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Topic: Bazedoxifene---why only one trial?

Forum: Clinical Trials, Research News, Podcasts, and Study Results —

Share your research articles, interpretations and experiences here. Let us know how these studies affect you and your decisions.

Posted on: Jan 16, 2016 12:53PM

Fallleaves wrote:

For those of you who haven't heard of Bazedoxifene (BZA), it is a selective estrogen receptor degrader (SERD), approved in Europe to treat osteoporosis, and approved in the U.S. with the addition of conjugated estrogens (CE's) for treatment of menopausal symptoms (Duavee). There are several threads on the discussion boards about it . There was a lot of excitement in 2013, when researchers at Duke University figured out it not only blocks estrogen receptors, but degrades them, and that it inhibited the growth of treatment resistant BC in vitro and in animal models. http://www.medicalnewstoday.com/articles/262039.ph...

So it looked like something that worked even better than Tamoxifen (and without the increased risk of endometrial cancer), and might be better than aromatase inhibitors (because it wouldn't cause loss of bone density). On the other hand, could destroying estrogen receptors create a kind of natural selection for estrogen negative cancer cells, which are typically more aggressive?

In 2013 Duavee was approved by the FDA.

Then last year Pfizer (which owns BZA), and the Dana Farber Cancer Institute started recruiting for a study of Palbociclib and BZA for Stage IV estrogen receptor positive patients.

https://clinicaltrials.gov/ct2/show/NCT02448771?te...


Am I alone in thinking one research study, with another drug, in heavily pretreated patients, is not enough?? Why not test it by itself? Why not create a trial to track women who are taking Duavee to see if they have an increased or reduced risk of breast cancer? Why aren't they researching the hell out of this? I know clinical trials are expensive, but in contrast (I made this point on another thread) there are about a dozen clinial trials being done on the use of methylnaltrexone for opioid related constipation. How is there so much money for that, and not for this?

How will the Moonshot Initiative deal with drugs like this? Could the government sponsor it's own tests of BZA on BC, with Pfizer's cooperation? And will they?

I'd love to hear everyone's thoughts on this.




Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/19/2013 Lumpectomy: Right
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Jan 16, 2016 01:17PM - edited Jan 16, 2016 01:19PM by leggo

My two cents.

Why only one trial? - Pfizer is pervasively corrupt. Easier to hide/manipulate the results of only one trial.

Why with another drug? - Pfizer owns both drugs. Why only gouge for one drug, when you can gouge for two.

Why so many constipation trials? - It's the one market Pfizer can't corner and it's probably the topic of many board room discussions as to how to dominate that condition....do whatever it takes.

How will the Moonshot Initiative affect it? - It won't.

Would Pfizer co-operate? - Absolutely not.

"Once more into the fray... Into the last good fight I'll ever know... Live and die on this day... Live and die on this day." - The Grey
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Jan 16, 2016 02:18PM Fallleaves wrote:

Leggo, I fear you are right. I'm also starting to wonder if the Moonshot Initiative isn't going to push research dollars into one direction, immunotherapy, while ignoring extremely promising drugs sitting right in front of us.

Dx 7/5/2013, IDC, 2cm, Stage I, Grade 2, 0/2 nodes, ER+/PR+, HER2- Surgery 8/19/2013 Lumpectomy: Right
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Jan 16, 2016 03:02PM leggo wrote:

The whole immunotherapy thing scares me for several reasons and like you mentioned, if that's what direction all of this is going to take, I'm disappointed...well, disappointed may not be the right word, but I am concerned.

"Once more into the fray... Into the last good fight I'll ever know... Live and die on this day... Live and die on this day." - The Grey
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Jan 16, 2016 03:53PM - edited Jul 27, 2020 11:00AM by TectonicShift

This Post was deleted by TectonicShift.
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Jan 16, 2016 06:07PM JohnSmith wrote:

I totally forgot about BZA. I still wonder how this drug ties into Dr. Craig Jordan's (Father of Tamoxifen) research on "estrogen induced cell death", if at all.

Are there any postmenopausal breast cancer patients taking BZA for osteoporosis?
Since the European Union approved BZA in 2009, it would be interesting to know if anecdotal evidence exists - supporting progression free survival (PFS) data - among the population of breast cancer patients taking it for osteoporosis.

I think Fallleaves did a good job to encapsulate some of the thoughts discussed in older BZA threads and raised some interesting questions.

At the 2015 SABCS last month, a Dana Farber group discussed BZA. Here's the Abstract.
P3-05-09 "Exploring bazedoxifene and palbociclib as potential therapeutic strategies for overcoming ESR1-mediated endocrine resistance"
Nguyen M, Buchwalter G, Luo F, Garraway L, Brown M, Jeselsohn R.
Dana Farber Cancer Institute, Boston, MA.
INTRODUCTION: Despite effective endocrine treatments, endocrine resistance remains a major clinical challenge. We and other groups have recently detected ligand-binding domain ESR1 mutations in metastatic estrogen receptor positive (ER+) breast cancers. Our preclinical studies showed that these mutations confer constitutive activity and relative resistance to tamoxifen and fulvestrant. In this study we sought to investigate therapeutic strategies to overcome resistance rendered by the ESR1 mutations. Since our previous studies showed relative resistance to tamoxifen or fulvestrant, we hypothesized that bazedoxifene, a high affinity third generation SERM/SERD could overcome resistance driven by the ER mutant resistance. Additionally, we hypothesized that inhibiting cyclin D1, a key ER transcriptional target gene and cell cycle regulator, is a second potential therapeutic strategy to circumvent resistance rendered by mutant ER. Therefore in this study we tested the effects of bazedoxifene, palbciclib and their combination on cell proliferation in the presence and absence of the ESR1 mutations.

METHODS: For this study we established doxycycline inducible MCF7 cell lines expressing the ER-LBD mutations (Y537S, Y537N and D538G) and WT-ER as control. Cell proliferation response to bazedoxifene, tamoxifen, fulvestrant, palbociclib and the bazedoxifene-palbociclib combination was evaluated.

RESULTS: Cells harboring mutant ER were relatively resistant to tamoxifen and fulvestrant, as expected, and remained sensitive to single agent bazedoxifene and palbociclib. The combination of bazedoxifene and palbociclib was found to be superior to the single agents and exhibits synergistic activity.

CONCLUSION: The combination of bazedoxifene and palbociclib inhibits mutant ER cell growth and other cell models of endocrine resistance and is a potential therapeutic combination.
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Ironically, the same time this BZA presentation was being made, Dr. Jordan (Father of Tamoxifen) and his research team were down the hall, presenting data on the paradoxical effect of Estrogen in breast cancer, found here, (i.e. Breast cancer cells once fueled by estrogen can be killed by the same hormone, raising the possibility that "estrogen therapy" after "estrogen deprivation" may overcome the cells' eventual resistance to hormone therapy.)
In that Abstract, they summarized by saying: "We conclude that, for the first time, we have observed the binding of a ligand to a receptor that changes conformation against time and evolves from an antagonist to an agonist conformation to trigger apoptosis. These observations have current relevance to the decryption of the protective effects of estrogen alone therapy against breast cancer incidence in the Women's Health Initiative (WHI) trial".
That large postmenopausal trial (WHI) launched in the early 1990's and is discussed at length here.

Wife was Age 45 at Dx 4/2014. BMX Surgery 6/2014 revealed: ILC, Stage 2 (Multifocal ILC, largest lesion 2.2 cm), Grade 2, ER+/PR+ (95%), HER2-, Ki-67 5-10%, Oncotype 11; Variant in the ATM gene Dx 4/8/2014, ILC, Left, 2cm, Stage IIA, Grade 2, 0/3 nodes, ER+/PR+, HER2- (IHC) Surgery 6/26/2014 Mastectomy; Reconstruction (left); Reconstruction (right)
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Jan 16, 2016 06:11PM ChiSandy wrote:

Why limit the trial to stage IV?

Diagnosed at 64 on routine annual mammo, no lump. OncotypeDX 16. I cried because I had no shoes...but then again, I won’t get blisters.... Dx 9/9/2015, IDC, Right, 1cm, Stage IA, Grade 2, 0/4 nodes, ER+/PR+, HER2- (IHC) Surgery 9/23/2015 Lumpectomy: Right Radiation Therapy 11/2/2015 3DCRT: Breast Hormonal Therapy 12/31/2015 Femara (letrozole)
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Jan 18, 2016 10:04AM Heidihill wrote:

Duavee is BZA with estrogen. I don't think any studies have been done with Duavee and bc but it would be interesting to see a trial of the drug used after estrogen deprivation, particularly after an AI.

Intermittent estrogenic stimulation is the premise of the SOLE trial. The deprivaton part is done with letrozole.



Dx 8/2007, IDC, Left, 2cm, Stage IV, metastasized to bone, Grade 2, 2/19 nodes, mets, ER+/PR+, HER2- (FISH)
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Oct 25, 2020 01:36PM izzy16 wrote:

heidi and others,

i posted this in another forum on bco but thought i'd post it here too...

there are currently at least 2 NCI trials in the US w Duavee (CEE/BZA)... one 11 center US trial w post menopausal DCIS patients undergoing surgery

https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2016-00066&r=1

and one trial in Kansas for peri and post-menopausal patients studying CEE/BZA for reducing benign breast tissue proliferation in women at moderate risk for breast cancer

https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2016-00902&r=1


I hope these trials help women going forward.

best,

izzy
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Oct 25, 2020 02:57PM exbrnxgrl wrote:

Izzy,

This thread has been inactive for 4 1/2 years. If you don’t get a response you may want to consider starting a new one on the subject. Take care

Bilateral mx 9/7/11 with one step ns reconstruction. As of 11/21/11, 2cm met to upper left femur Dx 7/8/2011, IDC, Left, 4cm, Grade 1, 1/15 nodes, mets, ER+/PR+, HER2- Surgery 9/7/2011 Lymph node removal: Left; Mastectomy: Left, Right; Reconstruction (left); Reconstruction (right) Dx 11/2011, IDC, Left, 4cm, Stage IV, Grade 1, 1/15 nodes, mets, ER+/PR+, HER2- Hormonal Therapy 11/21/2011 Arimidex (anastrozole) Radiation Therapy 11/21/2011 Bone Hormonal Therapy 6/19/2014 Femara (letrozole) Hormonal Therapy Aromasin (exemestane)

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