solfeo--I don't think my doc was really looking at the estradiol levels. He seemed more concerned with the other things. I had a baseline TVUS about a year into Tamoxifen. It was actually my suggestion based on what I had learned here. The baseline showed a slightly thickened lining, uterine fibroids and ovarian cysts as well as a slightly enlarged uterus. My gyn at the time immediately started throwing around "hysterectomy" and a full abdominal one saying that since I'd never had kids they couldn't do it vaginally (!). Fortunately my dad's a doc and suggested a second opinion and I found my current guy who did such a great job. He actually just did some watchful waiting for about a year before deciding that my lining was getting too thick. I don't think he really cared about my levels or if they were any part of the problem. My ovarian cysts were getting bigger too as well as the fibroids. Finally he just said "It's coming out!" and that was it. I'm 53 now so I'm sure menopause wasn't too far away. And I'm trying to avoid the AIs just because I don't feel the slight benefit is worth the worse SEs, much less the heart and bone issues that I'd like to avoid. So I'm at 4 years and going to 5 on Tamoxifen at which time we'll do a BCI test and figure out what to do then based on the results.

Thanks ladies.

Sure does make me wonder if high estradiol while on tamoxifen could be an indicator of who might go on to develop the uterine changes. Just because no one has put it together yet doesn't mean there might not be a connection. Kind of makes sense though, doesn't it? One way they determine which substances are estrogenic is by looking at whether exposure causes an increase in uterine weight. I wasn't given a TVUS because the ASCO standards recommend against it in premenopausal women. Didn't feel the need to ask because I don't plan to be on tamoxifen very much longer and I haven't had any warning signs.

I did not have chemo so my periods were not affected by that. My last period before I had the random one in April was in September of 2015. That was two months before I started tamoxifen, so I had already skipped a month before tamoxifen. That was also the point where my weight loss had reached a significant level, so I had also lost a bunch of estrogen along with the fat. BUT, that was also the highest stress time after the diagnosis, waiting for surgery that had been postponed several times. So the stress very well could have messed with my periods. Now I weigh a total of 139 lbs. less and I'm in the "normal" BMI range. I certainly didn't expect higher estradiol now than when I was morbidly obese.

Can I just whine for a moment? I am so sick and freaking tired of always being in a state of dilemma because it seems like everything about my case has been in a gray area making every decision less than clear cut. My doctors suck with gray areas because they are completely lacking in creativity. I know I'm not alone here but it's really bugging me today. And I've had other weird bloodwork in the last few weeks too. I'm starting to dread looking at the results. Heaven knows what the endoxifen test is going to tell me because that's another gray area.

If anyone else can share their estradiol levels while on tamoxifen, along with details about their menopausal status and what their doctors said about it, it would really help me decide what to do next.

Hi Lisey. I had the blood drawn at my regular lab. It was a special order that they had to send out but they didn't say where. It usually says on the report. I'll let you know if I find out.

As I've mentioned I have never had bad hot flashes while on tamoxifen. They got a little worse when I doubled the dose but that went away after a month or so. I get slightly uncomfortably warm a couple of times per day but that's about as bad as it gets. I wonder if the high estradiol explains that? I do have other side effects though, like constipation, insomnia and I'm also prone to muscle injury since I've been on tam. That has all been manageable with supplements and avoiding muscle strain.

Hi Solfeo and Shep,

I would really appreciate knowing any other labs who tests for Endoxifen. My Onc says I should just 'have faith it is working"... then she laughed and shook her head and said "I bet that doesn't work for you, right?" I'm into facts and figures.. gotta know it's effective or I'm switching to an AI/ OOPH. If it's effective and I'm SE free I'll consider myself lucky.

I do think that Lattice implant is a really cool idea to test for future mets. I'm excited about the future tech.

Solfeo

I skimmed the article that you posted. I think I need to talk to my MO given my high estrogen levels! I found a 2010 study done in Norway. I don't understand a lot of what is it in, but they are drawing associations between blood levels of tamox and estrogen levels.

http://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-10-313

Associations between tamoxifen, estrogens, and FSH serum levels during steady state tamoxifen treatment of postmenopausal women with breast cancer

Abstract

Background

The cytochrome P450 (CYP) enzymes 2C19, 2D6, and 3A5 are responsible for converting the selective estrogen receptor modulator (SERM), tamoxifen to its active metabolites 4-hydroxy-tamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam, endoxifen). Inter-individual variations of the activity of these enzymes due to polymorphisms may be predictors of outcome of breast cancer patients during tamoxifen treatment. Since tamoxifen and estrogens are both partly metabolized by these enzymes we hypothesize that a correlation between serum tamoxifen and estrogen levels exists, which in turn may interact with tamoxifen on treatment outcome. Here we examined relationships between the serum levels of tamoxifen, estrogens, follicle-stimulating hormone (FSH), and also determined the genotypes of CYP2C19, 2D6, 3A5, and SULT1A1 in 90 postmenopausal breast cancer patients.

Methods

Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Estrogen and FSH levels were determined using a sensitive radio- and chemiluminescent immunoassay, respectively.

Results

We observed significant correlations between the serum concentrations of tamoxifen, N-dedimethyltamoxifen, and tamoxifen-N-oxide and estrogens (p < 0.05). The genotype predicted CYP2C19 activity influenced the levels of both tamoxifen metabolites and E1.

Conclusions

We have shown an association between tamoxifen and its metabolites and estrogen serum levels. An impact of CYP2C19 predicted activity on tamoxifen, as well as estrogen kinetics may partly explain the observed association between tamoxifen and its metabolites and estrogen serum levels. Since the role of estrogen levels during tamoxifen therapy is still a matter of debate further prospective studies to examine the effect of tamoxifen and estrogen kinetics on treatment outcome are warranted.

I got my endoxifen results. They actually tested the level of tamoxifen and all of the metabolites so I got more information than I bargained for. Results are below, and Lisey, the name and address of the lab is at the end.

-------------------------------------------------

Tamoxifen 86 ng/mL
Reporting Limit: 1.0

Tamoxifen undergoes demethylation to
N-desmethyltamoxifen and tamoxifen and
N-desmethyltamoxifen are hydroxylated to
4-hydroxytamoxifen and
4-hydroxy-N-desmethyltamoxifen (endoxifen),
respectively. Tamoxifen is a prodrug; the
pharmacological effects are mediated through its
hydroxylated metabolites.

A dose-concentration relationship has been identified
for tamoxifen.
In patients receiving 1, 5, or 20 mg/day tamoxifen for
28 days, mean (range) plasma tamoxifen
concentrations were:
1 mg/day = 7.5 (2.9 - 120.9) ng/mL
5 mg/day = 25.2 (1.9 - 180.9) ng/mL
20 mg/day = 83.6 (8.7 - 134.4) ng/mL.
The ratio of whole blood concentration to serum or
plasma concentration is unknown for this analyte.

*

4-Hydroxy-Tamoxifen 3.1 ng/mL
Reporting Limit: 1.0

A dose-concentration relationship has bee
n identified
for 4-hydroxytamoxifen, an active tamoxifen metabolite.

In patients receiving 1, 5, or 20 mg/day tamoxifen for
28 days, mean (range) plasma 4-hydroxytamoxifen
concentrations were:
1 mg/day = 0.6 (0.4 - 6.0) ng/mL
5 mg/day = 1.3 (0.4 - 5.9) ng/mL
20 mg/day = 3.1 (0.4 - 7.3) ng/mL

Hydroxylation of tamoxifen to 4-hydroxytamoxifen is
catalyzed by CYP2D6 and genetic polymorphisms which
result in low CYP2D6 activity (poor metabolizers) or
co-administration of drugs which inhibit CYP2D6 can
greatly reduce plasma concentrations of
4-hydroxytamoxifen reducing the overall efficacy of
tamoxifen.
The ratio of whole blood concentration to serum or
plasma concentration is unknown for this analyte.

*

N-desmethyltamoxifen 180 ng/mL
Reporting Limit: 1.0

A dose-concentration relationship has been identified
for N-desmethyltamoxifen, an inactive tamoxifen
metabolite.

In patients receiving 1, 5, o
r 20 mg/day tamoxifen for
28 days, mean (range) plasma N-desmethyltamoxifen
concentrations were:
1 mg/day = 9.9 (1.3 - 135) ng/mL
5 mg/day = 36.2 (3.6 - 282.2) ng/mL
20 mg/day = 112.3 (14.3 - 211.6) ng/mL
The ratio of whole blood concentration to serum or
plasma concentration is unknown for this analyte.

*

Endoxifen 12 ng/mL
Reporting Limit: 1.0

Hydroxylation of N-desmethyltamoxifen to endoxifen, an
active tamoxifen metabolite, is catalyzed by CYP2D6 and
genetic polymorphisms which result in low CYP2D6
activity (poor metabolizers) or co-administration of
drugs which inhibit CYP2D6 can greatly reduce plasma
concentrations of endoxifen reducing the overall
efficacy of tamoxifen.

Women receiving 30 mg tamoxifen/day for
10 - 112 (average = 42) days had a mean (range)
endoxifen plasma concentration of
8.6 +/- 7.0 (3.0 - 28.0) ng/mL.

In one study, patients taking a CYP2D6 inhibitor along

with 20 mg/day tamoxifen for four months had mean
plasma endoxifen concentrations of 14.8 +/- 10.6 as
compared to patients taking only tamoxifen (mean plasma
concentration = 26.7 +/- 15.4 ng/mL). In comparison,
CYP2D6 poor metabolizers had mean plasma endoxifen
concentrations of 7.2 +/- 2.3 ng/mL.

The ratio of whole blood concentration to serum or
plasma concentration is unknown for this analyte.

Analysis by High Performance Liquid Chromatography/
TandemMass Spectrometry (LC-MS/MS)

Testing has been performed by:
NMS Labs
3701 Welsh Road P.O. Box 433A
Willow Grove, PA 19090

Solfeo, I sent the info on the lab to my oncologist, and I called them. They charge between $350 - $550 (plasma vs. blood) for the Endoxifen test. I also found Quest Diagnostics offer it, so am asking for a price from them. I find it hard to fathom that this test is as expensive as the mammaprint. Sigh...

I would like to start some discussion about what level of endoxifen is high enough. Try to arrive at our closest guess to what defines "normal," which hasn't been established yet scientifically. I'll start by resurrecting one of BarredOwl's excellent posts (hope that's OK BO). The target in this one was 30 nmol/mL and my result was 12 ng/mL. I didn't realize at first that we were dealing with different units and 12 seemed very low. But I tried to calculate the conversion from nmol's to ng's and it looks like my level is closer to 40 nmol/mL, which would be above the target.

Is there anyone here smart enough to check that math because I'm not sure I did it right?

I didn't have time to look at every study yesterday but I ran across at least one more that attempts to determine a threshold. I'll post that a little later and I plan to keep reading until I have to leave for my appointment with MO. I want to have some understanding of what we are shooting for before before I see him. I kind of feel like he is going to say he doesn't know because that is how he has responded to all of my questions about endoxifen so far.

---------------------------------------

BarredOwl:

I believe that there is a good deal of uncertainty regarding the relationship between CYP2D6 genotype and endoxifen levels, and it does not appear to be entirely intuitive. As I noted yesterday, an unexpected level of complexity beyond CYP2D6 genotype alone was seen in this small study:

TADE study, Fox (July, 2016): http://clincancerres.aacrjournals.org/content/clincanres/22/13/3164.full.pdf

"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. . .

. . . To put these data into clinical context, if a clinician knows a patient has PM genotype, then it cannot be assumed that endoxifen level will be low. One of 8 PM patients had baseline endoxifen levels above 15 nmol/L and PM patients had a 63% chance of achieving endoxifen levels above 15 nmol/L with dose escalation. Conversely, 16% (18/108) UM/EM and IM patients had endoxifen levels <15 nmol/L even when use of concomitant inhibitors was excluded. Those on moderate to strong CYP2D6 inhibitors had an 80% chance of having levels below 10 nmol/L. Importantly, if the baseline endoxifen level was <10 nmol/L, the patient had a 72% chance of substantial endoxifen increase with dose escalation, independent of genotype. In all situations, the measurement of endoxifen takes into account known factors such as genotype, concomitant inhibitor, and adherence/absorption, as well as unidentified factors and could ensure that potentially effective levels are maintained, or help the clinician to decide whether an alternative to tamoxifen, such as an aromatase inhibitor, should be recommended.

While 5/8 (63%) of poor metabolizers ("PM") reached 15 nmol/L target, none of them reached the 30 nmol/L target (See Table 2). The optimal level of endoxifen is still not well-defined in my opinon. For the purposes of the TADE dose-escalation study, this was their approach:

"At the time of commencement of the study, there were few data available to indicate a therapeutic level for endoxifen. Hence, for the purposes of evaluating the effect of dose escalation, an empirical approach was taken to define the study target of 30 nmol/L. Since then, two studies have been published that indicate that an endoxifen level of approximately 15 nmol/L may be a critical level for anticancer effect. The Women's Healthy Eating and Living (WHEL) Study of 1,370 patients with ER-positive early breast cancer reported that relapse rates were higher for patients in the lowest quintile of endoxifen levels corresponding to levels < 5.9 ng/mL (or 14.2 nmol/L). More recently, Saladores and colleagues, have shown in 306 premenopausal women on adjuvant tamoxifen that those with low (<14 nmol/L) compared with high (>35 nmol/L) endoxifen concentrations were associated with shorter distant relapse-free survival (19)."

This was a small study, and more work needs to be done: "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."

Those with the option of an aromatase inhibitor (AI) or ovarian suppression plus an AI can avoid these uncertainties.

BarredOwl

[But see, Hertz (2016) re poor metabolizers, http://theoncologist.alphamedpress.org/content/early/2016/05/25/theoncologist.2015-0480.abstract]

MO confirmed that my endoxifen is "probably within the therapeutic range." He is still not accepting this test was necessary, or even that the increased dose brought it up. Whatever.

On the estradiol, not so clear. He gave me a lot of information that conflicted with everything else we have seen. He wants me to stay on 40 mg of tamoxifen alone for 4 more months and check estradiol again then. If it's still high he thinks I should consider switching to AI/OS at that time. With my endoxifen level adequate I think it's probably OK to wait a little longer, but every day you wait you wonder if you are waiting too long. The only difference 4 months makes is that it may buy me enough time to get to menopause and help me avoid OS. Although I'm not feeling as confident as I used to that it is right around the corner. When do you accept that you're just delaying the inevitable?

I need more information about the estradiol and a second opinion.

On a plus side, I just heard from my miracle worker Onc nurse. Apparently Kaiser will now test for Endoxifen for only $30! Holy shit sign me up. : )

Hi solfeo:

Here are a couple of references (none very new) that I found regarding determining menopausal status and the challenges of same in patients receiving tamoxifen.

(1) Denduluri Reply (Journal of Clinical Oncology 25, no. 24 (August 2007) 3788-3789):

http://ascopubs.org/doi/full/10.1200/jco.2007.11.5998

(pdf version available under PDF tab)

(2) Vos (2012), "Menopausal status and adjuvant hormonal therapy for breast cancer patients: A practical guideline"

http://www.nnf-info.nl/uploads/publicaties/EMC/2012%20Menopausal%20status%20and%20adjuvant%20hormonal%20therapy%20for%20breast%20cancer.pdf

These two articles are behind paywalls. It may be worth purchasing Ortmann (2011):

(3) Ortmann (2011), "Which factors should be taken into account in perimenopausal women with early breast cancer who may become eligible for an aromatase inhibitor? Recommendations of an expert panel"

http://www.cancertreatmentreviews.com/article/S0305-7372(10)00104-0/abstract

"Such treatment [with AIs] should be initiated only after careful consideration of the patient's age, menstrual history and the effects of tamoxifen (which may make hormone levels an unreliable guide to ovarian function)."

(4) Clemons (2007), "Identifying menopause in breast cancer patients: considerations and implications"

http://link.springer.com/article/10.1007/s10549-006-9401-y

"Unfortunately, defining post-menopausal status can be fraught with difficulty, especially when cancer therapy is either recently completed (e.g. chemotherapy), or ongoing (e.g. tamoxifen and/or luteinising hormone-releasing hormone analogues)."

I guess you already know this from personal experience.

BarredOwl

Thanks BarredOwl. I'm trying to read everything. I did find a useful chart at one of the links you posted.

(2) Vos (2012), "Menopausal status and adjuvant hormonal therapy for breast cancer patients: A practical guideline"http://www.nnf-info.nl/uploads/publicaties/EMC/2012%20Menopausal%20status%20and%20adjuvant%20hormonal%20therapy%20for%20breast%20cancer.pdf

They recommend Tamoxifen without OS for someone in my situation, with monitoring of hormone levels. Everyone with estradiol above post-menopausal levels in the "Uncertain Menopausal Status" group is lumped together, and the recommendation doesn't change if estradiol level is elevated due to tamoxifen. There is no discussion specific to that at all, which means it wasn't even considered as a variable. And of course that's the complicating factor that could mean these recommendations may not be best for me, and the question I can't get clearly answered.

The more I read the more I understand, but it sinks in slowly in the form of scientific jargon. It would have been so much better to hear it simplified by my MO, but you can't discuss something he won't admit exists. He was very sarcastic and different from prior appointments. He also discounted my use of magnesium for the leg cramps. He said I have no way to know if the magnesium is working or not. Well, I certainly do know because I don't get the cramps when I take it and I do get them when I forget even for one day. I have duplicated these results many times. I liked him at first but now I can see we are just not complimentary personality types at all. I guess I should start shopping around for a new MO.

Ladies,

I need help understanding my Endoxifen level from the test I got. I know you guys are experts at this, so here goes. I need help convert ngs to nmols.. I think to see if I'm over the 30nmls/ml. (As a review... I'm an ultra rapid CYP2D6 metabolizer, been on Tamoxifen 7 months - not one side effect so I think it's a sugar pill.) By the way, Kaiser did this test for free for me, since it's in their list of approved tests and testing with a docs orders doesn't cost anything.

Component Results
Component
Reference lab test name
TC 91998
Specimen source
SERUM
Reference lab test results
FLEXITEST 2
Comment:
FLEXITEST 2
--------------TESTS-------------RESULTS--------UNITS--REF. RANGE---
Interpretation SEE NOTE
"The level of Endoxifen for this patient is above the lowest
quintile range. This suggests no additional increased risk for
cancer recurrence based on tamoxifen and metabolite levels [1]."
Endoxifen 26.00 ng/mL 6.01-43.19
Tamoxifen 77.00 ng/mL 12.54-233.07
N-Desmethyl Tamoxifen 136.00 ng/mL 2.59-373.96
4-Hydroxy Tamoxifen 3.00 ng/mL 0.24-5.05
N-Desmethyl-4'-Hydrox Tam 5.00 ng/mL 1.17-19.95
4'-Hydroxy Tamoxifen 3.00 ng/mL 0.40-6.33
The clinical interpretation of the quantitation of Tamoxifen and
its metabolites is not yet fully established. The assay shows
good agreement with published data from a clinical trial [1].
That study showed that women in the lowest quintile of values for
Endoxifen had a 26% greater chance of recurrence than those in
the upper 80% of values. Therefore we have used that quintile
threshold for interpretation of results for this assay.
Endoxifen quintiles:
20th Percentile 6.00
40th Percentile 12.29
60th Percentile 21.29
80th Percentile 27.18
100th Percentile 72.01
1. Tamoxifen metabolite concentrations, CYP2D6 genotype, and
breast cancer outcomes., Madlensky L, Natarajan L, Tchu S et.al.,
Clin PharmacolTher. 2011 May;89(5):718-25
For more information, please refer to
http://education.QuestDiagnostics.com/faq/FAQ146 This link is
being provided for informational/ educational purposes only.)

HOw do you interpret the statement that your value on Endoxifen is 26 and that you are above the lowest quintile? looks like you are in the 60th and 80th?? what am I missing

Lisey, I am 99% sure that you are golden in the 80th percentile. I would say 100% sure but I am not a doctor or mathematician. I am ~40th percentile and my doctor told me I am above the threshold. He didn't know the exact ng/ml to nmol/l number but he knew I was in the therapeutic range. I tried to estimate it myself online but had the same problem with the conversions that you did. I can't remember exactly how I did it, but I believe that when I plugged in most of what I reasoned might be similar substances I always got above 30. I rough calculated an average and between that, what my doctor said, and the study that broke the levels into quintiles, I concluded that mine was OK. Your level is over double mine.

If you really want to know you could try calling the lab.

I changed generic brands and my side effects have changed. I get more hot flashes, and my constipation has improved a lot. I think it might be affecting my heart more though, which I plan to discuss with my MO in February. I switched from Teva to Watkins brand, and the latter seems to dissolve a lot easier. The Teva pills were very hard and maybe didn't absorb as well. It would be interesting to know if my endoxifen has changed with the change of brands. Try Watkins if you want some hot flashes but there is really no reason to worry that it isn't working when your level is so high.