Therapeutic Estradiol for Breast Cancer

Not currently recruiting at 15 trial locations

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Must not be taking: Chemotherapy, Immunotherapy, Hormonal, others

Disqualifiers: Uncontrolled hypertension, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether estradiol, a form of estrogen, can help treat ER beta positive, triple negative breast cancer. This cancer lacks certain hormone receptors but may have an excess of a receptor called ER beta. The study aims to determine if estradiol can slow or shrink these tumors. Women with this type of breast cancer, who have experienced its spread to nearby tissues or beyond and have undergone up to three chemotherapy regimens, might be suitable candidates. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires participants to stop using strong inducers or inhibitors of CYP3A4 before registration. Additionally, no chemotherapy, immunotherapy, biologic therapy, hormonal therapy, monoclonal antibodies, or targeted therapies are allowed within 14 days prior to registration.

Is there any evidence suggesting that estradiol is likely to be safe for humans?

Research has shown that estradiol, a type of estrogen, is likely safe for treating breast cancer. Studies have found that vaginal estrogen therapy does not increase the risk of early death from breast cancer. This is encouraging for breast cancer survivors, suggesting estradiol could be a safe option.

Other studies indicate that local estrogen therapy does not raise the chance of cancer returning or increase death rates in people taking tamoxifen, a common breast cancer medication. This provides more evidence that estradiol is well-tolerated.

While these studies focus on vaginal or local estrogen, they offer useful insights into the safety of estradiol. This is especially important for those considering joining a trial where estradiol is used. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for breast cancer involve chemotherapy, targeted therapy, or hormone therapy that lowers estrogen levels. But estradiol works differently, as it is a form of estrogen itself. Researchers are excited because estradiol aims to exploit a unique vulnerability in some breast cancers that become resistant to standard treatments. This approach could offer a new pathway for patients whose cancers no longer respond to conventional therapies.

What evidence suggests that estradiol might be an effective treatment for breast cancer?

Research has shown that estradiol, a type of estrogen, might slow the growth of certain breast cancer cells. In lab studies, cancer cells with high levels of a specific hormone receptor called ER beta grew more slowly when exposed to estrogen. This finding is significant because some triple-negative breast cancers, which lack other hormone receptors, still have high ER beta levels. Estradiol, which participants in this trial will receive, could potentially shrink these tumors by interacting with ER beta. Although studies on vaginal estrogen use showed no increased risk of breast cancer recurrence, the exact effect of estradiol on this specific cancer type remains under investigation. ^{1 2 3 5 6}

Who Is on the Research Team?

Matthew P. Goetz

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for postmenopausal women with a specific breast cancer type that's spread within the body or to nearby areas. Participants must have ER beta positive, triple negative tumors and be in good general health (ECOG status 0 or 1). They should not have had more than three prior chemo treatments for metastatic breast cancer and must agree to undergo necessary biopsies.

Inclusion Criteria

My cancer's size or presence can be tracked with scans.

Your hemoglobin level should be at least 8 grams per deciliter within 14 days before joining the study.

I have gone through menopause.

Exclusion Criteria

I have a history of blood clotting disorders.

I have had 2 or more blood clots in the last 5 years.

I have not had a blood clot in my veins or lungs in the last year.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive estradiol orally three times daily for 28-day cycles, with biopsies and blood samples collected at specified intervals

6 months

Biopsies at end of cycle 1, blood samples on day 1 of cycle 1, end of cycle 1, and end of treatment; imaging at baseline, end of cycles 2, 4, and 6, then every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Annual follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol

Trial Overview The study tests how effective estradiol, a form of estrogen, is on patients whose tumor cells overexpress ER beta but lack other hormone receptors. The goal is to see if estradiol can shrink these specific types of tumor cells. Various imaging techniques like CT scans will monitor the results.

How Is the Trial Designed?

Group I: Treatment (estradiol) Experimental Treatment 5 Interventions

Patients receive estradiol PO TID for days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo a tissue biopsy at the end of cycle 1, collection of blood samples on C1D1, at the end of cycle 1, and at the end of treatment. In addition, patients undergo CT, MRI, or PET scans at baseline, at the end of cycles 2, 4, and 6, and then every 8 weeks until disease progression.

Estradiol is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Approved in United States as Estradiol for:

• Moderate to severe vasomotor symptoms due to menopause
• Vulvar and vaginal atrophy due to menopause
• Hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
• Prevention of postmenopausal osteoporosis
• Palliative treatment of breast cancer
• Palliative treatment of prostate cancer

Approved in Canada as Estradiol for:

• Menopausal symptoms
• Hypoestrogenism
• Osteoporosis prevention
• Breast cancer palliation
• Prostate cancer palliation

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Selective estrogen receptor modulators (SERMs) and antiestrogens, such as raloxifene and bazedoxifene, are safe options for postmenopausal women as they do not increase breast cancer risk and may even offer protection against it.

The combination of conjugated estrogens with bazedoxifene has shown an improved breast safety profile compared to traditional hormone therapies, with no increase in breast density or pain over two years, indicating a safer alternative for managing menopausal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective estrogen receptor modulators and the combination therapy conjugated estrogens/bazedoxifene: A review of effects on the breast. Pickar, JH., Komm, BS.[2018]

Tamoxifen effectively reduces the risk of estrogen receptor-positive breast cancer by at least 50% in both pre- and postmenopausal women, highlighting its efficacy as a preventive treatment.

Newer agents like aromatase inhibitors have shown even greater reductions in breast cancer risk (up to 65% with exemestane and 60% with anastrozole) for postmenopausal women, but there is a need for more targeted therapies for premenopausal women with estrogen receptor-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventative therapies for healthy women at high risk of breast cancer. Sestak, I.[2020]

A comprehensive safety review of Estratest and Estratest HS, based on over 1 million woman-years of exposure from 1989 to 1996, found no significant safety concerns, with only 863 adverse events reported, which is relatively low given the extensive use.

The most common adverse events were typical of estrogen and androgen therapies, such as weight gain and headaches, and serious adverse events were rare, indicating that these medications are safe when used as directed, with manageable risks associated with their androgen component.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety surveillance of esterified estrogens-methyltestosterone (Estratest and Estratest HS) replacement therapy in the United States. Phillips, E., Bauman, C.[2019]

Third-generation aromatase inhibitors (AIs) like anastrozole, letrozole, and exemestane have emerged as effective alternatives to tamoxifen for treating postmenopausal breast cancer, particularly in hormone receptor-positive cases, as shown in the ATAC trial with over five years of follow-up.

Fulvestrant, a new type of estrogen receptor antagonist with no partial agonist activity, represents a promising option in breast cancer treatment, and the review discusses future sequencing strategies for using AIs earlier in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New developments in the treatment of postmenopausal breast cancer. Howell, A.[2018]

Tamoxifen has been a groundbreaking treatment for breast cancer, but raloxifene offers a safer alternative with a lower risk of endometrial cancer and is being studied for breast cancer prevention.

Aromatase inhibitors (AIs) have shown greater efficacy than tamoxifen for both first-line and second-line therapies, and the pure antiestrogen fulvestrant is equally effective, highlighting the importance of these therapies in managing breast cancer, especially in cases resistant to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estrogen receptors as therapeutic targets in breast cancer. Ariazi, EA., Ariazi, JL., Cordera, F., et al.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37917089/

Vaginal Estrogen Therapy Use and Survival in Females ... Results of this study showed no evidence of increased early breast cancer-specific mortality in patients who used vaginal estrogen therapy ...

2. ajog.org ajog.org/article/S0002-9378(24)01126-8/fulltext

Vaginal estrogen use in breast cancer survivors The pooled data from these studies suggest that vaginal estrogen use is not significantly associated with an increased risk of breast cancer recurrence among ...

3. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2811413

Vaginal Estrogen Therapy Use and Survival in Breast Cancer Results of this study showed no evidence of increased early breast cancer–specific mortality in patients who used vaginal estrogen therapy compared with ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.578

Use of local estrogen therapy among breast cancer ... Conclusions: The use of vaginal estrogen among this SEER-MHOS cohort of breast cancer patients showed improved survival outcomes. These findings ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39521301/

Vaginal estrogen use in breast cancer survivors Breast cancer recurrence was the primary outcome. The secondary outcomes included: breast cancer mortality and overall mortality. Pooled unadjusted odds ratios ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0305737225000027

Safety of topical estrogen therapy during adjuvant ... Topical oestrogen use does not appear to increase recurrence or mortality risk in breast cancer survivors on tamoxifen.