getting their pharmcogenetics tested... Tamoxifen, AIs

Anonymous

getting their pharmcogenetics tested... Tamoxifen, AIs

Lisey

There are a lot of long posts on the CYP2D6 pathway for Tamoxifen.  Your medical enzyme pathways are important to know if Tamoxifen and other drugs will work for you at the normal dose.  The Mayo Clinic has published a report agreeing with this assessment (https://cpicpgx.org/content/guideline/publication/tamoxifen/2017/tamoxifen_reprint.pdf)  Also https://newsnetwork.mayoclinic.org/discussion/new-international-practice-guidelines-for-tamoxifen-treatment-based-on-cyp2d6-genotype/ 

I used www.kailosgenetics.com and order the rxcomplete test.  Not only did I find out I'm a Ultra-rapid metabolizer on the CYP2D6 pathway, I also found out I"m a Met/Met (double mutation allele) on the COMT enzyme.  COMT is the trashman for our bodies and cleans out trash estrogen.  I have very little COMT due to the mutation.  It makes sense I got ER+ breast cancer and also estrogen based Melanoma.   I had my whole family take the test...  my husband is a Met/ met too... (which means so are our kids)  and he was just diagnosed with Melanoma as well.   

Ladies, please consider getting tested.  When I got tested it was 'alternative' because my Oncologist had never heard of it.  Science and studies are finally starting to catch up.  

applejuice

Hi Lisey,

I consider doing the testing before i start Tamoxifen and just a few days ago i posted asking about what provider to go with. Did your MO prescribe it? My MO suggested to take a commercial test for CYP2D6 genotype as she does not routinely prescribe it (which doesn't make sense to me). I also learned that some providers require blood and saliva for testing ( e.g. Kalios only require saliva)

Lisey

My MO had never heard of it, I found Kailos thanks to the ladies on another thread a few years ago.  They were one of the 4 FDA approved labs in 2016, and I absolutely love that they will work directly with the patient.  I just plugged in my docs names, and then 'informed' my doctors of my family I had ordered this test and they 'needed' to authorize.  I'm paying for it myself, so you can just be assertive.  My kids pediatrician had no idea what it was either, but as long as insurance isn't involved, they don't care. 

It is my view that in a decade or so this will routine screening on newborns.  It's information we absolutely should know about our own pathways. 

FarAwayToo

So, what do your doctors do with the information from the test? Obviously, it makes sense if you are taking Tamoxifen, but I couldn't find anything specific for AIs. I recall looking at another similar test, but my AI (letrozole) wasn't on the list - they only tested for efficacy of Exemestane, I would like to know more about my genome, but I can get "in my head" if I find out something is "wrong" with me, so I'm hesitating. I am all for actionable info, does the test you are referring to provide it?

Lisey

I know the other 3d4 pathway is tested, the trick is to go to drugs.com and see what the primary pathway your medicine is on. As for me , when I found out I was low on the COM T Enzyme I was able to up my green tea catechins, to help block er levels. My husband found out he can't take nsaids... these tests are truly important for far more than breast cancer

Rah2464

I just received the results from my OneOme testing and surprise! I am potentially a poor metabolizer of Tamoxifen. I was hoping to stay on this treatment, even with the side effects, to avoid going on an AI due to my osteopenia. Looks like that won't happen now. I have not had a dialogue with my MO yet, and the testing needs to be a bit more comprehensive to make a final decision. I know there is some controversy over measurement of CYP2D6 but knowledge is power. So happy now that these tests are more economical and available to us.

mellee

I'm thinking of getting this test done. I was diagnosed a little over 2 years ago with a cancer that was 100% ER positive. Theoretically, tamoxifen should work really well. But it didn't. I had a local recurrence where cancer cells seeded during the biopsy grew big enough to form a palpable lump within 18 months.

Now I'm on Zoladex, and as soon as my estrogen levels are low enough, I'll be switched to an AI. But I can't help but wonder why they didn't test my CYP2D6 pathway metabolism. I even asked my MO about it soon after starting tamoxifen. She dismissed it, but now I wonder: am I a poor metabolizer? Is that why it didn't work for me?

Lisey

Just so you know, none of my doctors were familiar with this testing and most just shook their heads at me.  I don't care.  Knowledge is power and I've learned so much I can start connecting dots...  It's also a reason I'm staying on Tamoxifen and when I had a hysterectomy in Nov, I insisted to keep my ovaries. (because I'm an ultra-rapid and Tamox treats me well).  Without knowing that, I may have opted to switch to an AI, and I am a poor metabolizer on the 3d4 pathway - so it may have failed me.

10 years and all babies will get their pathways checked... if you wonder how else this could save someone, read this article:

https://youscript.com/a-mothers-story-avoiding-my-babys-potential-overdose/ 

mellee

I didn't realize the test also looks at pathways used by AIs. That will be important information for me to have before they switch me from tamoxifen to exemestane. Thanks for the info, Lisey!

mellee

Lisey, is this test you took? https://www.kailosgenetics.com/pgxcomplete

I'm not seeing that AIs are on the list. Am I missing something?

Lisey

I could only find this test actually for your AI: https://www.biomol.com/products/toolkits/other/aromatase-cyp19a-inhibitor-screening-kit-fluorometric-g-bn01142.100

Lisey

I could find this test from a different company for your AI: https://www.biomol.com/products/toolkits/other/aromatase-cyp19a-inhibitor-screening-kit-fluorometric-g-bn01142.100  

AliceBastable

I don't quite trust ".com" sites to have the consumers' best interests in mind on medical issues, unless recommended by my doctor.

mellee

Thanks, Lisey. I'll be talking about these tests with my MO when I see her next. And bringing a copy of the report you referenced in your original post!

Salamandra

Hey Alice,

I agree that it's worthwhile to be skeptical of a .com site, but anyone can buy a .org site too.

Rah2464

Mellee I am very sorry to hear of your recurrence. If you do decide to take a test ( I took OneOme which requires initiation of your test by your doctor) I would also be curious about your results. There is still a lot of conflicting results regarding the CYP2D6 pathway but who knows? I know that the test I took did reference a mild issue for me with one of the AIs. I'll have to pull up the data again and see.

Lisey really glad to hear you are an ultra metabolizer that is great news! I hope the Tamox route treats you very well. Thanks for sharing your information. What is the 3D4 pathway and AI connection? That is a new one to me

Lisey

the AIs use the P450 family pathways... the 3A4 is one of them, responsible for about 25% of all medication pathways.  I remember that the Ais don't use the same pathways as Tamoxifen 2D6, and think some you at least a percentage of the P450 3A4..   But I'm not certain since I'm avoiding Ais since Tamox works well for me. 

As for the site, due diligence ladies... do your research yourselves and realize most doctors will never suggest these tests as they are cutting edge and not a standard of care (yet) .. 

mellee

Rah2464 - I am planning on getting tested and will definitely update here with the results. Thanks for the OneOme tip. Their RightMed test looks at the AI exemestane (which my MO wants to switch me to) as well as tamoxifen, so it sounds like a good option for my situation.

applejuice

I had blood draw just yesterday for this test. After I spoke with MO again she said will do it, no problem but she said she will send it to Mayo. I will sure come back and tell what i find out. I started Tamoxifen on March 14 but i still fell she rather wanted me on AI

Rah2464

I finally connected with my MO's assistant about my test results. I was confirmed to be an intermediate metabolizer. It was interesting once my MO reviewed the results, more data was released into my report that I accessed online.

For a little while longer I will continue to stay on Tamoxifen at the 20mg dose. I take 10 mg morning and 10 mg evening. My MO feels that as long as I stay on that dose and am judicious about taking it (I am - I have missed one dose when I was doing colonoscopy prep) that I am getting enough levels. But who really knows? So does that mean I get an "effective" dose of say 10 mg because I am an intermediate metabolizer?

She did say that since I am an intermediate metabolizer, I need to have a dialogue with her about any additional medicines I might need that could lower that metabolic activity, like certain depressants and certain meds for acid reflux etc. Luckily so far I don't need those.

This information is just one piece of the puzzle. If you research the various studies there doesn't seem to be a consistent documented correlation between your CYP2D6 gene composition and how well you do on Tamox. I ran across one study that looked at plasma concentration of endoxifen (metabolite of Tamoxifen) which found some correlations with concentration levels. Think I will keep plugging away at that one. Just frustrating that a critical medication for so many women isn't monitored to determine its efficacy.

At least with this test result I know that I need to be careful with any additional meds, and that as soon as possible I will switch to an AI.

Lisey

HI Rah,

So from what I understand there are two types of drug metabolism.  Tamoxifen is a 'pro-drug' , a type which requires metabolism first for the drug (endoxifen) to be formed.  Therefore, it's the reverse of the other type of metabolism where you would want slow metabolism to get all the drug in your system.   Which means an ultrarapid like myself would probably do well on a lower dose, but a intermediate would actually need MORE tamoxifen to make the same Endoxifen needed.

Here's what one of our chief scientist posters said in another thread:

BarredOwl: 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.

The 4 metabolism types are:
UM: Ultrarapid metabolizer
EM: Extensive metabolizer  (NORMAL)
IM:  Intermediate metabolizer
PM:  Poor metabolizer

Rah2464

Thanks, Lisey, for the additional information. Maybe some day we will get a definitive test for dosing levels and efficacy

FarAwayToo

Here is a question: if one is on AI, is it sufficient to measure estradiol level to see if it's working? If I understand mechanisms of Tamoxifen and AI correctly, the former works to block estrogen receptors of the cells, and while estrogen level in the blood may remain high, it should not "enter" cancer cells and therefore prevent tumor growth. For AIs, the end goal is to reduce circulating estrogens to a very low level.

There is some controversy on what level of estradiol is considered "good" for those on AIs, but isn't a relatively low level a good enough indicator that AI is metabolized normally?

Also, just a word of caution - I'm an IT/security professional, and I'm super wary about giving anyone access to know and store my genetic data. Most companies have poor understanding of data security and protection, don't follow best practices, and as a result, are victims of hacks and security breaches. It's enough that everyone in the US who ever had any credit has their SSN floating somewhere on dark web (hello Equifax), I need to know for sure what I will do with the info I get out of a genetic test before I risk the same with my DNA info.

2002chickadee

FarAwayToo -- that's a great question, I'm going to ask my MO. Let us know if you learned anything since you last posted.