Bazedoxifene stops breast cancer resistant growth
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http://petitions.moveon.org/sign/assess-the-efficacy-of?source=c.url&r_by=8507318
Bazedoxifene is approved for the treatment of post-menopausal osteoporosis in Europe. However, Pfizer currently has no plans to either evaluate this drug in breast cancer treatment or to license it as an osteoporosis treatment in the USA. If you have a vested interest in seeing that Bazedoxifene is evaluated for use in breast cancer, I encourage you to sign the petition urging Pfizer to move forward to assess the efficacy of Bazedoxifene in treating late stage ER positive breast cancers.
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From what I gather Pfizer has done nothing so far to have this drug BZA investigated. They offer Duavee a combination of BZA (
Bazedoxifene) and another drug, CEE. This Duavee drug increases estrogen! My Stage 4 wife is taking estrogen BLOCKERS. Maybe someone could explain.
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Mike - sadly, IMO Pfizer is after the HUGE market $$$$$$$$$$$$$$$$$$$ for Duavee to post-menopause women. We had just submitted the BZA petition to Pfizer last year when a few weeks later they announced their new drug Duavee. I felt such a huge disappointment that treating hormonal breast cancer is such a low priority to Pfizer.
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From what I gather Pfizer is just going to do nothing about BZA. Faslodex, a SERD (selective estrogen receptor degrader), is the only FDA approved one out their. BZA would be a pill whereas Faslodex is a once a month shot into the muscle (ouch) and doesn't work that well. No pharmaceutical is interested in SERD research. My wife is post-menopause so Tamoxifen won't do for her. What does she do when her aromsen doesn't work any more? I never wanted to believe those conspiracy nut types about "big pharma." Well this whole BZA business with Pfizers proves them right.
WIFE's Cancer:
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I know nothing about the petition since I arrived in 2014.
In terms of Duavee (Conjugated Estrogens / Bazedoxifene) increasing estrogen, perhaps it's part of a new generation of drugs that deal with hormone therapy resistance. Let me try to explain.
We all know that tumor resistance can occur in a subset who are hormone receptor (HR+) positive. After numerous years on Tamoxifen, Fulvestrant & AI's, these therapies can fail when some of the cells adapt and thrive, despite being deprived of estrogen.
Here's where things get weird about this estrogen / resistance issue.
In 2001, researchers said that low doses of estrogen could actually kill tumor cells in post menopausal women, but the exact mechanism that caused this was unknown.
In 2005, Dr. V. Craig Jordan, the "father of Tamoxifen", and his research team elucidated on the mechanism (pathway) that caused this "estrogen induced cell death".
Breast cancer cells once fueled by estrogen could be killed by the same hormone, which raised the possibility that "estrogen therapy" after "estrogen deprivation" may overcome the cells' eventual resistance to hormone therapy.
Sounds totally absurd, right?
In 2011 Dr. Jordan released more research "Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A "New" Biology of Estrogen-induced Apoptosis" which further explains this estrogen paradox.To me, perhaps that is part of the purpose of Pfizer's drug, Duavee, since you said it increases estrogen. Honestly, I haven't heard of the drug until this post today.
Dr. Jordan was just hired by The University of Texas, MD Anderson Cancer Center (he starts Oct 2014). The press release announced his focus was on the new biology of estrogen-induced cell death.
Honestly, I've only been around here a few months and just scratched the surface of breast cancer knowledge. Sorry if I'm rehashing old news everyone already knows.
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My impressions are that there is WONDERFUL research done previously and now by some of our best universities and teaching hospitals. The proof is in all the published journals and articles we read. My speculation is these potential treatments will NOT go any further than the journals who published them - UNLESS some Pharma or Biotech companies shows interest to fund and pursue clinical trials. They are in control IMO. Obviously they decide what drug discovery pipeline they will invest in that will result in the largest pay off to their shareholders. The bottom line here is big business in control and making a bleep load of money and it doesn't matter how it is made......
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when I read threads like this it helps me understand the conspiracy theorists. It is immoral to allow corporate interest determine research on life saving options. I know this is an incredibly naive statement, but at its root it is fact. I was part of the petition. We did quite well and got about 500 signatures. I'm afraid sex after 50 is a bigger market. This is really depressing me today.
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LtotheK - thanks to your help writing this petition - we actually got over 7,000 signatures if I recall !!! I got confirmation of receipt by sending multiple certified mail copies to various higher ups to ensure it wasn't "misplaced". You said it well - sex is the target market .....
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cp418 there were 7000??? Rock Star! Someone else please pick up the baton and continue the advocacy.
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My research on Bazedoxifene (BZA) shows that given alone, it has different effects on different tissues. In bone, it acts as an estrogen. In breast, it modulates and even destroys estrogen receptors (like Faslodex), even in cases of Tamoxifen resistance. It targets ER alpha, in particular, and sits on canniboid receptors like CB2, down-regulating mutant cell expression.
Paired with CEE, BZA apparently retains these properties. Thus, as above studies cite, CEE's benefits are retained in some tissues, with risks in others reduced/eliminated. Promising as this sounds, it strikes me as more of a (less risky) HRT for some BC patients than a preventive agent per se. New studies of CEE/BZA with breast safety as sole end point are needed. In the meantime, I also would like to see BZA approved and would sign and help circulate a petition.My research on estrogen therapy for Tamoxifen resistance shows this: long-term estrogen deprivation causes estrogen receptors to lose ability to use estrogen (or feed ER+ mutant cells). Introducing estrogen to this environment causes apoptosis instead of proliferation. In science there are few true paradoxes. Whether estrogen proliferates or kills existing tumors has much to do with timing.I see no current studies on this either, and can only speculate that it's because demonstrating this end point sells no patent-able (profitable) substance. -Same old story. No one to pay for vetting a therapy which could benefit so many, but whose sales would benefit no one entity. Perhaps instead of a petition, we need to pool our pennies in a new paradigm: crowdsourcing. Here's one example.
Peace and health to all. -
This was posted on what appears to be a pharma-rep forum that I just stumbled onto.
"Several of the bet known kols are totally behind duavee. An HRT that does not cause breast cancer, vaginal bleeding. Studies being released now showing similar efficacy as premarin 0.45mg/mpa with half the drop out rate due to adverse events. There were less drop out due to adverse event than placebo group, holy crap! Since premarin cannot be genericized and pfizer wisely declined to attempt to separately get bazo mono approved this time around, they could have as the fda reviewed both packages - there will be no generic version forever and ever."
Am I right to assume that this is all about keeping BZA from going generic and cutting into their profits?
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I am interested in finding a European clinic/endocrinologist who will prescribe BZA to patients with osteoporosis and history of breast cancer. My onc has said I may soon be taken off Femara (stage 3) because my osteoporosis has continued to worsen over the 4 yrs. I have taken it. My bones hurt like those of an elderly woman. I would go to Europe for a 2nd opinion and opportunity to try BZA.
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Yes Kay. You found the estrogen deprivation / resistance research too!
I've found more research and will eventually post a new thread, since it warrants discussion.
I don't want to hijack this BZA thread and take it off topic.
In terms of Pfizer's drug, Duavee (BZA / conjugated estrogens), I know it's used to treat hot flashes due to menopause and the prevention of postmenopausal bone loss.
Haven't they started trials to see if it's useful for breast cancer too? -
John, I haven't yet come across info on trials with that end point. If anyone has, I would love to see it also. Meantime, in vitro and in vivo animal studies with this end point are very promising.
(edited to add):
Though estrogen has been villified by the WHI, if one looks more closely, it is the progestin used in the CEE/MPA arm that caused breast drama. The CEE only arm fared well breast-wise. Older (and in later studies) younger women alike. I reiterate: Conjugated equine estrogens administered alone showed reduced breast risk in these studies. In the SERC BZA/CEE, what little proliferative power CEE has on occult tumors is mitigated and unlike Tamox, eliminated, as target receptors are not only down-regulated but degraded entirely. A fair question: In light of these facts, is it even necessary to lobby or go across the pond for BZA mono?Do we have the drug we're looking for in our hands at this moment?
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Great question, alpineartist! Maybe I should be going across the pond for BZA/CEE. I probably should wait for human BC trial results though. The extra estrogen may be of no help if there are no receptors.
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Heidi, BZA/CEE is now available on this side of the pond. -FDA approved in October last year and on doctors' shelves earlier in 2014.
And you are right, according to my study, about the missing receptors. Not only would it be of no help in making cancer worse, it could be the silver bullet in finishing it off.
As mentioned in the studies in previous posts (above), it appears that lost receptors are the very mechanism by which estrogen switches its action from proliferative (cancer feeder) to apoptotic (cancer killer). And BZA apparently even kills cancer cells that have become resistant to Tamoxifen and AIs. And remember, it not only shuts them off, it eliminates them, making the estrogen component in the drug itself less likely (or even unable) to stimulate cancer growth. Promising as all this sounds, I sympathize with your desire to see true trials before acting on this.
In the meantime, deep within a previously posted study, I found something most interesting, possibly the reason that CEE showed protective rather than proliferative in these studies. In vitro, CEE was absolutely unable to stimulate xenografts that Estradiol easily stimulated, even in very high doses.CEE exerted no effects on tumor weight compared with CEE/BZA or vehicle. To potentially explain the lack of CEE stimulation, we postulated that the CEE dose was not sufficient to stimulate tumor growth and repeated the study using 10, 30, and 50 mg/kg CEE rather than 3 mg/kg. Neither the wild-type MCF-7 xenografts (Fig. 5D) nor the hypersensitive LTED (19) xenografts (Fig. 5E) grew in response to 10, 30, or 50 mg/kg CEE. To confirm absorption and deconjugation of these high doses of CEE, we measured uterine weight and found substantial stimulation over vehicle control levels (data not shown). These findings demonstrated an unexpected lack of the ability of CEE to stimulate xenograft growth, even at high doses.
Here, we have CEE not stimulating. Add BZA and certain components of cancerous changes are reduced to far below "normal." -Fascinating. Cancer reduction even in the presence of estrogen!
In the bioidentical camp, CEE has been criticized, mainly because it is derived from horse urine and its molecular makeup is not enough like that of human-made estrogen. But the more I read on this substance (a combination of many estrogens) the more it is confirmed that one should stay clear of camps, and trust only the studies. A cursory "google" will bring up other studies where CEE was much less proliferative to begin with than more human-like estrogen molecules such as E2. It appears the ideal partner in a drug such as this, where the need is to help menopausal-aged women with estrogen loss symptoms while at the same time not raising risk (or even lowering it) in uterine and breast tissues. Perhaps lowering it significantly.
In my opinion, we can watch this drug for trials with cautious optimism, and may be hearing very encouraging things about it. I'm setting a "Google alert" for BZA/CEE breast cancer trials."Health and peace to all. Have a wonderful Holiday weekend,
Kay
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Alpineartist you really know your subject though it's a bit hard for me to understand some of it. My wife is POST menopausal and I guess BZA/CEE doesn't apply to her. Her estrogen blocker is still working but I fear the day it won't. Keep us informed.
Wife's Cancer stats:
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Hi - for those who are following up on BZA from the petition we submitted last year. (petition now closed after our submission) There has been no further contact/update with Pfizer.
https://community.breastcancer.org/forum/73/topic/808467?page=3#post_3771143
https://community.breastcancer.org/forum/73/topic/814241?page=1#post_3772683
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Mike, it appears that bazedoxifene (without CEE) may be useful in the inhibition of both Tamoxifen (used most often in pre-menopausal cases) and Aromatase Inhibitor (used in post-menopausal cases)-resistant tumors alike. One study quotes:
"Breast cancer remains the most commonly diagnosed cancer among women and the leading cause of cancer mortality in women worldwide. While targeted therapies such as tamoxifen and aromatase inhibitors are effective in treating estrogen receptor (ER) positive tumors, de novo and acquired resistance remain an impediment to durable clinical responses. However, ERα remains a therapeutic target in breast cancers that are resistant to both first and second line endocrine interventions. Evaluation of the molecular pharmacology of clinically relevant ER modulators revealed that the third generation selective estrogen receptor modulator (SERM) bazedoxifene had a unique mechanism of action and inhibited the growth of both tamoxifen sensitive and resistant ERα positive breast cancer xenografts. These findings provide strong support for the clinical evaluation of bazedoxifene in breast cancer patients who relapse while undergoing treatment with tamoxifen and/or an aromatase inhibitor."
This is BZA only. Major studies have yet to be done on the BZA/CEE combo, or SERC.
But again, numerous studies (one, quoted below) seem to show that the other part of the combo (CEE) has an unexpected ability to inhibit breast tumors after a certain interval of estrogen deprivation:"The paradoxical reduction of breast cancer incidence in women receiving estrogen alone is consistent with a model that this hormone causes apoptosis in women deprived of estrogen long term as a result of the cessation of estrogen production after the menopause. Understanding of the kinetics of occult tumors suggests that breast cancer "prevention" with anti-estrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation."
I believe that this means that Tamox and AIs treat existing tumors effectively, but new (de novo) tumors threaten several years later because they may never have really prevented by these agents. New growth may not be a resistance to the drugs at all, but a misunderstanding of how these drugs actually work (and when they do not). If this is so, hope remains, or so it seems. -Same study, new quote:
"Our in vivo data suggest that the combination of a SERM, bazedoxifene (BZA), with conjugated equine estrogen (CEE) acts to block maturation of the mammary gland in oophorectomized, immature mice. This hormonal combination is defined by the generic term, tissue selective estrogen complex or TSEC. Xenograft studies with the BZA/CEE combination show that it blocks the growth of occult, hormone dependent tumors in nude mice. These pre-clinical data suggest that the BZA/CEE TSEC combination may prevent the growth of occult breast tumors in women."
Here we see true prevention of new tumors. Could it be that the preventive tool that Tamox/AIs may not be, BZA/CEE is? -Even with the estrogen in it?
Could it be that after Tamox/AIs have cleared the body of existing tumors, a sufficient time of estrogen deprivation can be identified, after which BZA/CEE can be introduced to begin the work of prevention by targeting those sleeping estrogen receptors for destruction? Intriguing questions, for sure. -Would that we had more answers.
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Alpineartist,
Not to confuse the issue, but as a side question (thinking outside the box)...
Would that possibly mean also then that it could work for TN patients (if TN perhaps happens to be a form of estrogen-resistance)?
My apologies for interrupting if my question is off track.
A.A.
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Good question, AA, which seems to me to be on topic, and certainly is outside the box.
If TN is a form of estrogen resistance (like antiestrogen-resistance), logic would be that this drug might be effective. I've not studied this so I cannot offer much, sorry. But I did find an interesting article or two on the actions of the 2nd gen SERM, Raloxifene (Evista) on TNBC in animal studies. Quote:
"These results indicated that raloxifene reduced cell proliferation, mediated through a mechanism involving the inhibition of proliferative mediators NF-κB and p38 rather than acting as an ER antagonist."
In this study, estrogen receptor seemed an insignificant factor in triple negative tumor cell death.
Which prompts another question. Do we understand the actions of SERMs as much as we say we do? There is evidence that they act on estrogen receptors. But do they act in additional ways which we have yet to discover?
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Thanks for feedback, alpineartist. One hesitation I have about it is related to your question. Would one succeed in controlling estrogen receptor bc only to find oneself dealing with ER- disease? I'm not trying to derail any efforts made thus far with so much dedication. I'm just thinking outside the box for anyone who might undersatnd it better than I do.
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The concerns of unintended effects of degrading ER's had occurred to me too, AA. I wish I had info which could shed light on our questions but right now I've been unable to come up with much. Will update if I do. Great short week!
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See this link. It sounds like something similar to BZA which Pfizer doesn't want to do tests on. Maybe someone else will market a similar medicine.
http://medicalxpress.com/news/2014-10-osteoporosis...
Wife: Stage 4 at dx with mets to spine, Dec 2012. Taxol then A-C. Clean for now but painful neuropathy in hands and wrists.
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Has anyone considered starting a petition on Change.org? They post a wide variety of petitions and seem to get pretty substantial distribution and results.
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A petition was created last year some time and got quit a few participants. I don't have all the details about it though. Their is a separate thread about it. Maybe do a search on this site for the thread. The petition went no where with Pfizer, they ignored it.
Mike, worried husband of Stage 4 BC wife.
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Mike, first off, let me say how sorry I am that your wife is dealing with this. I can't imagine how rough it is for the two of you but I do know that I HATE the fact that I brought this into my husband's life and I imagine your wife does, too.
Thanks for your response regarding the petition. I'm sorry it's been done and got nowhere with Pfizer. Maybe it would be wise to either try again (just keep buzzing around and bugging them) OR try to open a follow up dialogue with Pfizer to try to learn why there's no follow up on this as well as educating them a bit on why it's so important.
I'm not saying you should find time to do this - but if someone out there is itching for a project, this might be worthwhile.
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This is the response we received from Pfizer posted in an earlier link.
From Pfizer - Vice President Corporate Affairs - Shreya Jani
"Thank you for taking the time to contact Pfizer. We share your interest and concern in ensuring that our investigational agend bazedoxifene reaches those patients who may benefit. As you may be aware, bazedoxifene is currently used for the treatment of hot flashes associated with menopause and the prevention of post-menopausal osteoporosis.
We are very interested in the results of Dr. McDonnell's per-clinical study of bazedoxifene in breast cancer cells and we are committed to understanding its mechanism of action. At the moment, Pfizer scientists are working closely with Dr. McDonnell and others to better understand the findings from this study and conduct appropriate preclinical experiments needed to help us make decisions on the next steps. Pfizer is committed to the discovery, investigation and development of innovative treatment options to improve the outlook for cancer patients worldwide.
Again, thank you for reaching out to express your concern on behalf of patients with breast cancer. I am happy to follow up as we learn more."
She would be your contact person to find out what they are currently doing with BZA.......
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Thanks so much, CP.
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