Triptorelin With Either Exemestane or Tamoxifen in Treating Premenopausal Women With Hormone-Responsive Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using triptorelin, exemestane, and tamoxifen may fight breast cancer by blocking the use of estrogen. It is not yet known whether giving triptorelin together with exemestane is more effective than triptorelin and tamoxifen in treating hormone-responsive breast cancer. PURPOSE: This randomized phase III trial is studying triptorelin and exemestane to see how well they work compared to triptorelin and tamoxifen in treating premenopausal women with hormone-responsive breast cancer.

Detailed Description
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OBJECTIVES: Compare the disease-free survival, breast cancer-free interval, distant recurrence-free interval and overall survival of premenopausal women with endocrine-responsive breast cancer when treated with triptorelin and exemestane vs triptorelin and tamoxifen. Compare the quality of life, including late side effects of early menopause, of patients treated with these regimens. OUTLINE: This is a randomized, international, multicenter study. Patients are stratified according to planned use of concurrent adjuvant chemotherapy (yes vs no), and number of positive lymph nodes (0 vs 1 or more). Treatment duration is 5 years. Patients are followed every 3 months for 1 year, every 6 months for 5 years, and then annually thereafter. Quality of life is assessed at baseline, every 6 months for 2 years, and annually for 3 years.

Official Title
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A Phase III Trial Evaluating The Role Of Exemestane Plus GnRH Analogue As Adjuvant Therapy For Premenopausal Women With Endocrine Responsive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: exemestane
* Drug: tamoxifen
* Drug: triptorelin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer Completely resected disease No clinically detectable residual loco-regional axillary disease Prior surgery for primary breast cancer of 1 of the following types: Total mastectomy with or without adjuvant radiotherapy Breast-conserving procedure (e.g., lumpectomy, quadrantectomy, or partial mastectomy with margins negative* for invasive disease and ductal carcinoma in situ) with planned radiotherapy NOTE: *If all other margins are clear a positive posterior (deep) margin is permitted, provided the excision was performed down to the pectoral fascia and all tumor has been removed OR a positive anterior (superficial; abutting skin) margin is allowed provided all tumor was removed Tumor confined to the breast and axillary nodes Tumor detected in internal mammary chain nodes by sentinel node procedure and is not enlarged is allowed Axillary lymph node dissection or a negative axillary sentinel node biopsy required Patients with negative or microscopically positive axillary sentinel nodes are eligible Positive sentinel nodes must have either axillary dissection or radiation of axillary nodes No distant metastases No locally advanced inoperable breast cancer, including any of the following: Inflammatory breast cancer Supraclavicular node involvement Enlarged internal mammary nodes (unless pathologically negative) Bilateral synchronous invasive breast cancer allowed if disease meets all other eligibility criteria No prior ipsilateral or contralateral invasive breast cancer Hormone receptor status: Estrogen and/or progesterone receptor positive At least 10% of the tumor cells positive by immunohistochemistry If > 1 breast tumor, each tumor must be hormone receptor positive PATIENT CHARACTERISTICS: Age Premenopausal Sex Female Menopausal status Premenopausal Estradiol in the premenopausal range after prior surgery OR meets the following criteria: Menstruating regularly for the past 6 months Has not used any form of hormonal treatment (including hormonal contraception) within the past 6 months Performance status Not specified Life expectancy Not specified Hematopoietic Not specified Hepatic No systemic hepatic disease that would preclude prolonged follow-up Renal No systemic renal disease that would preclude prolonged follow-up Cardiovascular No systemic cardiovascular disease that would preclude prolonged follow-up No prior thrombosis (e.g., deep vein thrombosis) and/or embolism unless patient is medically suitable Pulmonary No systemic pulmonary disease that would preclude prolonged follow-up Other Not pregnant or nursing Fertile patients must use effective nonhormonal contraception No history of noncompliance to medical regimens No other nonmalignant systemic disease that would preclude prolonged follow-up No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, nonbreast carcinoma in situ, contralateral or ipsilateral carcinoma in situ of the breast, or other nonrecurrent invasive nonbreast malignancy, including any of the following: Stage I papillary thyroid cancer Stage IA carcinoma of the cervix Stage IA or B endometrioid endometrial cancer Borderline or stage I ovarian cancer No psychiatric, addictive, or other disorder that would preclude study compliance PRIOR CONCURRENT THERAPY: Biologic therapy Prior or concurrent neoadjuvant or adjuvant trastuzumab allowed Chemotherapy No prior neoadjuvant or adjuvant chemotherapy Endocrine therapy No prior tamoxifen, other selective estrogen-receptor modulators (SERMs) (e.g., raloxifene), or hormone replacement therapy for more than 1 year before breast cancer diagnosis No prior neoadjuvant or adjuvant endocrine therapy since diagnosis of breast cancer No concurrent oral or transdermal hormonal therapy No other concurrent estrogen, progesterone, or androgens No other concurrent aromatase inhibitors No concurrent oral or other hormonal contraceptives (i.e., implants or depot injections) Radiotherapy See Disease Characteristics No prior ovarian radiotherapy Surgery See Disease Characteristics No prior bilateral oophorectomy Other No concurrent bisphosphonates, except in the following cases: Bone density is at least 1.5 standard deviations below the young adult normal mean Participation in a randomized clinical study testing bisphosphonates in the adjuvant breast cancer setting No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: T+OFS<br>Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus tamoxifen 20mg orally daily for 5 years. Tamoxifen (T) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin. | Drug: tamoxifen<br> <br> * Other names: Nolvadex;Drug: triptorelin<br> <br> * Other names: Decapeptyl Depot;|
| Experimental: E+OFS<br>Ovarian function suppression (OFS) by triptorelin (GnRH analogue) 3.75mg by im injection q28 days for 5 years plus exemestane 25mg orally daily for 5 years. Exemestane (E) begins after the completion of adjuvant chemotherapy if given, or approximately 6-8 weeks after the initiation of triptorelin. Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin. | Drug: exemestane<br> <br> * Other names: Aromasin;Drug: triptorelin<br> <br> * Other names: Decapeptyl Depot;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival | Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow up. | 5-year estimate reported at a median follow-up of 72 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast Cancer-free Interval | Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to the invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up. | 5-year estimate reported at a median follow-up of 72 months | 
| Distant Recurrence-free Interval | Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free interval is defined as the time from randomization to breast cancer recurrence at a distant site; or censored at date of last follow-up | 5-year estimates reported at a median follow-up of 72 months | 
| Overall Survival | Estimated percentage of patients alive at 8 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive. | 8-year estimates, reported at a median follow-up of 9 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage II breast cancer, stage IIIA breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, stage IA breast cancer, stage IB breast cancer