Extended Endocrine Therapy for Premenopausal Women With Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability of the combination of two drugs (letrozole and leuprolide) in women who have already taken tamoxifen for at least 4.5 years. Letrozole, an aromatase inhibitor (which blocks an enzyme that produces estrogen), is a drug that is FDA approved. It has been shown to reduce the risk of breast cancer recurrence in postmenopausal women with breast cancer who have been previously treated with tamoxifen. Letrozole works by stopping the production of estrogen in parts of the body other than the ovaries. Leuprolide is a drug that stops a women's ovarian cycles. This process is known as ovarian function suppression. Stopping a women's menstrual cycle may be effective against breast cancer for some patients when given as initial therapy. The combination of letrozole and leuprolide is considered a standard treatment for women with metastatic breast cancer, and is also sometimes used for treatment of premenopausal early stage breast cancer, but it has not been accepted as a standard of care treatment.

Detailed Description
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Participants will be given a monthly intramuscular injection of leuprolide. Six to eight weeks after the first leuprolide injection, participants will be instructed to begin taking letrozole pills by mouth at home each day. During this research study, participants will also be offered injections of zoledronic acid to preserve bone mineral density. If desire, these injections will be given every 6 months for a total of 4 injections during the course of the research study. The treatments in this research study may increase the risk of bone density loss, so vitamin D and calcium supplements will be recommended to participants. The following tests and procedures will be performed during the research study: Physical Exam (every visit); Blood tests; Urine test (beginning and end of treatment); Imaging (annual mammograms); Bone Density (DXA) Scan (beginning and end of treatment); Questionnaires (throughout the study). Participants will be on this study for about two years.

Official Title
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Extended Endocrine Therapy for Premenopausal Women With Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: leuprolide
* Drug: letrozole
* Drug: zoledronic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women 18 years of age or older History of invasive ER+ or PR+ breast cancer treated with at least 4.5 years of tamoxifen No current evidence of recurrent invasive disease or metastatic disease. Patients may have a history of bilateral breast cancer Premenopausal (estradiol level in premenopausal range, >20pg/ml, within the prior 28 days) Liver function tests and creatinine <2.5 times the upper limit of normal within the 28 days prior to enrollment ECOG Performance Status 0-1 Must agree to use non-hormonal contraception (condoms, diaphragm, IUD, sterilization, abstinence, etc) and no other hormonal therapy during trial and until 3 months after letrozole is stopped Negative pregnancy test within 14 days prior to enrollment Patient must be able to speak, read and write in English Exclusion Criteria: Previous treatment with an oral or IV bisphosphonate in the prior two years History of cancer other than breast cancer within 5 years excluding basal/squamous cell skin carcinoma in situ of the cervix Women with evidence of current local recurrence or metastatic breast cancer Pregnant women Nursing women Women who are currently taking tamoxifen and are unwilling to stop this medication Women with a known deleterious BRCA 1 or BRCA 2 mutation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Letrozole-Leuprolide<br>Patients will receive 2.5mg oral letrozole daily and either 7.5mg monthly of Leuprolide IM or 22.5mg every three months of Leuprolide IM. Zoledronic acid 4mg IV every 6 months x 4 will also be offered optionally. | Drug: leuprolide<br>* Given intramuscularly beginning on day 1 and then either 7.5 mg every month or 22.5 mg every 3 months for two years<br>* Other names: Lupron;Drug: letrozole<br>* Taken orally once a day 6-8 weeks after initial leuprolide administration<br>* Other names: Femara;Drug: zoledronic acid<br>* If desired, given intravenously every 6 months for a total of 4 injections (optional)<br>* Other names: Zometa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability at One Year of Ovarian Function Suppression (OFS) Using Leuprolide and Letrozole. | The tolerability at one year of ovarian function suppression (OFS) using leuprolide and letrozole in this patient population. Specifically, the number of patients who discontinued treatment prior to one year due to toxicity. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ovarian Function Suppression (OFS) Combined With Aromatase Inhibition Combined With Intravenous Bisphosphonate Therapy on Bone Mineral Density. | Ovarian function suppression (OFS) combined with aromatase inhibition combined with intravenous bisphosphonate therapy on bone mineral density in this patient population. | 2 years | 
| The Effect of OFS Combined With Aromatase Inhibitor Therapy on the Incidence and Severity of Menopausal Symptoms, Sexual Dysfunction, Musculoskeletal Complaints, Other Side Effects and Overall Quality of Life. | OFS combined with aromatase inhibitor therapy on the incidence and severity of menopausal symptoms, sexual dysfunction, musculoskeletal complaints, other side effects and overall quality of life in this population. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hormone-receptor positive, tamoxifen, letrozole, zoledronic acid, leuprolide