Opinions welcome-- do I get a fourth opinion on hormonal treatments?

[saleboat]

Hi everyone,

(Warning, long post...)


I'd really appreciate some advice. I wonder if I don't fit into the description below, which is from another thread on this site:



"I am always concerned for the group of patients that come from the old school, that my doctor knows best."



I never know when to 'push' and when to accept well-reasoned advice. I'm currently treated at Sloan-Kettering, and one of the reasons that I went there (out of network) was that so I could have peace of mind and not double-check everything that was being recommended to me-- which is my nature. But the more I dig into PubMed, the more I recognize that I just don't have the training to evaluate the medical literature.



I am content that I received the best chemo treatment available to me (at the time-- TOPO testing wasn't on my radar screen) but I continue to wonder about my hormonal treatment. AIs seem to show the least advantage vs Tamox in women who are both ER+ and PR+ (I was 95%/90%). But then again, for Her2+ patients, there's some evidence that Tamox isn't as effective as an AI. Maybe this is because Her2+ women are less likely to be both ER+ and PR+? I don't know. It does seem to be that young women who go into chemopause do better overall. Then I think, maybe I should just have my PTEN tested, then I can stop worrying about the hormonal stuff. (THIS STUFF MAKES ME CRAZY!!!)



My Onc at Sloan thinks Tamox is best (unless I want to go into a trial, and I don't) and the two other Oncs I consulted agree with Tamox. But I wonder-- how many pre-meno/Her2+ women do they see? Is there some other 'expert' that I should go to-- like the guru up in the mountain cave-- for a final reading of the situation? I've also showed my Onc the study that was posted on this site about liver enzymes and ability to metabolize Tamox-- I've called Mayo to see if this is now protocol for young women, but haven't been able to find someone responsive. My Onc doesn't seem very interested. Most pre-meno women seem to have at least chemical shut-down of their ovaries (out of trial) and some even take an AI. SO-- do these women's Oncs know something that my Oncs don't?



I really want to get on with living my life, but I don't want to stick my head in the sand on these issues. (The other big one is whether or not to have a brain MRI...) I can't really talk to my husband about these issues, or at least I choose not to, because his father is about to start high-dose chemo and stem-cell transplant for relapsed lymphoma. We're really up to our eyeballs in this cancer crap (as is everyone here...)



SO-- thank you for taking the time to read this— I feel better just having written it.

Jen

[AlaskaAngel]

Hi Jen.

I will be interested to see what others have to say about your question. Take heart -- the problem isn't that YOU aren't educated enough, it is that the experts aren't sure either!

You and I both are HER2 positive, and strongly ER+ and strongly PR+. (Where we differ is that you have had Herceptin and I have not, and you are stage III and are in the high-risk younger age group and I am stage 1 and dx'd at 50, so take all that into account.)

I have not been able to find a satisfactory answer to the question either. I did 1 3/4 years of tamo before I was aware of any controversy about it, and then raised the question with my PCP in Alaska, who contacted my onc, a general medical onc, about it. I was told only that because I was now menopausal I could choose to switch to an AI if I wanted to; in other words, no one really had the answer. I switched over.

PR is something they haven't spent much time understanding. I keep my ear out for what Dr. Richard Elledge has to say about it.

I hope Lani or Joe might see something out there to help with this question.

A.A.

[R.B.]

I would guess you are sick of trying to understand all of this. I am a man and not a sufferer and am constantly saddened that even basic stats are not available. Why does the govt. or some charities put some money into setting up a central anonymous treatment data base to try and continualy monitor and provide useful treatment stats - I suppose because it is nobodies interest once a product is approved and out there in the market (an answer that is not wanted may come back with continual monitoring) - Human nature again.

I am sorry I cannot give you answers just pointers to a few posts already on this site which may help guide your thougths or arm you with questions for your advisers.

If you use the search engine above right search (above right on the pink bar) and put in Tamoxifen you will find quite a lot of posts raising issues as to tamoxifen and the alternatives. (including Cyclin D expression, and another marker which MAY be contra indicative)

If you check under Rupali and fertility there was a long post with lots of links relating to pre-menopausal issues.

To add even more questions there are some posts on chemo and ablation which make interesting reading. There have been questions as to how much of the effect of some chemos is due to the chemo and how much to ablation.

A further problem is the lack of stats (or difficulty in finding them at all for premenopausal patients let alone sub groups as to the efficacy of various treatment options.

If you have not done so it is worth looking at the side effects of the various options too - a search on google should help there. There are also links to various sites on this site that deal with side effects etc.

These must be impossibly difficult decisions, and at the end of the day only one you can make, taking into account all that is important to you.

RB

[saleboat]

Thank you A.A. and R.B.

You're right-- there are no easy answers.

Has anyone here met with Dr. Eric Winer? He did a paper on OA as a treatment for early stage breast cancer (I copied in the link below), and I think he's on the board of this site, so maybe he'll be able to resolve the conflicting evidence regarding Tamox and Her2.

http://www.jco.org/cgi/reprint/23/25/5869

Thanks again for your responses. I appreciate the support.

Jen

[Bev]

Hi Jen, stage 2, 47 now, premenopausal, now chemopausal. My fogged brain seems to have concluded that AI's are more effective by some percentage point and have less side effects(ie uterine cancer)if you are post menopausal.

The onc said I can switch on my one year anniversary of chemopause to AI' s from tamoxifen. I imagine they'll do blood work on estradiol levels to see if I'm in menopause. Onc says if you're not truly in menopause the AI's have zero efficacy. There are studies recruiting now to evaluate ovary ablation and AI v. the usual with tamoxifen. So it may be worthwhile to look into a study. Try "clinical care options" on google. BB

[R.B.]

Saleboat

If you have not had a look at the fats issue omega three and six I would urge you to do so.

A good book to fire interest is Smart Fats by M Scmidt. It is informative well written thought provoking and rings alarm bells.

Once you start reading in depth on the subject for me it is impossible not to want to howl that people should be aware. For me balancing omega three and six (which means effectively cutting out most oils) will be a bigger issue than smoking in twenty to thirty years.

RB

[saleboat]

Thank you RB for always keeping that issue front of mind for us. I've purchased one of the books that you suggested (by Barry Sears) and found it helpful.

Jen

[R.B.]

Smart Fats is MUCH MORE thought provoking AND particularly for women.

If you consider it in its wider context it has pertinece to brain mets.

I found a copy for $5 on the WEB - it is a definate MUST buy and read.

A trial I have posted on this site showed 70% differential in risk of tumours being invasive based on Omega three / DHA content in breast tissue taken at the same time (the third with highest dha content had 69 % lower risk than the bottom third).

For me for the sake of some dietary change figures like that are too big to ignore - why they have not done large scale tests is beyond me except a sneaking sad suspicion that reserachers dont get funds for telling drugs companies how not to make money......

If you have the funds you can get tested for your fat profile which I think would be really useful. The details of some labs are in the book.

Fats in breast tissue change in about three months it is reported. Gluteal tissue it is reported can take years

(I have no interest in the book and no idea who the author is I just have been searching for buying and reading books on the subject as well as lots off the net trials etc. I was particularly impressed by this book......)

Thanks for the response.

RB

[al from Canada]

This is all very good adice. My question, and it has been for years now, the medical tx standard is not to mix ER inhibitors with chemo. The more I read the less sense it makes. Why aren't we adding say, an AI with herceptin AND xeloda or one of the others? My question is limited to metastatic disease. Not doing so is making less sense all the time.


Regards,
Al

[panicked911]

Hi Jen:

Like you I am at Sloan and highly triple positive (er, pr, Her2) interestingly my onc immediately switched me to AI from Tomaxifen which the surgeon had started me on right after my lumpectomy on 10/5.

I know tomaxifen was working - I could feel it - breats were much less dense, ent down a full cup size etc within three weeks of starting it. Amazigly i felt great on it as well - all the achs and pains were gone and my energy level shot up.

Yet once I started herceptain and began lupron shots I was switched to Arimidex - bam - the aches and pains were pack, energy level plumeted . Asked to be switxched back to Tomaxfen and was told not now - neeed to stay withthe arimidex or another AI much less riskier.

So here I am now trudging along - steps are a nightmare b/c of the pai in the knee joints and if i sit to long in one place i "stiffen up" - despite all of this - still believe small price to pay .... I was diagnosised at stage 1 and am determined to remain there .....

[saleboat]

Hi--

Thanks for the message. If I'm not mistaken, you (Panicked911--Ann?) did not have chemo, right? I wonder if that fact makes Sloan's hormonal recommendation a bit different.

I tell you, my mind swirls on this one, because it seems as though the recommendations (in general) are all over the map.

Thanks again,
Jen

[AlaskaAngel]

I don't know about you, Saleboat, but the farther back in time one's diagnosis happened, the less real information there is to work with. Just to start with there is the question of whether one truly is strongly HER2 positive or not, since until recently they didn't know that IHC was less reliable than FISH. My path report is from early 2002 and even though it was done at a central testing facility there is no information about any characteristics other than ER, PR and HER2.

So then I think, well, maybe I should push to have my tumor block re-analyzed for PTEN and other characteristics. I think it just might even make sense to use Onco-Dx to get better information for us, even though we have already had treatment. But it seems like everyday there are more "characteristics" that are showing promise in terms of testing, and there is some logic in waiting because a tumor block isn't something to waste piece by piece.

It just may also be true that chemotherapy simply pushes recurrence out farther on the timeline rather than reducing the actual number of recurrences, and as HER2's we do know they don't have reliable long-term statistics specific to HER2's regardless of ER and PR.

My personal opinion is that with all the uncertainty involving treatment for patients who are HR+, at the very least the breast care guidelines should be revised to stop advising chemo over the alternative of ovarian ablation and hormonal therapy for Stage 1's until the new clinical trial is completed, especially given that 60% of Stage 1's will never even have recurrence with surgery alone as therapy, and that less than 20% of ALL stages who do receive chemotherapy will benefit from it.

AlaskaAngel

[AlaskaAngel]

Association between HER-2/neu and the progesterone receptor in oestrogen-dependent breast cancer is age-related.

Breast Cancer Res Treat. 2005; 91(1):81-7 (http://www.medscape.com/medline/publicationbrowser/123?pmid=15868434) (ISSN: 0167-6806)




Huang HJ; Neven P; Drijkoningen M; Paridaens R; Wildiers H; Van Limbergen E; Berteloot P; Amant F; Christiaens MR; Vergote I
Division of Gynaecologic Oncology in Department of Obstetrics and Gynaecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

In oestrogen receptor-positive (ER+) breast cancer, HER-2/neu and the progesterone receptor (PR) are inversely associated. This explains a lower response to anti-oestrogens if ER+ breast cancers are HER-2/neu positive. One randomized study however, showed that premenopausal women with an ER+ breast cancer respond to anti-oestrogens independent of HER-2/neu. We therefore hypothesized an age-related association between HER-2/neu and PR in ER+ breast cancers. Receptors for ER, PR and HER-2/neu were analysed by immunohistochemistry (IHC). A uni- and multivariate analyses was carried out to assess this relationship in 1104 women with an ER+ breast cancer. We observed an inverse association between HER-2/neu and PR only after age 45. There were 173 women of age45 years. In multivariate analysis, only tumour grade (p=0.005) but not PR status was associated with HER-2/neu in women age45 years group, both PR status (p=0.001) and tumour grade (p=0.001) were independently associated with HER-2/neu. In ER+ breast cancers from women age>45, PR was positive in 76.9% if HER-2/neu negative but in 53.4% if HER-2/neu positive (p<0.001) and the median quantitative PR levels are 150 and 75 respectively in HER-2/neu negative and HER-2/neu positive tumours (p=0.002). This age effect of HER-2/neu on the PR status was not seen in women age 45 years but not in women age...

(sorry, this was all I could get of the article...)



A.A.

[saleboat]

So, you really are an angel! Thank you for posting this.

If I understand it correctly, if one is over age 45, and Her2+/ER+, it is less likely that one would also be PR+. This may explain the fact that Tamox is less effective for Her2 patients than AIs-- AIs are most effective (vs. Tamox) in patients that are ER+ and PR- (if I'm remembering correctly). So if breast cancer typically affects older women, and older women are more likely to be ER+ and PR- when also Her2+, I can see why the data regarding Her2 and the efficacy of Tamox vs. AIs looks as it does, on the surface. So in my case, being that I'm highly ER+/PR+, I have less reason to believe that AIs would be superior.

Phew! That took a lot out of me. (Now I need some chocolate.)

Do you think I have it correct?

Thanks everyone for your posts to this question.

Jen

[AlaskaAngel]

Jen, they are just beginning to analyze this stuff. There is another article you might want to look at if you can access it.

Correlation of HER-2 Status With Estrogen and Progesterone Receptors and Histologic Features in 3,655 Invasive Breast Carcinomas



Priti Lal, MD; Lee K. Tan, MD; Beiyun Chen, MD, PhD

[BEVIE]

I have also wondered if hormonal therapy delays recurrence OR is it possible that ER/PR+ cancers don't come back as often as the ER/PR- tumors? I was DX 5 1/2 yrs. ago and took tamoxifen for 8 months the side effects were horrible I then took Arimidex for 3 1/2 yrs. It has been 10 months since I stopped and I think so far so good, I am going for a PET scan next month just to be sure that the spine problems are from arthritis and not mets I also have a strange lump deep in the arm pit that the surgeon is going to check out. So I wonder how long after hormone treatment ends do the ER+ cancer's return (if/and when) ?

[saleboat]

Hi Bevie-- Wow, over 5 years, yippie! I'm sure the fears never go away.

I don't know that much about the question that you've asked-- I doubt that there's much data. I would make the uneducated guess that you're pretty far out of the woods given how quickly Her2+ bc tends to recur vs. Her2-.

I'm also including a link which was in the 'supplementary materials' part of the Herceptin study that was published last year in the New England Journal of Medicine. It breaks down the study results by hormonal status, as well as number of nodes. It doesn't have the history that would be applicable in your case, but it might be interesting to others who are following this thread (the interesting tables are on the later pages).

http://content.nejm.org/cgi/data/353/16/1673/DC1/1

Good luck with your tests.

Jen

[AlaskaAngel]

If those who are strongly ER+ and strongly PR+ do best of all (?) .... will we really ever know whether they actually need ANY additional therapy, since anyone who is HR+ has gotten tamoxifen or an AI for ages now.....? ... and now if they are strongly HER2 positive they are getting traztuzumab as well....

AlaskaAngel

[Becky]

For statistics on hormone driven cancer (general info - not necessarily combined with Her 2 status), the first 2 years are the greatest chance of recurrence (much like hormone negative cancer's rate of recurrence) however, hormone driven cancer also has the same (higher) rate of recurrence between 7-9 years out as well. Hormone negative cancer does not have this repeat blip. I do feel this is from the supressive effect of tamoxifen (since this is older data and AI's have not been in use that long). Preliminary data collaberates that AIs will reduce all rates of recurrence in hormone driven cancer.


For the record, I am (of course) Her 2+ but ER + and PR-. I got my ovaries removed in order to use Arimidex since Jen is correct that AIs do work better for ER+ and PR- (than tamoxifen in this pathology group). Since I was still premenopausal, this was just one of the reasons I had my ovaries removed as Herceptin with an AI made the most sense for me (ovarian cancer also runs in the family so I had multiple reasons).

Kind regards

Becky

[AlaskaAngel]

Hi Becky.

I know the numbers show that ER+, PR- 's do better with an AI. But if ER+PR+'s do better with tamoxifen is it really because of the tamoxifen, or because they never needed anything in the first place? Especially if they are strongly ER+ and strongly PR+?

A.A.

[BEVIE]

Has anyone seen studies that show the percentage where early stage HER2, ER/PR positive have recurrences? I haven't come across very many women that like myself are triple positive early stage that have had recurrences, Could that be because we were not likely to recurred in the first place or is it because of hormonal treatment and being as they really just started testing HER2 about the time I was DX 5 or 6 yrs ago the tamoxifen, arimidex, etc. still in our systems delaying recurrence? I know that they retest new tumors or mets to see if they are HER2 but I wonder how many of these were triple positive?

[Becky]

I am not sure that tamoxifen works better than an AI in strongly positive ER/PR cancer. It has been proven that AIs work better. It just that when you compare studies of:

1. tamoxifen in ER/PR+ vs ER+/PR- - the women who are positive for both do better. However, the probability that the women who are PR- are probably also Her2+ or positive for another Her pathway is most likely high. Therefore, do they do worse because of tamoxifen resistance (really just cross signaling) or because if they were just ER+, it doesn't work as well. My opinion on this is that if a ER+/PR- woman took tamoxifen and she was only that and not Her2+ or Her1+ or anything else, tamoxifen should work just as well as it does in a ER/PR + woman.

2. comparing AIs in the same population as above. There was only one study that compared Arimidex to ER/PR+ women to ER+/PR- women. It would make sense that Arimidex might be more beneficial in a woman that is only ER+ as AIs disrupt estrogen manufacture in the adrenals and fat cells. Currently, there is no known disruption of progesterone.

That said, it is also well known that being PR+ only (and ER-) is not enough for a true cancer to occur. Known literature states that PR will cause a cell to grow (in size and to maturity) but it cannot, by itself, cause it to reproduce uncontrollably. Therefore, one has to assume that a woman who is PR+ but ER- has another driver for uncontrolled cell division. For some of us who may be PR+ but ER-, we know that driver is Her2. For others, it is Her 1 or 3 or other things not measured or discovered yet.

Also, being + for PR is supposed to be a good progostic factor but I really don't think enough research has been done on the PR to truly determine its related function to breast cancer and the determination of its early loss when the Her pathway is involved (as many at least maintain higher ER+ levels than PR+ levels in Her2 disease).

I think anyone who is highly ER/PR needs to be on an antihormonal regardless of Her pathway status. What needs to be assessed is which ones are the best ones to be on and more work needs to be done in this area for premenopausal women who are also Her2+ (especially if they are not highly positive and have lost the positive nature of the progesterone receptor).

Sorry this is so longggg.

Kind regards

Becky

[AlaskaAngel]

(I wonder, since Pak1 affects ER, I wonder if it affects PR and/or HER2 at all, or if PR and/or HER2 affect Pak1.):

Increased protein expression may explain tamoxifen resistance
Reuters Health
Posting Date: May 16, 2006

Last Updated: 2006-05-16 16:00:20 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Pak1 (p21-activated kinase-1), a protein that activates estrogen receptors (ER) and localizes in the nucleus of breast tumors, appears to induce tamoxifen resistance in ER-positive cancers, investigators report.

Many patients with ER-positive tumors either do not respond to tamoxifen treatment or develop resistance to the agent. Pak1 is known to phosphorylate proteins, including ER-alpha. Studies have suggested that Pak1 phosphorylation of ER-alpha activates the receptor and modulates its response to estrogens and antiestrogens.

Dr. Goran Landberg, from Lund University in Malmo, Sweden, and associates evaluated Pak1 and ER-alpha expression in 403 primary breast tumors from premenopausal patients who had been randomly assigned to tamoxifen or no tamoxifen following surgery and radiation therapy. They report their findings in the Journal of the National Cancer Institute for May 17.

The researchers assessed Pak1 levels in ER-alpha-positive tumor tissue by immunohistochemical staining with a polyclonal antibody against Pak1. Their results showed that 19% of tumors had high cytoplasmic Pak1 expression, and 13% were positive for nuclear Pak1 staining.

The investigators observed that lobular breast cancers were more likely to be Pak1 negative (78%) compared with ductal (50%) or medullary (30%) breast cancers. Pak1 staining was also associated with higher histologic grade and increased tumor cell proliferation, indicating a more malignant phenotype.

Dr. Landberg's group also found that among patients who were treated with tamoxifen, tumors with the lowest expression of Pak1 had longer recurrence-free survival than patients not treated with tamoxifen.

In contrast, among patients with high expression of Pak1, tamoxifen had no effect on recurrence-free survival.

In the untreated control group, which included both ER-negative and ER-positive tumors, Pak1 staining intensity in the cytoplasm of the nucleus was not associated with outcome.

"Our results raise the possibility that premenopausal breast cancer patients whose tumors overexpress Pak1 most likely will not respond to tamoxifen and may need to be offered alternative endocrine treatment," Dr. Landberg's team maintains.

They also suggest that "therapies that target Pak1 expression or activity may therefore represent a strategy to increase the endocrine treatment response in breast cancer."

In a related editorial, Dr. V. Craig Jordan, from Fox Chase Cancer Center in Philadelphia, further discusses the ramifications of the phosphorylation network in cancer cells.

He believes that knocking out Pak1 activity would not overcome tamoxifen resistance, but that "a combined attack at multiple upstream targets would be more likely to succeed."

"Regardless," he concludes, "the clinical correlations reported by Holm et al. indicate that packing tumor cell nuclei with Pak can perturb tamoxifen's action. The tumor, once 'Paked up,' has no alternative but to grow."

J Natl Cancer Inst 2006;98:657-659,671-680.

[Becky]

I like that last sentence - "perturb tamoxifen" - very interesting (and probably incorrect) choice of words.


In June we will do the endocrinology chat. After ASCO, and then I will be more ready to do a good job of it.

I am off the board for the next week or so. Going to Dallas to see my niece graduate (taking my mom along). Just figured I'd mention it so it doesn't seem rude that I'm not answering anyone.

Becky

[AlaskaAngel]

I like that idea! Thanks, Becky for all your efforts to help everyone. Hope the trip is a good one for you.

AlaskaAngel