Duavee Shows Promise in Breast Cancer Study

Relief and Protection–can Duavee do both?

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An abstract was presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago about the medication Duavee and its potential promise in preventing breast cancer for those at high risk. The trial is appropriately called the PROMISE study.

Duavee is the trade name for conjugated equine estrogens (CEE, a.k.a. Premarin) and bazedoxifene (BZA), and it is effective therapy for symptoms of menopause and prevention of osteoporosis. Bazedoxifene is a selective estrogen receptor modulator or SERM, meaning in some tissues it acts like an estrogen and in others it acts like an anti-estrogen. When it comes to the endometrium (lining of the uterus), bazedoxifene is an anti-estrogen, and can be used in place of progesterone or a progestin to protect the uterine lining from cancer due to estrogen in MHT. Regarding breast tissue, bazedoxifene is also an anti-estrogen. Bazedoxifene acts like estrogen on bone, and is beneficial in preventing osteoporosis. You can read in more depth about Duavee in this post. The combination of Premarin and bazedoxifene is also called a tissue-selective estrogen complex or TSEC.

In addition to the uniqueness of bazedoxifene as an anti-estrogen on breast tissue, Premarin was shown in the WHI to reduce both the incidence of breast cancer as well as breast cancer mortality. This is quite likely due to Premarin’s unique biochemistry; it has at least 50 different estrogens, and while some act just like estrogens, others are SERMS.

Important side note/rant: when you hear people bashing the WHI they interestingly are usually only bashing the Premarin and progestin arm that showed an increase risk of breast cancer, they seem to have no issues accepting the data from the Premarin only arm that showed a reduced risk of breast cancer. But if you think the investigators screwed up royally in one arm of the study, why would you trust their data on the other arm? The answer to me can only be that some people cherry pick the data, which is not a good sign of someone dedicated to an evidence-based practice.

Because of how bazedoxifene has performed on breast tissue in animal studies and Premarin’s unique effect on the breast, many of us favor it for patients at high-risk for breast cancer. There is a pilot study of Duavee for relief of vasomotor symptoms that evaluated 28 women in the late menopause transition who were at high risk for breast cancer based on one or more of the following: family history of breast cancer < age 60, increased mammographic density, prior biopsy showing proliferative breast disease, multiple prior biopsies, or a an elevated risk for breast cancer based on screening score. Women had breast biopsies at baseline and at 6 months. As expected, there was an improvement in menopause symptoms with Duavee, but there there was also favorable impact on a fibroglandular volume in the breast and a reduction in Ki-67, a protein marker that reflects how fast cells are growing and dividing, among those with higher values of Ki-67 at baseline. Higher values indicate more growth and division and are a marker for risk of progression of DCIS to invasive cancer, so a reduction in those values is a positive marker.

Admittedly, using Duavee for women at higher risk for breast cancer is not supported by robust literature as the WHI didn’t include women at high risk for breast cancer and we have very little data on how Duavee performs over the long-term for women at increased risk of breast cancer or those with DCIS (ductal carcinoma in situ), but when we don’t have solid science we have to make do with what we have and just be honest about the limitations. It makes sense that Duavee would be the safest option for MHT breast cancer wise, but without more data, it’s more of a solid hypothesis that needs more data.

This new study takes us a little further down the road to understanding how Duavee might be an option for women at higher risk for breast cancer. Three caveats. (1) This is an abstract so the data has not yet been peer-reviewed. (2) It’s a very short term study that can’t tell us much except that it’s worth looking into further, which is how science is supposed to work. We find something promising, and so we take the next step. (3) I wasn’t at the meeting so didn’t hear the presentation, so the results are coming from what was reported online. I was also able to get some information about the study from it’s registration.

The PROMISE study is a clinical trial for women with estrogen-receptor positive ductal carcinoma in situ (DCIS), which is sometimes called stage 0 breast cancer. DCIS is common and makes up about 20-25% of new breast cancers. In the United States about 60,000 women are diagnosed with it each year. If left untreated, anywhere from 25-60% of women with DCIS will develop invasive breast cancer. Treatment for DCIS can be a lumpectomy (often with radiation) or mastectomy. Some women will also be offered endocrine therapy (tamoxifen or an aromatase inhibitor). There is even research looking at close observation for people with low risk DCIS. There are a lot of nuances regarding treatment for DCIS, and there is ongoing research into tailoring options, and I am not the person to explain any of those nuances.

The investigators wanted to learn what effect Duavee would have on breast tissue for women with DCIS who are postmenopausal? This is a phase 2 trial that randomized women to take either Duavee or placebo for 4 weeks between the time they received their DCIS results from biopsy and their subsequent surgery. Since the women all had biopsies and were all going to have surgery, this gave the investigators an ideal opportunity to see the impact of Duavee on breast tissue, including markers like Ki-67, that indicate the potential to transform into invasive cancer. They also wanted to know how Duavee affected symptoms of menopause and quality of life. Their formal primary and secondary objectives are as follows:

Primary Objective:

To determine if CE/BZA reduces proliferation as measured by Ki-67 protein expression

Secondary Objectives:

1. To determine if CE/BZA modulates expression of ERα, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2).

2. To determine if CE/BZA modulates a previously validated set of epithelial markers of progression.

3. To determine if TSECs will restore expression of the stromal marker CD36 and repress pro-tumorigenic ECM proteins and soluble factors.

4. To determine if a short intervention with CE/BZA results in any difference in Quality of Life (QOL) as it relates to menopausal symptoms in postmenopausal women with DCIS.

5. To determine if a short intervention with CE/BZA has a favorable side effect profile compared with other endocrine therapy interventions using the validated Breast Cancer Prevention Trial Eight Symptom Scale (BESS) questionnaire.

A total of 141 patients were enrolled, and 117 completed the study. Here are the results from the meeting abstract:

The mean absolute change in Ki-67 was -5.62 (SD=10.2; p=0.003) in the CE/BZA arm and -1.07 (SD=10.8; p=0.6) in the placebo arm, with a greater reduction in CE/BZA arm (p=0.016).

And the conclusions:

In this prospective randomized clinical trial, CE/BZA significantly reduced epithelial proliferation in ER+ DCIS with no impact on quality of life compared to placebo. These results support consideration that CE/BZA is a safe option to manage menopausal symptoms for women concerned about their risk of developing breast cancer, and provide supportive evidence that CE/BZA may reduce the risk of developing invasive breast cancer.

Here is the report on the trial results from Northwestern, the lead investigator's institution:

Kulkarni’s team found the drug significantly reduced cell growth in breast tissue, a key marker of cancer progression. Unlike other breast cancer prevention drugs, which can cause difficult side effects and lead patients to decline taking medication, Duavee was well tolerated by trial participants.

“What excites me most is that a medication designed to help women feel better during menopause may also reduce their risk of invasive breast cancer,” said Dr. Kulkarni, who also is a Northwestern Medicine breast surgeon and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Kulkarni said the women most likely to benefit from Duavee are those at elevated risk for breast cancer due to a personal history of high-risk lesions such as atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS) or prior DCIS — and who are also experiencing menopausal symptoms. These women are typically advised against standard hormone therapies, leaving them with few menopausal treatment options. Duavee may offer a promising alternative.

While a larger study with longer term follow up is needed before Duavee can be considered for breast cancer prevention, Kulkarni said she was encouraged by the early results, particularly because the drug is already FDA approved and widely available.

Back to the Caveats and the Promise

This study is only 4 weeks, and while there was a significant decrease in one marker of cell proliferation, it obviously doesn’t inform us about long term outcome, so we can’t conclude anything except this is an exciting finding and definitely warrants more research. Assuming everything holds up when the subsequent paper is peer-reviewed, this work supports the small body of literature that we have about the safety of Duavee for those at high risk for breast cancer.

Hopefully, this provides Pfizer, who makes Duavee, with enough data to move forward with some larger clinical trials for DCIS. Looking forward to what the science may bring.

References

Fabian, Carol J., et al. "Effect of bazedoxifene and conjugated estrogen (Duavee) on breast cancer risk biomarkers in high-risk women: a pilot study." Cancer Prevention Research 12.10 (2019): 711-720.

van Seijen M, Lips EH, Thompson AM, Nik-Zainal S, Futreal A, Hwang ES, Verschuur E, Lane J, Jonkers J, Rea DW, Wesseling J; PRECISION team. Ductal carcinoma in situ: to treat or not to treat, that is the question. Br J Cancer. 2019 Aug;121(4):285-292. doi: 10.1038/s41416-019-0478-6. Epub 2019 Jul 9. PMID: 31285590; PMCID: PMC6697179.

Wang, J., Li, B., Luo, M. et al. Progression from ductal carcinoma in situ to invasive breast cancer: molecular features and clinical significance. Sig Transduct Target Ther 9, 83 (2024). https://doi.org/10.1038/s41392-024-01779-3

Yue W, Wang J, Atkins KA, Bottalico L, Mesaros C, Blair IA, Santen RJ. Effect of a tissue selective estrogen complex on breast cancer: Role of unique properties of conjugated equine estrogen. Int J Cancer. 2018 Sep 1;143(5):1259-1268. doi: 10.1002/ijc.31401. Epub 2018 Apr 16. PMID: 29577272; PMCID: PMC6377943.

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