Hormone Therapy +/− Everolimus for Breast Cancer

(e3 Trial)

Recruiting at 1458 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Southwest Oncology Group

Must be taking: Hormone therapy

Must not be taking: mTOR inhibitors, Trastuzumab

Disqualifiers: Metastatic cancer, Uncontrolled diabetes, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 6

Duration: 2-5 years

1939 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate, goserelin acetate, leuprolide acetate, anastrozole, letrozole, or exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet know whether hormone therapy is more effective when given with or without everolimus in treating breast cancer. PURPOSE: This randomized phase III trial studies how well giving hormone therapy together with or without everolimus work in treating patients with breast cancer.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like strong CYP3A4 inhibitors or inducers during the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

Is hormone therapy with or without Everolimus safe for breast cancer treatment?

Hormone therapies like letrozole and tamoxifen are generally safe but have different side effects. Letrozole may increase the risk of bone fractures and heart issues, while tamoxifen may increase the risk of uterine cancer and blood clots. Always discuss potential side effects with your doctor. ^{1 2 3 4 5}

How does the drug combination of hormone therapy and Everolimus differ from other breast cancer treatments?

This drug combination is unique because it combines hormone therapy with Everolimus, a drug that inhibits a protein called mTOR, which can enhance the effectiveness of hormone therapy like letrozole, leading to better outcomes in terms of progression-free survival compared to hormone therapy alone. ^{6 7 8 9 10}

What data supports the effectiveness of the drugs used in the Hormone Therapy +/− Everolimus for Breast Cancer trial?

Research shows that letrozole, an aromatase inhibitor, is more effective than tamoxifen in improving disease-free survival and reducing breast cancer recurrence in postmenopausal women with hormone-sensitive breast cancer. Additionally, studies indicate that aromatase inhibitors like anastrozole, letrozole, and exemestane have better efficacy and tolerability compared to tamoxifen. ^{4 5 8 11 12}

Who Is on the Research Team?

Mariana Chavez-MacGregor, MD, MSc

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for high-risk breast cancer patients who've had surgery with negative margins and appropriate axillary staging. They must have ER or PR positive status, not be on trastuzumab, have controlled diabetes if applicable, no uncontrolled lung disease, able to take oral meds, not pregnant/nursing, completed standard chemo prior to randomization, performance status 0-2 by Zubrod criteria. No recent heart attacks or severe cardiac disease.

Inclusion Criteria

I have more than one cancer spot in my breast, each far apart.

I have breast cancer in both breasts, diagnosed within a month of each other.

I have more than one cancer spot close to the biggest tumor in the same area of my breast.

Exclusion Criteria

My stomach and intestines work well and can absorb medication properly.

I do not have hepatitis.

I am not using, and will not use strong CYP3A4 inhibitors or inducers.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive an approved endocrine therapy for 2-5 years and either a placebo or everolimus for 1 year

2-5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

10 years

Every 6 months for 2 years, then yearly

What Are the Treatments Tested in This Trial?

Interventions

• Anastrozole
• Everolimus
• Exemestane
• Goserelin Acetate
• Letrozole
• Leuprolide Acetate
• Tamoxifen Citrate

Trial Overview The study tests hormone therapy's effectiveness against breast cancer when given alone versus alongside everolimus. Hormone therapies include tamoxifen citrate and others that lower estrogen levels in the body. Everolimus may inhibit tumor growth by blocking enzymes needed for cell growth.

How Is the Trial Designed?

Group I: Arm II Experimental Treatment 7 Interventions

Patients receive an approved endocrine therapy regimen as in arm I. Patients also receive everolimus PO daily for 1 year in the absence of disease progression or unacceptable toxicity.

Group II: Arm I Placebo Group 7 Interventions

Patients receive an approved endocrine therapy comprising tamoxifen citrate\*, goserelin acetate\*\* or leuprolide acetate\*\*, or an aromatase inhibitor (anastrozole, letrozole, or exemestane) for 2-5 years. Patients also receive a placebo PO daily for 1 year in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Arimidex for:

• Breast cancer
• Early breast cancer in postmenopausal women

Approved in United States as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer

Approved in Canada as Arimidex for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• Treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Approved in Japan as Arimidex for:

• Breast cancer

Who Is Running the Clinical Trial?

Southwest Oncology Group

Lead Sponsor

Trials

389

Recruited

260,000+

SWOG Cancer Research Network

Lead Sponsor

Trials

403

Recruited

267,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Letrozole is an effective treatment for postmenopausal women with early-stage or advanced hormone-sensitive breast cancer, showing a 43% reduction in disease recurrences when used as extended adjuvant therapy beyond standard tamoxifen treatment.

In advanced breast cancer, letrozole outperformed tamoxifen in terms of time to disease progression (9.4 months vs. 6.0 months) and has a similar tolerability profile, making it a recommended first-line therapy according to treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. Simpson, D., Curran, MP., Perry, CM.[2018]

Tamoxifen is the standard treatment for postmenopausal women with hormone-sensitive early breast cancer, but it has side effects that have led researchers to look for safer alternatives.

Third-generation aromatase inhibitors like anastrozole, letrozole, and exemestane have shown better efficacy and a more favorable side effect profile compared to tamoxifen in randomized trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant aromatase inhibitor therapy for early breast cancer: A review of the most recent data. Grana, G.[2018]

In a randomized trial, letrozole significantly improved disease-free survival by 19% and reduced the risk of breast cancer recurrence by 28% compared to tamoxifen in postmenopausal women with hormone receptor-positive early breast cancer.

Letrozole is considered cost-effective, providing an additional 0.343 quality-adjusted life years (QALYs) at an incremental cost of Can$ 8,110, resulting in a cost per QALY gained of Can$ 23,662 from the Canadian healthcare perspective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective. Delea, TE., El-Ouagari, K., Karnon, J., et al.[2022]

Letrozole has been fully approved by the FDA for treating postmenopausal women with hormone receptor-positive early breast cancer, showing a significant improvement in disease-free survival compared to tamoxifen, with a hazard ratio of 0.87 in the adjuvant trial.

While letrozole is effective, it is associated with a higher risk of bone fractures and myocardial infarction compared to tamoxifen, which has its own risks such as endometrial cancer and thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. Cohen, MH., Johnson, JR., Justice, R., et al.[2021]

Anastrozole and letrozole significantly improve disease-free survival compared to tamoxifen in postmenopausal women with early-stage breast cancer, based on results from Phase III trials.

Switching to an aromatase inhibitor like anastrozole or exemestane after 2 to 3 years of tamoxifen therapy reduces the risk of cancer recurrence more effectively than continuing tamoxifen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. Berry, J.[2007]

Neoadjuvant endocrine therapy, particularly with aromatase inhibitors like letrozole, anastrozole, and exemestane, is proving to be a safe and effective alternative to chemotherapy for certain breast cancer patients.

This therapy can help convert inoperable breast tumors to operable ones, allowing for less invasive surgical options, and also provides a chance to study the biological effects of these treatments on tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant use of endocrine therapy in breast cancer. Macaskill, EJ., Dixon, JM.[2022]

Citations

1. New Zealand pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in postmenopausal women with breast cancer. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Superiority of letrozole to tamoxifen in the first-line treatment of advanced breast cancer: evidence from metastatic subgroups and a test of functional ability. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Adjuvant aromatase inhibitor therapy for early breast cancer: A review of the most recent data. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms? [2019]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of letrozole versus tamoxifen as initial adjuvant therapy in postmenopausal women with hormone-receptor positive early breast cancer from a Canadian perspective. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of adjuvant hormonotherapy on tear functions in patients with breast cancer. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Mammalian target of rapamycin inhibitors in combination with letrozole in breast cancer. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Are all aromatase inhibitors the same? A review of controlled clinical trials in breast cancer. [2007]

11. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant use of endocrine therapy in breast cancer. [2022]

12. Ireland pubmed.ncbi.nlm.nih.gov

Progress in endocrine approaches to the treatment and prevention of breast cancer. [2021]