Are there tests for tamoxifen resistance?

PAKNC

I'm in a clinical trial, randomized to active surveillance instead of surgery, and just had my 6-month check in. Unfortunately, there has been progression of my DCIS even though I'm on Tamoxifen. I expected some change but given that it's low to intermediate grade, not as much as it did. My provider told me that I may be a non-responder to Tamoxifen. I'm glad I had this experience before pursuing surgery because it now makes me take a second look at treatment options. I don't want to take AI's because I have arthritis in my spine already and have scoliosis. Also, my Mother got osteoporosis, I think in part from breast cancer hormone treatment - she lost about 6 inches of height over the years and gained a widow's hump - it crippled her and was painful.

I've read that CYP2D6 is a genetic marker that can provide insight into how well a woman metabolizes tamoxifen and certain other drugs. Has anyone used 23andme data to research this or received a test? I'm sure it's not perfect but I'd like to know if there are some signs that I'm not a great candidate for a drug, especially if it has a lot of difficult side effects.

I follow a fairly healthy diet, and am not on any medication that would interfere.

Rah2464

Paknc - Sorry to hear your DCIS continued to be active even with the addition of Tamoxifen. I have been on Tamoxifen for about 2 1/2 years now My MO ordered the OneOme testing for me back in 2019 for the CYP2D6 gene. I came back an intermediate metabolizer, which may explain some of my difficulties with side effects. The problem is the absolute science on Tamoxifen metabolization via this pathway only is somewhat unclear. To top it all off, there is no established bloodwork testing to check for those wonderful effective metabolites that do all the work for us . This just blows my mind. We take a strong medicine with no markers to help determine efficacy. When you take a cholesterol drug, you measure the results. Why not this?

If you do decide to test for the pathway, I hope you will post your results.

PAKNC

Thanks for this info. I'm going to ask about testing, and will post results if I get it. I'm now likely going to have a mastectomy, given my small breast size and the fact that I want to avoid AI's, rather than a lumpectomy, which I had initially scheduled this summer before joining the clinical trial. I am now skeptical that Tamoxifen is doing much for me!

I can add to the anecdotal evidence of side effects indicating that the drug is working. Tamoxifen has not been difficult for me to take - little aches and pains here and there, some hot flashes but nothing major. I attributed this to my age, and the fact that when I went through menopause, I did not experience many issues. What I was more concerned about was the potential impact on my liver. I had some labs run a month ago and I was prediabetic - I was not this way a few months earlier before starting Tamoxifen. There is some research showing that endocrine therapy makes older women more vulnerable to Type 2 diabetes, if they already have the predisposition. Looks like I do, despite being normal weight.

I'll be curious to hear what the surgeon team / oncologist say.

Salamandra

Just FYI depending on how important lumpectomy/mastectomy is for you, there are other SERM options besides tamoxifen.

I couldn't tolerate tamoxifen (and I tried hard). I'm taking toremifene now. There is a lot of retrospective evidence and growing prospective evidence that toremifene is non-inferior to tamoxifen for preventing recurrence even in premenopausal women, and even more for menopausal women.

MelissaDallas

PAKNC, there are also some recentstudies on genomics (way beyond metabolism pathways) as to tamoxifen resistance. Might be worth talking with a genetics counselor. Here is one study. Color Genomics has a panel for a bunch of medication genes, but don't know what it encompasses.

https://ascopubs.org/doi/10.1200/JCO.2005.05.145

Jelson

https://www.mayo.edu/research/centers-programs/center-individualized-medicine/patient-care/pharmacogenomics/drug-gene-testing/cyp2d6-tamoxifen Testing seemed to be the rage in 2009, but not so much lately. I got it and was determined to be an extensive metabolizer. I have shared one article, but there are others where the Mayo Clinic continues to recommend it and explain that problems in lab testing have muddied the results. In any event, I was glad to learn that I was an extensive metabolizer because I felt I was getting the full benefit since it was breaking down to endoxifen efficiently even though I might have been suffering from more side-effects - though I didn't sense that I was until I was diagnosed with endometrial cancer!! and have wondered whether that was related to being an extensive metabolizer. When I was diagnosed I scoured the internet for clinical studies about the connection between tamoxifen and endometrial cancer and found a few linking tamoxifen/endometrial mostly in post-menopausal women. I just saw the 23andMe offer on a medication panel, but I didn't understand why it was a subscription $29 per year. Anyway - it looks at other genetic markers which impact our ability to benefit from a variety of drugs, so I may take advantage of that. I agree with commenters above, You would think after how many decades of prescribing tamoxifen, more would be known about it. Good luck with your treatment plan going forward PAKNC!

PAKNC

I did the Color Genomics test and plan to talk with a genetics counselor about my results and potential interaction with Tamoxifen and other endocrine therapy. We know that the answer re: the drug resistance is more complicated than what I have results on but I thought it would be interesting as a beginning conversation. I am thinking that the insulin resistance I started developing while on tamoxifen hindered my body's ability to process the drug, but not sure that is captured by this test. I am normal in some areas but not in others. According to the web site, People who are poor or intermediate metabolizers may take longer to break down (metabolize) medications. For some medications, this means they may remain at higher or active levels in the body for longer than expected. For other medications (prodrugs) this means that the body more slowly converts them into their active form.

Metabolizers

CYP1A2 *1/*1F Rapid metabolizer

CYP2C19 *1/*1 Normal metabolizer

CYP2C9 *1/*2 Intermediate metabolizer Activity Score: 1.5

CYP2D6 *35/*35 Normal metabolizer Activity Score: 2

CYP3A4 *1/*1B Indeterminate

CYP3A5 *1/*3 Intermediate metabolizer

CYP4F2 *1/*1 Normal metabolizer

DPYD *1/*1 Normal metabolizer Activity Score: 2

NUDT15 rs116855232 CC Normal metabolizer

TPMT *1/*1 Normal metabolizer

Non-metabolizers

F5 rs6025 GG Variant absent

IFNL3 rs12979860 CT Unfavorable response

SLCO1B1 rs4149056 TT Normal function

VKORC1 rs9923231 GG Normal function

Rah2464

PAKNC looks like you are a normal metabolizer on the CYP2D6 pathway which is wonderful. That is the main pathway to metabolize Tamoxifen. I did the OneOme test a couple years ago and I am an intermediate metabolizer. So my Onc makes sure to evaluate any medication I take that might interfere, as well as tightly controls any supplements. I also take my Tamoxifen twice a day, 10 mg each. That really helped with side effects for me. This stuff is so very complicated. Hard to imagine that we still do not have a way to measure efficacy of the drug we are taking to save our lives. Drives me absolutely bananas

Ladyc2020

I recently got the results of the CYP2D6 and I’m 4*/4* poor metabilizer - very likely I’m not getting benefit from tamoxifen though of course it’s not an absolute. Am now changing to zolodex and genera. Pretty concerned about bone side effects now.

Rah2464

Ladyc2020 sorry to hear you came back a poor metabolizer. If it is any consolation at all my bones went to crap while on Tamoxifen (my MO says she has had a handful of patients for which this occurred) so it isn't a guarantee. What I would push for is a baseline Dexa with repeats once a year to monitor your bone health. I went two years and got behind I don't want that to happen to you.

Ladyc2020

thank you for this! I’m on an every 2 year dexa scan but perhaps yearly is best. I do have osteopenia already.

Rah2464

Ladyc2020 I hope you can do that. I met with an endocrinologist and he recommended walking daily up to 3 miles as a weight bearing exercise to improve bone health. Also if you are not getting 1200 mg of calcium daily in your diet, you should be supplementing. He had an interesting cheat sheet on how to convert calcium in supplements to elemental calcium I will root around and see if I can find it and post. Might be helpful for others as well. I am supposed to begin reclast, keep waiting to complete my covid vaccine before I start working on the timing. Guess I am putting it off.

Ladyc2020

Rah - thank you! I do walk a fair bit already, and know that’s important. Hope to do other types of exercise at some point. I’d definitely appreciate knowing more about converting the calcium! I am taking calcium 2x a day now.