Study of Anastrozole, Letrozole, or Exemestane With or Without Tamoxifen in Treating Postmenopausal Women With Hormone-Responsive Breast Cancer That Has Been Completely Removed By Surgery

Study Overview
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Brief Summary
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RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking use of estrogen by the tumor cells. Anastrozole, letrozole, and exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether giving tamoxifen followed by anastrozole, letrozole, or exemestane is more effective than giving anastrozole, letrozole, or exemestane alone in treating breast cancer. PURPOSE: This randomized phase III trial is studying giving tamoxifen followed by either anastrozole, letrozole, or exemestane to see how well it works compared to anastrozole, letrozole, or exemestane alone in treating postmenopausal women with hormone-responsive invasive breast cancer that has been completely removed by surgery.

Detailed Description
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OBJECTIVES: To compare sequential tamoxifen for 2 years followed by anastrozole, letrozole, or exemestane for 3 years vs anastrozole, letrozole, or exemestane for 5 years in terms of disease-free survival in postmenopausal women with nonrecurrent, nonmetastatic invasive endocrine-responsive breast cancer. To compare disease-free survival in patients treated with anastrozole vs letrozole vs exemestane. OUTLINE: This is a multicenter study. Patients are stratified according to hormone receptor status (estrogen receptor [ER]-positive and progesterone [PgR] receptor-positive disease vs ER-positive and PgR-negative disease vs ER-negative and PgR-positive disease vs ER- or PgR-positive disease or ER or PgR status unknown), HER-2/neu status (positive [3+ by IHC or positive by fluorescence in situ hybridization ( FISH)] vs negative vs unknown), prior chemotherapy (none vs adjuvant vs neoadjuvant vs both adjuvant and neoadjuvant), and nodal status (pN0 vs pN1 vs pN2 vs pN3). Patients are randomized to 1 of 6 treatment arms. Arm I: Patients receive oral anastrozole once daily for 5 years. Arm II: Patients receive oral exemestane once daily for 5 years. Arm III: Patients receive oral letrozole once daily for 5 years. Arm IV: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral anastrazole once daily for 3 years. Arm V: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral exemestane once daily for 3 years. Arm VI: Patients receive oral tamoxifen citrate once daily for 2 years followed by oral letrozole once daily for 3 years. Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity. After completion of study therapy, patients are followed periodically.

Official Title
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A Phase III Study Comparing Anastrozole, Letrozole and Exemestane, Upfront (for 5 Years) or Sequentially (for 3 Years After 2 Years of Tamoxifen), as Adjuvant Treatment of Postmenopausal Patients With Endocrine-responsive Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: anastrozole
* Drug: exemestane
* Drug: letrozole
* Drug: tamoxifen citrate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed invasive breast cancer completely removed by surgery Any T, any N No recurrent or metastatic disease Estrogen or progesterone receptor-positive disease in primary tumor, as defined by 1 of the following: At least 10% of tumor cells positive by immunohistochemistry At least 10 fmol/mg cytosol protein by ligand binding assay Patients with HER-2/neu positive tumors are eligible provided they receive trastuzumab (Herceptin®) according to the registered schedule PATIENT CHARACTERISTICS: Female Postmenopausal, defined by ≥ 1 of the following: Age ≥ 60 years Age 45-59 and satisfying 1 or more of the following criteria: Amenorrhea for ≥ 12 months AND intact uterus Amenorrhea (secondary to hysterectomy, hormone replacement therapy (HRT), or chemotherapy) for < 12 months AND follicle-stimulating hormone within the postmenopausal range Underwent prior bilateral oophorectomy at any age >18 years No concurrent illness that contraindicates adjuvant endocrine treatment No other invasive breast cancer or invasive malignancy within the past 10 years, except adequately cone-biopsied squamous cell or basal cell skin cancer or carcinoma in situ of the cervix No concurrent disease that would place the patient at unusual risk PRIOR CONCURRENT THERAPY: See Disease Characteristics Adjuvant or neoadjuvant chemotherapy must be completed prior to study entry At least 1 month since prior and no concurrent HRT More than 30 days since prior systemic investigational drugs No prior tamoxifen as part of any breast cancer prevention study Prior or concurrent locoregional radiotherapy allowed No other concurrent experimental drugs No concurrent bisphosphonates, unless indicated as treatment for osteoporosis

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
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A - anastrozole<br>Up-front adjuvant anastrozole for 5 years | Drug: anastrozole<br>* 1 mg per day, orally<br>|
| Experimental: B - exemestane<br>Up-front adjuvant exemestane for 5 years | Drug: exemestane<br>* 25 mg per day, orally<br>|
| Experimental: C - letrozole<br>Up-front adjuvant letrozole for 5 years | Drug: letrozole<br>* 2.5 mg per day, orally<br>|
| Active Comparator: D - tamoxifen followed by anastrozole<br>Switch adjuvant treatment with tamoxifen for 2 years followed by anastrozole for 3 years | Drug: anastrozole<br>* 1 mg per day, orally<br>Drug: tamoxifen citrate<br>* 20 mg per day, orally<br>|
| Active Comparator: E - tamoxifen followed by exemestane<br>Switch adjuvant treatment with tamoxifen for 2 years followed by exemestane for 3 years | Drug: exemestane<br>* 25 mg per day, orally<br>Drug: tamoxifen citrate<br>* 20 mg per day, orally<br>|
| Active Comparator: F - tamoxifen followed by letrozole<br>Switch adjuvant treatment with tamoxifen for 2 years followed by letrozolefor 3 years | Drug: letrozole<br>* 2.5 mg per day, orally<br>Drug: tamoxifen citrate<br>* 20 mg per day, orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 5 years | 
| Distant metastasis-free survival |  | 5 years | 
| Cumulative incidence of contralateral breast cancer as first event |  | 5 years | 
| Breast cancer-free survival |  | 5 years | 
| Cumulative incidence and type of second non-breast invasive cancer |  | 5 years | 
| Effects on lipid profile |  | 5 years | 
| Toxicity as assessed by NCI CTCAE v3.0 |  | 5 years | 

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