646/pdf/tpj201434a.pdf

"Our data clearly show that endoxifen formation follows the same principle in pre- and postmenopausal women driven by CYP2D6. Yet, its contribution to formation is estimated at approximately 53% suggesting that other factors contribute to the bioavailability of endoxifen."

This July 2016 article re the TADE study (122 participants) also suggests a similar unexpected level of complexity beyond CYP2D6 genotype alone: "Our data show that the use of CYP2D6 genotype alone gives an imperfect guide to endoxifen level on standard dose tamoxifen and after dose escalation."

Fox (2016), "Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring—The TADE Study": http://clincancerres.aacrjournals.org/content/clincanres/22/13/3164.full.pdf

The Fox article was profiled in the Highlights for that issue of the journal:

"Low endoxifen levels are associated with an impaired outcome in breast cancer patients treated with tamoxifen. Endoxifen relies on CYP2D6 metabolism but genotype does not consistently correlate with outcome. In 122 tamoxifen-treated patients, Fox and colleagues found that concomitant medications (14%), CYP2D6 genotype (24%), compliance and absorption (21%), and unknown factors (52%) all contributed to low endoxifen. The authors then increased the tamoxifen dose in those with low endoxifen and found that the best predictor for reaching a therapeutic level was the baseline endoxifen level and not CYP2D6 genotype. It was concluded that therapeutic monitoring of endoxifen requires more attention."

Consensus guidelines are not likely to change until additional clinical trial evidence is accrued as Fox notes: "Our study did not seek to define an optimal therapeutic endoxifen concentration and we acknowledge that before monitoring of endoxifen levels in tamoxifen-treated patients can be accepted as standard of care, prospective studies are required to prove a link between endoxifen level and anticancer effect."

BarredOwl

It would have been interesting to know my before and after dose adjustment endoxifen levels, although I expect we can't really compare ourselves to others with so many factors involved. On top of the 2D6 I was also around 35 BMI when I started tamoxifen. I was steadily losing at that point so it probably became less of a factor as time went on. I'm around 27 right now, and still losing, so under the magic number of 30. When they establish a cutoff like that it doesn't mean that someone with 30 has a much higher risk than a 29. It's incremental and they have to draw the line somewhere. With my 100% ER+ cancer, losing the weight was a top priority. I literally started my diet the day after diagnosis and I have lost 123 lbs to date with 25-30 to go. The closer I get to goal the slower it gets.

I raised my tamoxifen dose to 40mg on June 24th so almost 3 weeks ago. I guess I'd characterize my hot flashes as around 50% more severe. Waking up sweaty in my sleep sometimes now too, but no full soaks yet like some women get. I'm probably cracked in the head but I love 'em as a tangible sign something is changing at the higher dose. However, for our newer participants I'll restate that whether there is a correlation between hot flashes and the effectiveness of tamoxifen or endoxifen levels is another point of controversy.

Solfeo,

I'll plan on testing, and pay out of pocket quarterly IF I come back as a poor / intermediate metabolizer and also have no symptoms on a normal dosage. I'm willing to pay to see numbers if I worry the tamox isnt working on me. Hell, I was willing to pay for the mammaprint when I thought it would be $4200... my oncologist told me they are going to charge me $500 since Kaiser rejected the test, but I'm fortunate in that I work full time from home and my husband works, so we'll spend whatever to make sure I'm making the right decisions for beating this cancer.

I frankly feel that if we were living in Canada (where there is a woman with a palpable lump just like mine having to wait 4 weeks to even be seen via mammogram).. We'd drive to the US or pay a private company to mammogram me in that situation. It becomes a class of haves and have nots where only if you can afford to pay $$$ will you get quality care. Sad but true..

Sorry, guys, brain went on a hike

Shep PM me if you want me to call them

Lisey send me that page number okey dokey

SAS, here's the article I found that was geared toward Premenopausal women only.. it is the largest study to date and had a ton of info... http://www.ncbi.nlm.nih.gov/pmc/articles/PMC430864...

It has been awhile since I read through the earlier part of this thread and my memory ain't what it used to be. The only thing I remember that wasn't accurate was some of the discussion, probably back in 2013, about how tamoxifen is metabolized vs. most other CYP2D6 substrates. That is the most confusing part for everyone. I can't remember who wrote it but it had to do with whether the dose should be increased or decreased in intermediate metabolizes because someone's doctor suggested 40mg and the info on the Genelex site seemed to indicate a lower dose. Is that it? I do know the reason for the confusion but before I go into a long explanation let me know if that is what we are talking about.

Other than that, I'm certainly capable of being wrong about things myself, although I don't think I have done that here. Would like to clear it up if have.

Hi Lisey:

Some confusion back in the thread (which Solfeo noted) and in general stems from mis-understanding of the distinction between a drug that is the "active per se" versus a drug that is a "pro-drug" which is metabolized to produce the active(s). This affects the appropriate dose adjustments in opposite ways.

One example would be a drug that is the "active per se", and for which metabolism via CYP2D6 reduces the amount of the active, producing inactive or less active metabolites. In a CYP2D6 ultra-metabolizer, the active drug would be rapidly converted to inactive or less active metabolites, so a dose increase would be considered. Conversely, in a poor metabolizer, the active sticks around, and a dose reduction might be considered (depending on its pharmacokinetics).

With a drug that is a "pro-drug", metabolism of the pro-drug via CYP2D6 produces the active(s) (e.g., tamoxifen is metabolized by CYP2D6 to produce the more active endoxifen metabolite). In a CYP2D6 ultra-metabolizer, the pro-drug (e.g. tamoxifen) would be rapidly converted to the active (e.g., endoxifen), so a dose decrease might be considered. Conversely, in a poor metabolizer (e.g., tamoxifen is not efficiently converted to the active endoxifen), a dose increase might be considered.

As noted above, we are awaiting prospective studies to prove a link between endoxifen level and anticancer effect.

BarredOwl

[EDIT: Note that the above is meant to illustrate the general concept only. Many factors must be considered for each drug (including tamoxifen) in consultation with a medical professional to ensure accurate, current, case-specific, expert professional advice. Such factors may include the evidence (if any) regarding the activity of each specific drug and its metabolites, the feasibility/effect (if known) of possible dose adjustments up or down, and the clinical data available (if any) re therapeutic efficacy of particular adjusted doses and long-term safety of such adjusted doses.]

Hi Lisey:

For people getting this type of pharmacogenomic testing who learn they have some alteration, each drug must be separately considered in light of its activity and the activity of its metabolites. My last post illustrates how for the same metabolic enzyme, the dose adjustments for different drugs may be different. The evidence regarding activity of each specific drug and its metabolites, possible dose adjustments up or down, therapeutic efficacy of adjusted doses, and long-term safety of adjusted doses should also be considered for each drug in consultation with a medical professional.

FDA has compiled a "Table of Pharmacogenomic Biomarkers in Drug Labeling" listing FDA-approved drugs with pharmacogenomic information in their labeling, which is a starting point for other drugs:

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

BarredOwl

Jelson and all :The Constipation thread has grown to be 40 pages of talking poop. By putting certain info in the topic box it avoids repetition of responses . Look at it from a structural point.

Lisey, Shep and Solfeo since you three are the most recent reviewers of the entire thread here. You likely have pages in mind that helped that were key to what you were learning.

Constipation thread:

"This thread will talk about constipation. The nemesis of cancer patients. If you post helpful information make sure to identify that all recommendations should be cleared with your doctor. Preferably, your Gastroenterologist (GI doc) or Primary Care Physcisin PCP). Cancer docs, I would say that this isn't there strong suit.

pg 10 description of Laxatives, stool softners, and usage dangers:

https://community.breastcancer.org/forum/6/topics/781867?page=10

Page 12 has a Question list & treatment plan to discuss with doc. Used several times as reference, I decided page 12 had so much info on it, I'd link it here.

https://community.breastcancer.org/forum/6/topics/781867?page=12

NIH National Cancer Institute : Gastrointestinal Complications–for health professionals (PDQ®)

http://www.cancer.gov/about-cancer/treatment/side-effects/constipation/GI-complications-hp-pdq

Link to rectal Issues thread: http://community.breastcancer.org/topic_post?foru...

Link to main BCO board thread: www.breastcancer.org/treatment...... http://www.breastcancer.org/tips/nutrition/during_...

Amusing Five Constipated Men

Puns are welcome, not often we get such a situation that is more worthy."

I've run into a few intermediate, extensive (normal) and ultra rapid metabolizers around these boards, but I don't think we have seen a poor metabolizer yet because they are relatively rare. I think a PM would be likely to already know from experience that some drugs don't work as expected in them - either by the increased side effects, or complete lack of efficacy.

As I've posted before, codeine and tramadol are both prodrugs metabolized by CYP2D6. As an IM they always had the desired effect in me, which was alleviating pain, so I never would have known they could have been working better since they did enough. I still have Tylenol 3 and tramadol leftover from my surgery. I didn't need much prescription pain relief after my BMX but they did help the few times I took them. Maybe a partial placebo effect? I haven't taken a lot of prescription drugs in my life but never noticed any untoward side effects either.

Here's a nifty table of CYP450 drug interactions:

http://medicine.iupui.edu/clinpharm/ddis/main-tabl...

And here is a list of CYP2D6 inhibiting and inducing herbs and supplements (the same site also has pages on the other CYP450s and other drug metabolizing enzymes):

http://herbpedia.wikidot.com/cyp2d6

Note that CYP2D6 is generally considered to be non-inducible. There are very few drugs and supplements that have been found to do that (rifampin and AHCC come to mind) but I don't think it's a good idea to try that because sometimes a substance can have different effects on CYP450 enzymes depending on dose (for example, inhibits at one dose, induces at another), or the effect changes as the substance metabolizes (starts out as an inducer, ends up as an inhibitor). It also seems to be a good idea to avoid other CYP2D6 substrates with tamoxifen as much as possible, because they can have an inhibitory effect through competition for the 2D6. You want to leave as much 2D6 available for the tamoxifen as possible.

Tamoxifen builds up slowly and stays in the system a long time, therefore it is probably not going to cause problems to interfere with it occasionally. You just don't want to be doing it on a regular basis.

(Edited to clarify 2nd to last paragraph)

Hahahahaha. Solfeo sweetie, would love to be a fly on the wall with you in a room with a bunch of docs.

But back to my point, if Jelson is open to changing the topic box. WHATEVER is put in there may help someone navigate the thread.

When threads get long it can be daunting.

HILoving

Thanks solfeo!!!!!

Solfeo, here is my question.... If you look at the study I posted about pre-menopausal women and Tamoxifen/CYP2D6, it shows a graph and even PM had endoxifen levels, a little lower perhaps, but they were keeping up on the lower side with the others. If you are postulating that Tamox doesn't get through with PM, how would you explain that? The researchers pointed out that while CYP2D6 was a primary gateway, it only was for about 50% and the rest is still other gateways. Poor Metabolizers, still got Endoxifen, just lower amounts and the researchers believe BMI and other factors to be at play. That is why they suggest that using metabolic rates is not a good indicator of whether Tamoxifen will work for a woman, but rather doing Endoxifen blood work and checking on that. Perhaps Tamox works on PMs but at a less than ideal level...

One study doesn't necessarily cancel out the others that found abnormally low endoxifen in PMs, at least at the levels they were looking for. I don't have time to go back and read the pre-menopausal study again, but my memory is telling me that the PMs did have shorter time to distant recurrence (correct me if I'm wrong, sometimes the studies jumble together, but that has been the finding in some studies). That is the end result that is important not that they had some level of endoxifen. If endoxifen is the problem, which we don't have proof yet, PMs probably don't have enough. Each person has 2 alleles. The possibilities are fully active, partially active and inactive. Someone with two partially active alleles is going make more endoxifen than someone with two inactive alleles, but they would both be poor metabolizers. You can extrapolate that to the other possible combinations. I used "next to none" as one of the possibilities but that was a poor choice of words. I probably should have just left it at not enough.

I don't think metabolism is the only factor as has been stated and I don't think anyone is disagreeing that testing endoxifen levels is a good idea, except maybe some of our doctors haha. I don't think you're going to find normal endoxifen levels in most PMs though, regardless of the other factors. It's true that normal hasn't been established, but some of the studies on dose adjustment suggest an optimal range, and PMs and IMs have been shown to have worse outcomes in some of the studies.

Also keep in mind that it takes a couple of months for endoxifen to build up. If you are a PM (I am guessing you are not or you would have mentioned a history of adverse drug reactions), you would have to take the tamoxifen for at least 2 months to get your steady state level, then you would have to adjust your dose for another few months to find out how much it went up, and that could go on for awhile before you finally figure out that it ain't working for you. Who wants to waste that kind of time? As an IM I at least have a reasonable expectation that my levels will normalize to justify the experimentation.

I hope that clears it up. You can never trust one study. You have to look at them all in total, but all this does is give you more information to consider. None of us can say for sure what it all means, including the scientists at this point in time. But I will stand by what I said about PMs. I don't think it's worth the risk and an AI would be a better choice.

You would think I would have covered everything in that last long-winded post, but since I didn't spell it out again I want to reiterate that I'm basing my conclusion on the studies that found levels couldn't be normalized in PMs with a dose increase. My conclusion is not going to be the same as everyone else's which is why I always tell everyone don't take my word for anything. I just try to add my interpretation to the conversation.