Tamoxifen, LHRH agonist, AI, oophorectomy??

[jane2638]

Dear all,

I started the "Tamoxifen anxiety" thread nearly two months ago, when I was starting chemo. Two months later, I'm still unsure how to proceed. There are a couple of articles out there that argue that her2neu, ER+/PR- cancers like mine are highly likely to be resistant to Tamoxifen. Since I am perimenopausal, my alternatives are 5 years on Zoladex, and an oophorectomy followed by an AI. My onc is recommending 2-3 years on Tamoxifen, followed by testing to see if I've gone through menopause, followed by an AI if I have. But I'm not sure I want to take the risk of 2-3 years on Tamoxifen if my cancer is resistant. The cancer center where I am does not do CP2DY6 (?) testing. I got some very useful responses from the previous thread so am hoping for the same this time. Any thoughts?

I still don't know how to do a signature, but my cancer was diagnosed in Oct. 2011, 0.7 cm, node negative, stage 1, grade 3, her2+, ER+/PR-. I am 49.

Thanks!
Jane

[tricia keegan]

Hi Jane,

In my own case I was highly triple pos so although a little younger than you at the time my onc and I agreed an ooph was the way to go for me and I still take arimidex and plan to continue. Is it possible to have the Tamox test done elsewhere to see if your body is metabolizing it if your cancer centre does'nt do it??
Maybe another opinion would help you, for me the ooph was the easiest op I ever had and I have no regrets so wish you luck in deciding.

[JennyB]

Hi Jane,

I am younger than you but have also ER+ PR - tumour, I recently got my period back and my onc and I have decided that I will have an ooph later in the year after 6 months on the Zoladex(ovaries shut down) injection just to make sure I handle the menapause ok! I am led to believe from other women it is a really easy op it is just the ramifications of it that worry me a little but nowhere near the ramifications of not having it!
I wish you well with your decision and whatever you decide will be right for you.
BTW the monthly injections are fine too and then you can take the AI instead of Tamoxifen this is what I am now doing.
Good luck
Jenny x

[Jackie07]

Hi Jane,

I had my hysterectomy/oophorectomy just before turning 51 because of the BRCA1-VUS component and family cancer history. I'd had chemopause since late 2003, so I did not experience much 'difference'. I do keep in mind that daily exercise is important because I've lost the many benefit of Estrogen.

To edit your treatment history in the Signature field - first go to User CP (on top of the Board-2nd from the left) From there, you will find 'Settings & Options' under 'Your Control Panel' Click on it and you will find 'Edit Signature' - that's where most of us save our treatment history.

I did a CYP2D6 test in 2010 because it was required by BCBS for me to continue taking Tamoxifen. There were some discussion on the Board at the time, and I believe the most recent research indicated that it's not as relavent as it was thought to be.

What is known (and the reason why my doctor put me back on Tamoxifen even after 5 years and after oophorectomy) is that continuing after 5 years results in a 4 % reduction in recurrence for Er+ BC suvivors.

[Jackie07]

Clin Pharmacol Ther. 2011 May;89(5):718-25. Epub 2011 Mar 23.
Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes.

Madlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, Nikoloff DM, Hillman G, Fontecha MR, Lawrence HJ, Parker BA, Wu AH, Pierce JP.
Source

Cancer Prevention and Control Program, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA.

Abstract

We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4-hydroxytamoxifen (4OH-tamoxifen), and N-desmethyltamoxifen (ND-tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)-positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study.

We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4-hydroxytamoxifen, and ND-tamoxifen.

For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55-1.00)).

The predictors of this higher-risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold.

[About endoxifen: http://www.sciencedaily.com/releases...1211141838.htm]

[Debbie L.]

Jane, my understanding of the issue (triple positive cancers being endocrine resistant) is that initially (many years ago, perhaps 10+), there seemed to be some indications that HER2+ cancer tended to be Tamoxifen resistant. But upon further examination, it was realized that it's more a tendency to pan-endocrine resistance. Early studies that seemed to show that AIs might be more effective than Tamoxifen for HER2+ cancers were apparently not reproducible. At least that's what I've read, although I do not have specific evidence to cite right now.

It's probable that anti-HER2 therapy (Herceptin, Lapatinib, probably others) increases the susceptibility to endocrine treatment but the details of how this happens, for how long it happens, etc, is not yet known.

Also, the most recent studies trying to link CYP2D6 metabolism to Tamoxifen efficacy were not able to find a link. Presentations at SABCS 2010 seemed to dramatically decrease interest in this line of inquiry (no link found between CYP2D6 variants and breast cancer recurrence for women taking Tamoxifen). Maybe the jury is still out on that one but I think the consensus among reliable oncologists is that CYP2D6 testing is not of any value.

Never hang your hat on just one (or even two) study reports. It's so tempting to think that we have clear answers. But alas, so often, we do not.

Since you are clearly one to ask the hard (but important) questions, it seems a logical next step for you to get more opinions about your specific situation, from higher up the food chain. Have you consulted with an NCI-designated Comprehensive Cancer Center about endocrine therapy options? http://cancercenters.cancer.gov/canc...ters-list.html It seems like this would be the perfect time for that, if you've not already done it.

Debbie Laxague

[Becky]

I also want to add that in the "olden" days, they would know that a cancer was hormone positive but they did not know that it was also Her2+. So even though the Tamoxifen may have been doing its job, there was nothing to supress the Her2 receptor so that would make the cancer recur. At least the Tamoxifen and Herceptin combo prevents that so in reality, you do not need to make decisions until the Herceptin therapy is over as the Tamoxifen will take care of the hormone receptors and the Herceptin will take care of the Her2 receptors.

I think (imho) that olden day tumors were not necessarily resistant to Tamoxifen, its just that there were 2 devils to deal with and nothing was done about the Her2 so that just took over.

[jane2638]

I really appreciate these thoughtful responses! I should stress that I am not triple positive but ER+/PR-, and one study found that the PR- part was predictive of Tamoxifen resistance. My onc is also quite skeptical of the CYP2D6 test.

Best,
Jane

[Becky]

I too am ER+ but PR neg. The problem with that, in the olden days, is that they did not know that if ER+ but PR neg, something else is going on with the tumor. ER does not get excited (to reproduce the cell) by itself. It likes another playmate (of which PR+ status does). So, if ER is + but PR is negative, who is ER playing with (or what's exciting it)? In our case, it is Her2 receptors. They will excite anything and they also will excite themselves. Hence, resistance due to Her2 positivity. If you were not also Her2 but only ER+, it would be troublesome.

There are also other theories. Some research has been done on the ERPR relationship and when they look at the tumor biochemically most ER+PR+ and ER-PR- tumors look the same but some ER+PR+ tumors actually look like ER-PR- tumors chemically/molecularly. Like they have too many receptors but perhaps they don't work. Vice versa is true too that an ER-PR- could behave as a hormone positive one. They did not take Her2 into account in this study. In this study ER+PR- could be either OR some were totally different (but only a few) and those are categorized as ER+PR-. What does this mean? Well, only if you get the tumor highly analyzed which is only available in a study do you really know and this may be why some tumors are resistant - they are actually behaving as a ER-PR- tumor and not a positive one. I really hope I am making some sense here.

There are also studies that show that blocking ER and Her2 simultaneously is the right way to go.

I will say that being ER+PR- myself, I am still here going on 8 years. I am still on Arimidex alone and did a year with Tamoxifen or Arimidex with Herceptin may have done something good or maybe just the chemo alone did it. I will never know for sure (and I had a node involved). It is a hard decision to make. Like you, I read the studies and got my ovaries removed to use Arimidex (I was 46 at the time). Since you are still on chemo, you have time to ponder, ask questions and come up with a plan you think is right for you.