Tamoxifen and HER2: are they compatable?

[al from Canada]

Good morning to all,

I would like to get some feedback on everyone's thoughts and on the research about taking Tamoxifen while on Herceptin. My understanding is that due to cross talk between the two receptors, that is HER2 and estrogen, the estrogen receptor, being over-ridden by the HER2 receptors, will actually build up a resistance to Tamoxifen. I've read some research that suggests taking Herceptin and tamoxifen together may actually create a condition that promotes tumor growth. I've also read a few reports that seemed to conflict with this view.
What seems to work very well is the concurrent use of Herceptin and aromatase inhibitors such as Arimidex. In fact, postmenopausal women who are HER2+ and estrogen positive, and not taking both drugs are actually been under treated.

I wonder how many women are taking the Herceptin and Tamoxifen together, and are they aware of some of this research?

The other thing I wonder about our cases like my wife's, horseshoes taking Herceptin and Xeloda and his ER+. Xeloda has a half life of 45 minutes and it then it changes into 5-FU which also has a half life of 45 minutes therefore theoretically, all the Xeloda should be out of your system within one day. As you only take 10 - 14 doses of Xeloda in one cycle, does it make sense to take, say arimidex, on those ten to fifteen off days. I asked our onc about this and his comment was that he wasn't aware of anyone trying it therefore he won't prescribe it. I think this is a very important question and I wounder if we could get a medical professional to comment?

Hope evryone has a great weekend,
Al

[Becky]

I can give you my opinion on this.

Firstly - besides the benefit of good scientific studies, I do not believe that Tamoxifen and Herceptin work well together. If you close your eyes and imagine the surface of the cell loaded with Her2 and ER receptors and now the Tamoxifen and Herceptin have to align with all these receptors. Both Tamoxifen and Herceptin are large molecules. In my mind, there HAS to be what is biochemically called - steric inhibition. Steric inhibition is like trying to get thru an overcrowded room to the buffet table. You just might not make it through to get there. Therefore, I feel that many of the receptors are free and not covered due to others being covered by both Tamoxifen and Herceptin. The uncovered receptors can still do their job and function. Especially the Her2 which is only producing proteins versus the ER which needs the estrogen (another large molecule) to attach to it to work. Therefore, the Her2 rules (and in my opinion, is more dangerous anyway).

However, AI's just reduce estrogen to a non existant or minimal level but do nothing to the receptors (there is just no estrogen to bond with them). Therefore, the surface is free and clear for the Herceptin to bond only with the Her2 receptors and there is "room enough" on the cellular surface for as many as possible receptors to be covered.

I was confident enough on this to get my ovaries removed to do the arimidex/herceptin blend. If, as the years go by, I am wrong, it is my mistake.

Secondly, on your question on Linda taking an AI - I cannot comment and this is why... Arimidex takes 2-3 weeks to fully begin to work. Likewise, it also takes 7-10 days for the body to begin to NOT inhibit aromatase so... you cannot just stop for a couple of days because it is still working. BUTTTT - she is also getting Herceptin (besides Xeloda) and that is like Her 2 tamoxifen which is also slowing down the cellular growth (which is why your onco doesn't want to give the Arimidex). You should discuss this at more length with Linda's onco. Maybe you will come up with logic to see if Arimidex will help.

At my cancer center I have a chemo friend with inflammatory bc who is Her2. She gets gemzar, herceptin, zometa, and avastin and she is on femara (an AI) and is doing fantastic.

We can discuss further if you wish.

Warmest regards

Becky

[Becky]

Al

I guess what I was trying to say with the Arimidex is that if you are receiving chemo, oncos don't like to give the hormonals because they slow down the cell growth. But it you are getting herceptin, that is also slowing down the cell growth. So... what is your doctor's logic since Linda (and everyone else) is getting chemo and herceptin? I think it just might be that for basic non Her2 cancer, the hormonal is given after chemo and radiation so that the chemo/rads kill the fast growing cells. Doctors have been taught (or conditioned) that that is the way to give the hormonals. But like I mentioned before, Herceptin is the "Her2 hormonal (not literally)".

Since I am not on chemo, the Arimidex/Herceptin mix makes good logic for an onco.

I would ask a lot of questions and be as ready as possible to respond to the possible answers the onco gives.

My chemo friend was first going to the Mayo clinic (although she lives in NJ) and they gave her the blend she is on (except they started with Xeloda which she could not tolerate (the hand and foot syndrome)). So they were giving Arimidex with chemo to her. Here in NJ, they did everything the same except Avastin (because the first phase trials were not published - as soon as there was some proof that it worked somewhat for bc, they added that back in). I think they threw everything at her because her cancer was everywhere (and a lot of it).

Maybe others on this board can comment on whether they are taking an AI with chemo and herceptin (although it doesn't seem like there are a lot of us Her2 that are also hormone positive as well).

Becky

[Lani]

The following is the second of two articles on this topic by a group at Yale:


1: Breast Cancer Res Treat. 2005 Aug;92(3):251-263.
Related Articles, Links
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In vitro and in vivo Effects of Combination of Trastuzumab (Herceptin) and Tamoxifen in Breast Cancer.

Wang CX, Koay DC, Edwards A, Lu Z, Mor G, Ocal IT, Digiovanna MP.

Departments of Internal Medicine (Section of Medical Oncology) and Pharmacology, Obstetrics and Gynecology, Pathology, and the Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, Room NSB288, 06510, New Haven, CT, USA, michael.digiovanna@yale.edu.

Extensive interactions between estrogen receptor alpha (ERalpha) and HER2 signaling pathways have been described. Using BT-474 human breast cancer cells, we have previously shown that the combination of tamoxifen (TAM) and Herceptin results in strong synergistic growth inhibition, enhancement of G(0)-G(1) cell cycle accumulation, inhibition of HER2 activity and a cytostatic effect without cell death. To further examine the underlying mechanism of synergy, we investigated the effect of this drug combination on ERalpha function and growth factor downstream signaling. TAM caused a small increase in ERalpha levels while Herceptin had no effect, and both drugs caused an increase in the level of Ser118-phosphorylated ERalpha. However, both TAM and Herceptin individually inhibited ERalpha transcriptional activity, although the combination did not have a greater effect than either single agent. Herceptin inhibited MAPK and Akt activity, while TAM had no effect on these either as a single agent or when added to Herceptin. Using a BALB/c athymic BT-474 in vivo xenograft model, the drug combination (Herceptin 0.3 mg/kg i.p. twice weekly, TAM 1.0 mg/mouse i.p. three times per week) showed a greater inhibition of tumor growth compared to either single agent. Tumor extracts and fixed sections were examined at the end of the treatment period for treatment-specific alterations: we noted a paradoxical proliferation-inducing effect of TAM that was reversed by the addition of Herceptin. Our results indicate that combined targeting of both peptide growth factor receptors and ERalpha represents a promising breast cancer treatment strategy.

PMID: 16155796 [PubMed - as supplied by publisher]


As I said, this is the second of two articles from Yale on the topic. Yet the whole story is not known. What appears to being more efficacious and intuitively so, because of its different mechanism of action is Faslodex aka fulvestrant, which works by degrading the estrogen receptor rather than blocking it or starving it of ligand. This is not specific to breast cancer cells, however, as it degrades estrogen receptors on all cells, just as AIs steal the ligand from estrogen receptors on all cells. (Tamoxifen, in contrast, has different agonist or antagonist effects on different estrogen-dependent cells in different parts of the body).It has been shown to be at least as effective as Arimidex and theoretically it may be more so, as breast cancer cells make their own estrogen via pathways involving three different enzymes, only one of which is aromatase--the others being a sulfatase and a 17hydroxysteroiddehydrogenase.

The following are articles discussing the use of Faslodex (which is usually given as part of a “compassionate use” program and which is, by the way, given as an injection) and Herceptin:


1: Eur J Cancer. 2005 Oct 14; [Epub ahead of print]
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Fulvestrant ('Faslodex') in pre-treated patients with advanced breast cancer: A single-centre experience.

Steger GG, Bartsch R, Wenzel C, Pluschnig U, Hussian D, Sevelda U, Locker GJ, Gnant MF, Jakesz R, Zielinski CC.

Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, 18-20 wahringer Gurtel, A-1090 Vienna, Austria.

Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects. This report describes the experience of a single centre including 126 postmenopausal women with advanced breast cancer (ABC) in a fulvestrant Compassionate Use Programme. All patients had previously received endocrine treatment for early or ABC. Patients received fulvestrant as first- (n=7), second- (n=51), third- (n=50) or fourth-line endocrine therapy (n=18) for ABC (median duration of treatment: 4 months [range 3-27(+) months], follow-up: 13 months [range 1-38(+) months]). Twelve patients had partial responses (PR) and 43 patients experienced stable disease (SD) 6 months (objective response rate: 9.5%; clinical benefit [CB] rate: 43.6%). Ten of 12 patients with a PR had HER2-negative tumours, and 9/12 had ER-positive and progesterone receptor (PgR)-positive disease (two patients had unknown HER2 status and one had unknown ER and PgR status). Nine of the 18 patients with HER2-positive tumours experienced CB with fulvestrant. Although CB rates were similar when fulvestrant was given as first- to fourth-line endocrine treatment, the proportion of those experiencing CB who had a PR appeared to decrease when fulvestrant was used later in the sequence. Fulvestrant was well tolerated; six patients experienced adverse events (all grade I/II). These data demonstrate that fulvestrant is an effective and well-tolerated therapy for patients with ABC progressing on prior therapies.

PMID: 16230005 [PubMed - as supplied by publisher]





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Review: 0*









1: Cancer Treat Rev. 2005;31 Suppl 2:S17-25. Epub 2005 Sep 29.
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Case studies of fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer.

Abram P, Maass N, Rea D, Simon SD, Steger GG.

Belvoir Park Hospital, Hospital Road, Belfast, Northern Ireland, UK.

Fulvestrant is a new oestrogen receptor (ER) antagonist that is licensed for the treatment of postmenopausal women with advanced breast cancer progressing following antioestrogen treatment and may also be effective in those progressing after non-steroidal aromatase inhibitors. The use of fulvestrant in a Compassionate Use Programme (CUP) in a 'real-life' setting has permitted its activity and tolerability profile in patients with different disease characteristics to be observed. Here, we present five case reports of fulvestrant use in postmenopausal women with advanced breast cancer progressing after prior endocrine therapy. Clinical experience from the CUP supports the published clinical trial data and suggests that fulvestrant is a valuable new treatment for postmenopausal women with advanced breast cancer, including those with visceral metastases and human epidermal growth factor receptor 2-positive disease.

PMID: 16199128 [PubMed - in process]


1: Cancer Treat Rev. 2005;31 Suppl 2:S10-6. Epub 2005 Sep 28.
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Fulvestrant ('Faslodex'): Clinical experience from the Compassionate Use Programme.

Steger GG, Gips M, Simon SD, Lluch A, Vinholes J, Kaufman B, Wardley A, Mauriac L.

Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, 18-20 Wahringer Gurtel, A-1090 Vienna, Austria.

Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects that is licensed in the USA, Brazil, Europe and elsewhere for the treatment of advanced breast cancer (ABC) in postmenopausal women following progression on other endocrine agents. This report consolidates clinical experience from the 'Faslodex' Compassionate Use Programme, including a total of 339 patients treated at eight cancer centres. Patients received fulvestrant as first- (n=22), second- (n=125), third- (n=105), fourth- (n=58), fifth- (n=22) or sixth-line (n=5) hormonal treatment for ABC, with two patients receiving fulvestrant after more than six other endocrine therapies. Objective response was achieved by 40 patients and stable disease lasting 6 months by 92 patients, giving overall clinical benefit (CB) in 132/339 patients (39%). The CB rate decreased as fulvestrant was used later in the sequence of endocrine treatments, from 46% (10/22) with first-line fulvestrant to 27% (6/22) with fifth-line fulvestrant. Increased benefit was found in patients with tumours expressing both ER and progesterone receptor (PgR) compared with other combinations, although good activity was reported in patients expressing either ER or PgR as well as in tumours expressing human epidermal growth factor receptor 2. Fulvestrant was well tolerated; adverse events were noted in 18/339 patients (5%). These findings concur with data from the clinical-trial setting and further support the assertion that greater benefit is derived when fulvestrant is used early in the treatment sequence.

PMID: 16198057 [PubMed - in process]
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1: Cancer Treat Rev. 2005;31 Suppl 2:S26-33. Epub 2005 Sep 28.
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The future of fulvestrant ('Faslodex').

Howell A.

CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.

Changes in clinical practice regarding favoured first-line and adjuvant treatments for postmenopausal women with advanced breast cancer (ABC) mean that it is becoming increasingly important to identify agents that are effective following aromatase inhibitor (AI) failure as well as tamoxifen failure. Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects that binds, blocks and degrades the ER. Fulvestrant is at least as effective as anastrozole following tamoxifen failure and also shows activity after progression on AIs. Its very good tolerability profile and novel mode of action, might offer potential for the use of fulvestrant in combination regimens, and there is also scope for investigating the use of loading and higher dose regimens in an attempt to further enhance efficacy. Here, the rationale and evidence for the efficacy of fulvestrant following AI failure and its combination with AIs and novel agents such as gefitinib and trastuzumab will be reviewed. The ongoing clinical development programme for fulvestrant will more fully the role of this valuable new agent in the treatment of postmenopausal ABC.

PMID: 16198056 [PubMed - in process]



1: Cancer Treat Rev. 2005;31 Suppl 2:S3-9. Epub 2005 Sep 28.
Related Articles, Links
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Clinical development of fulvestrant ('Faslodex').

Howell A, Abram P.

CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.

This paper outlines the development of fulvestrant, the first in a new class of antioestrogen agents with no agonist effects, to be used for the treatment of hormone receptor-positive advanced breast cancer in postmenopausal women. The role of the oestrogen receptor in breast cancer growth and development and the evolution of pharmacological strategies to manipulate it are also discussed. Preclinical and clinical evidence for the efficacy of fulvestrant are also reviewed, along with the tolerability profile of this agent in relation to other endocrine therapies. Further research will define the role of this exciting new agent in the endocrine treatment of breast cancer.

PMID: 16198055 [PubMed - in process]

As you can see, these are hot off the press.

This is a much less helpful post than the one (two) I originally wrote, both of which were “eaten” when trying to switch between programs to retrieve the articles and copy and paste them. I do not know how to save my post well and this has discouraged me from posting on previous occasions, in fact this morning before answering your post I had sworn never to post again!

Good luck!

Hope this helps,
Lani

[Lani]

Becky:
It used to be thought that only 10% of her2 positive patients were hormone receptor positive. Recent work by S.Jeffreys at Stanford and others now estimate it to be 45-55%. The degree of hormone sensitivity may be less than the %hormone sensitivity, as there appears to be a smaller QUANTITY of hormone receptors (work of M.Pegram of UCLA). So this quandary may be affecting more patients than you think. Also, in Europe until recently few hormone positive patients (or hormone negative patients, for that matter) were tested for her2.
Al:
I am not certain if your real question had to do with combining antiestrogens with herceptin or combining chemo with antiestrogens (and herceptin).Again, hoped this helped!

[Unregistered]

Al,

I am triple positive and finding that this does seems to be unusual. Although I was premeno before chemo, blood work indicated I will remain postmeno and will go on an AI after rads. All that I have read indicated this is the best scenario, because there is some concern about tamoxifin with herceptin. I think Gina had a post with links back some time ago, which was totally over my head at the time, however, it made more sense to me reading it recently. I will try to find it for you.

Sassy

[Scott]

Becky,

Did you find any data about the Tamoxifen blocking Herceptin from attaching the receptor or vice versa? I have been fighting with this senario as my wife is currently on this combination. The yale data that was posted is a few years old and I haven't seen any thing new. It has become sort of a dead issue in the research arena concerning Tam or A.I. combined with Herceptin.

The possibility that steric hindrance between the Tamoxifen and Herceptin molecules may interfere with one or the other at the cell surface is a good point that hadn't cross my mind. One more thing to consider though is that if the Tamoxifen crowds out the Herceptin from binding its receptor, then in theory the epidermal growth factor would also be crowded out and not reach the Her2 receptor at the surface. This obviously isn't the case as we know the Her2 receptor is active when women are treated with Tamoxifen and sometimes quickly develop resistance to the drug. I think there are so many Her2 receptors at the surface that there is allows going to be room for Herceptin to attach somewhere. I would like to see people continue to share what they know about this topic if they have more to add.

Scott