Estradiol for Advanced Breast Cancer

(ESTHER Trial)

Overseen By Research Nurse

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Dartmouth-Hitchcock Medical Center

Must not be taking: Investigational therapies

Disqualifiers: CNS disease, Thrombosis, 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: Unknown

Duration: Up to 12 months

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of estradiol, a form of hormone therapy, for women with advanced breast cancer. Researchers aim to determine if women with specific genetic changes in their cancer benefit more from this treatment. The treatment involves using 17b-estradiol until the cancer progresses. Women who are post-menopausal, have estrogen-receptor positive (ER+) breast cancer that has spread or recurred, and have tried at least one other hormone-based therapy might be suitable candidates for this trial. As a Phase 2 trial, the 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 that you stop taking any current anti-cancer therapies during the study, except for Trastuzumab and anti-resorptive bone therapies, which are allowed. If you are on any investigational cancer therapy, you must have stopped it at least 3 weeks before joining the trial.

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

Research has shown that estradiol, a type of estrogen, is under study as a treatment for advanced breast cancer. Some studies suggest it might increase breast cancer risk due to its effect on hormone levels. However, in certain forms like creams or vaginal treatments, it hasn't significantly increased cancer recurrence in survivors.

The current trial is in Phase 2, indicating that the treatment has passed initial safety tests. This suggests estradiol is generally safe, but researchers continue to gather detailed safety information. Participants should carefully consider the potential risks and benefits before joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for advanced breast cancer, which often include hormone therapies like tamoxifen or aromatase inhibitors, Estradiol offers a unique approach by utilizing a form of estrogen itself. This treatment is particularly intriguing because it works by exploiting the cancer's reliance on low estrogen levels, potentially causing the cancer cells to stop growing. Researchers are excited because Estradiol could provide a new option for patients whose cancers have become resistant to other hormone therapies, offering a possible new avenue for those with limited alternatives.

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

Research has shown that estradiol, a type of estrogen, may offer benefits in treating breast cancer. Some studies found that using vaginal estrogen in breast cancer survivors does not increase the risk of cancer recurrence. In fact, these studies suggest it may help some patients live longer. Estradiol interacts with hormone receptors in the body, potentially affecting cancer cell growth. While concerns exist about estrogen and cancer risk, the specific effects of estradiol on advanced breast cancer, especially in individuals with certain genetic traits, remain under investigation. In this trial, participants will receive 17b-estradiol until disease progression. These findings suggest estradiol might benefit some individuals with advanced breast cancer. ^{1 4 6 7 8}

Who Is on the Research Team?

Mary D. Chamberlin

Principal Investigator

Dartmouth-Hitchcock Medical Center

Are You a Good Fit for This Trial?

This trial is for post-menopausal women with ER+ advanced breast cancer who have tried at least one endocrine therapy before. It's not suitable for those with a recent heart attack, congestive heart failure, high-risk previous cancers, stroke history, brain metastases unless stable for 3 months, or a history of blood clots.

Inclusion Criteria

My cancer has spread or returned and cannot be cured with treatment.

I am a post-menopausal woman with estrogen receptor-positive breast cancer.

I have had hormone therapy for advanced cancer.

Exclusion Criteria

Any investigational cancer therapy in the last 3 weeks

I am not on cancer treatments except possibly Trastuzumab or bone therapies.

My brain condition has been stable for at least 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients will be treated with 17b-estradiol until disease progression

Up to 12 months

Regular visits as per protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Observational Phase (optional)

After disease progression on 17b-estradiol, patients will be treated at their oncologist's discretion

Until further disease progression

What Are the Treatments Tested in This Trial?

Interventions

• Estradiol

Trial Overview

The ESTHER study is testing if estradiol treatment benefits patients whose breast cancer has specific ESR1 mutations more than those without these mutations. No other anti-cancer treatments are allowed during the trial except certain bone therapies and Trastuzumab in some cases.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 1 Intervention

Treatment Phase: Patients will be treated with 17b-estradiol until disease progression. At this point, the patient will end protocol therapy

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?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Published Research Related to This Trial

The 7-day estradiol transdermal patch (Climara) effectively reduces hot flushes in women, with a mean decline of 74.6% for the higher dose compared to 64.5% for the lower dose, showing comparable efficacy to traditional hormone therapies.

The Climara patch is well tolerated, with a low withdrawal rate due to adverse events (8.9%), primarily related to skin reactions, and it demonstrated better adhesion compared to other patches, making it a practical option for estrogen replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy. Gordon, SF.[2019]

Anastrozole significantly improves survival and tolerability in postmenopausal women with advanced breast cancer compared to megestrol acetate, and it also prolongs time to progression compared to tamoxifen in first-line therapy for hormone receptor-positive (HR+) disease.

In the adjuvant setting, anastrozole shows superior efficacy and tolerability over tamoxifen, making it a preferred treatment option for HR+ early breast cancer, and it also reduces the risk of contralateral breast cancer, suggesting its potential as a chemopreventive agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of anastrozole across the breast cancer continuum: from advanced to early disease and prevention. Nabholtz, JM.[2018]

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]

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]

In a Phase II study involving pre- and peri-menopausal women with advanced breast cancer, the combination of Zoladex and tamoxifen showed no adverse endocrinological interactions and extended the time to disease progression compared to Zoladex alone.

The combination treatment was particularly effective in patients with estrogen receptor (ER) positive tumors, leading to a higher proportion of static disease, while responses in ER negative tumors were rare, especially in those with high cell proliferation rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Zoladex plus tamoxifen versus Zoladex alone in pre- and peri-menopausal metastatic breast cancer. Nicholson, RI., Walker, KJ., McClelland, RA., et al.[2019]

Anastrozole is an effective treatment for advanced breast cancer in postmenopausal women, showing comparable efficacy to megestrol acetate without the associated weight gain, based on results from two multicenter clinical trials.

As a highly selective aromatase inhibitor, anastrozole offers maximal estrogen depletion with a convenient once-daily oral dosing regimen and fewer side effects than other hormonal therapies, making it a promising option for patients who have progressed after tamoxifen therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anastrozole: a new addition to the armamentarium against advanced breast cancer. Buzdar, AU.[2019]

Tamoxifen is being evaluated in ongoing clinical trials involving over 24,000 healthy women to determine its effectiveness in preventing breast cancer, with results expected by the year 2000.

While tamoxifen may provide significant benefits in breast cancer prevention, it is associated with adverse effects such as transient bone loss in premenopausal women and potential uterine complications in postmenopausal women, leading to investigations of alternative drugs like raloxifene and toremifene.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Status of antiestrogen breast cancer prevention trials. Powles, TJ.[2016]

Anastrozole, a third-generation nonsteroidal aromatase inhibitor, is now considered a first-line treatment for postmenopausal women with advanced breast cancer, based on recent studies.

It has also been shown to be an effective and well-tolerated alternative to tamoxifen for adjuvant treatment in postmenopausal women with early breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Changes in endocrine therapy: anastrozole and advanced breast cancer in postmenopausal women. Nabholtz, JM.[2018]

In a study involving 200 postmenopausal women, the topical micellar nanoparticle estradiol emulsion (MNPEE) significantly reduced the frequency of moderate to severe hot flushes, with a mean reduction of 11.1 hot flushes per day by week 12 compared to placebo.

MNPEE was found to be safe and well tolerated, demonstrating significant improvements in both the frequency and severity of vasomotor symptoms over a 12-week treatment period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estradiol in micellar nanoparticles: the efficacy and safety of a novel transdermal drug-delivery technology in the management of moderate to severe vasomotor symptoms. Simon, JA.[2013]

Endocrine therapy (ET) is crucial for treating estrogen receptor-positive breast cancer, with options including ovarian function suppression, selective estrogen receptor modulators, and aromatase inhibitors, which can significantly reduce recurrence risk, especially in patients under 50.

While third-generation aromatase inhibitors have shown superiority over tamoxifen in reducing recurrence, some breast cancers develop resistance to endocrine therapy, prompting the exploration of additional treatments like CDK4/6 inhibitors and mTOR inhibitors to enhance efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current medical treatment of estrogen receptor-positive breast cancer. Lumachi, F., Santeufemia, DA., Basso, SM.[2020]

Citations

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ajog.org

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Vaginal estrogen use in breast cancer survivors

The use of vaginal estrogen in patients with a history of breast cancer does not appear to be associated with an increased risk of breast cancer recurrence.

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Estrogens and breast cancer

Estrogen may increase breast cancer risk by inducing the progesterone receptor and augmenting progesterone signaling.

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sciencedirect.com

sciencedirect.com/science/article/pii/S0960977624001498

Clinical significance of serum estradiol monitoring in ...

A total of 706 patients were enrolled, including 482 women with OFS in combination with AI. Among them, 116 women (16.4 %) exhibited E2 levels exceeding 2.72 pg ...

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9452594/

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Estradiol heightens the risk of breast cancer in postmenopausal women and preclinical studies have demonstrated that progestin engenders progenitor cells in ...

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sciencedirect.com

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ascopubs.org

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The aim of this study was to review the safety and serum estrogen levels of hormonal therapy in patients with BC history presenting with VVA symptoms.