Letrozole or Tamoxifen in Treating Postmenopausal Women With 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 letrozole may fight breast cancer by reducing the production of estrogen. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. If is not yet known which treatment regimen is most effective for breast cancer. PURPOSE: Randomized double-blind phase III trial to compare the effectiveness of letrozole with that of tamoxifen in treating postmenopausal women who have breast cancer that has been surgically removed.

Detailed Description
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OBJECTIVES: Compare adjuvant letrozole vs tamoxifen administered for 5 years in postmenopausal women with operable, hormone receptor-positive breast cancer. Compare these treatment regimens given sequentially vs continuously in this patient population. Compare these treatment regimens in terms of overall survival, disease-free and systemic-free survival, safety, and tolerability in this patient population. OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to adjuvant chemotherapy (prior therapy vs no prior or concurrent therapy vs concurrent therapy), prior surgery (modified radical mastectomy vs a lesser surgical procedure), and participating center. Patients are randomized to one of four treatment arms. Arm I: Patients receive adjuvant oral tamoxifen daily for 5 years. Arm II: Patients receive adjuvant oral letrozole daily for 5 years. Arm III: Patients receive adjuvant oral tamoxifen daily for 2 years followed by adjuvant oral letrozole daily for 3 years. Arm IV: Patients receive adjuvant oral letrozole daily for 2 years followed by adjuvant oral tamoxifen daily for 3 years. Patients may receive concurrent radiotherapy. Some patients receive concurrent adjuvant chemotherapy beginning within 8 weeks after surgery and continuing for no more than 6 months. Patients are followed annually. PROJECTED ACCRUAL: A total of 5,180 patients (1,295 per treatment arm) will be accrued for this study within 6 years.

Official Title
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A Phase III Study to Evaluate Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women With Receptor (ER and/or PgR) Positive Tumors

Conditions
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Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed resectable adenocarcinoma of the breast pT1, pT2, pT3, or minimal dermal involvement on pathology only pN0, pN1, pN2, or M0 Negative nodal status At least 8 nodes are negative Unknown nodal status Less than 8 nodes examined and no pathological finding Positive nodal status Any positive finding independent of the number of nodes examined Negative sentinel node or no prior nodal dissection allowed if all other criteria met Must have had total mastectomy, lumpectomy, or quadrantectomy Should have prior chest wall radiotherapy after segmental mastectomy or histopathologic T4 dermal involvement Stage I, II, or IIIa allowed if the tumor is completely removed macroscopically and margins of the resected tumor are microscopically free of tumor Must undergo chest wall radiotherapy or second resection if microscopic disease at the mastectomy margins No bilateral disease except in situ disease, either ductal or lobular of the contralateral breast Postmenopausal Regardless of prior hormonal replacement therapy (HRT) or hysterectomy: Bilateral oophorectomy and any age Radiologic castration and amenorrheic for at least 3 months and any age Not postmenopausal at the start of adjuvant chemotherapy AND and completed at least 6 courses of prior cyclophosphamide, methotrexate, and fluorouracil (CMF) or at least 4 courses of prior anthracycline-cyclophosphamide continuation therapy and at least age 45 with follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) postmenopausal levels No prior HRT: Prior hysterectomy and less than age 55 with FSH/LH/E2 postmenopausal levels Prior hysterectomy and at least age 55 No prior HRT or hysterectomy: Amenorrhea more than 1 year and less than age 50 Amenorrhea more than 6 months and at least age 50 Prior HRT regardless of hysterectomy: At least 1 month since prior HRT and less than age 55 with FSH/LH/E2 postmenopausal levels At least 1 month since prior HRT and at least age 55 FSH/LH/E2 postmenopausal levels and uncategorized No distant metastases, including bone scans showing hot spots unconfirmed as benign disease or skeletal pain of unknown cause At least 10% hormone receptor-positive tumor cells Hormone receptor status: Estrogen receptor positive AND/OR Progesterone receptor positive PATIENT CHARACTERISTICS: Age: 30 and over Sex: Female Menopausal status: Postmenopausal Performance status: Not specified Life expectancy: Not specified Hematopoietic: WBC greater than 3,000/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin greater than 10 g/dL Hepatic: Bilirubin less than 3.0 mg/dL SGOT or SGPT less than 1.5 times upper limit of normal No hepatic disease that would preclude study Renal: Creatinine less than 1.8 mg/dL No renal disease that would preclude study Cardiovascular: No cardiovascular disease that would preclude study Prior deep vein thrombosis allowed if medically stable Pulmonary: No lung embolism Other: No other prior or concurrent malignancy within the past 5 years except adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix No prior noncompliance to medical regimens No other nonmalignant systemic diseases that would preclude follow-up HIV negative PRIOR CONCURRENT THERAPY: Biologic therapy: Prior immunotherapy or biological response modifiers (e.g., interferon) allowed Chemotherapy: See Disease Characteristics Prior adjuvant or neoadjuvant chemotherapy allowed Concurrent adjuvant chemotherapy allowed Endocrine therapy: See Disease Characteristics Prior neoadjuvant hormonal therapy allowed (e.g., antiestrogens, progestins, or aromatase inhibitors) if no more than 4 months duration and no disease progression Prior corticosteroids allowed At least 4 weeks since prior HRT Prior adjuvant antiestrogen therapy allowed if less than 1 month duration and immediately after surgery, radiotherapy, and/or chemotherapy Prior antiestrogens for chemoprevention allowed if at least 18 months between completion of chemoprevention and diagnosis No other concurrent antiestrogens or aromatase inhibitors No concurrent raloxifene No concurrent systemic HRT with or without progestins of more than 3 months duration Radiotherapy: See Disease Characteristics Concurrent radiotherapy allowed Surgery: See Disease Characteristics Other: At least 30 days since prior systemic investigational drugs At least 7 days since prior topical investigational drugs Concurrent bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 120 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tamoxifen<br>Tamoxifen for 5 years after randomization. | Drug: tamoxifen citrate<br>* Tamoxifen 20 mg daily oral administration.<br>|
| Experimental: Letrozole<br>Letrozole for 5 years after randomization. | Drug: letrozole<br>* Letrozole 2.5 mg daily oral administration.<br>|
| Experimental: Tamoxifen, then letrozole<br>Tamoxifen for 2 years after randomization, then letrozole for the next 3 years. | Drug: letrozole<br>* Letrozole 2.5 mg daily oral administration.<br>Drug: tamoxifen citrate<br>* Tamoxifen 20 mg daily oral administration.<br>|
| Experimental: Letrozole, then tamoxifen<br>Letrozole for 2 years after randomization, then tamoxifen for the next 3 years. | Drug: letrozole<br>* Letrozole 2.5 mg daily oral administration.<br>Drug: tamoxifen citrate<br>* Tamoxifen 20 mg daily oral administration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease free survival. | Time from randomization to recurrence (including recurrence restricted to the breast after breast conserving treatment), metastasis, appearance of a second primary tumor, or death from any cause, whichever occurs first, assessed up to end of year 2015, for a maximum of 17 years | Up to end of year 2015 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Time from randomization to death from any cause, assessed up to end of year 2015, for a maximum of 17 years | Up to end of year 2015 | 
| Safety | Morbidity information will be recorded using the Adverse Event Form (AE). | 5 years after randomization. | 
| Systemic relapse | Time from randomization to appearance of any recurrent or metastatic disease in sites other than the local mastectomy scar, the ipsilateral breast in case of breast conservation, or the contralateral breast, assessed up to end of year 2015, for a maximum of 17 years | Up to end of year 2015 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, breast cancer in situ, recurrent breast cancer, ductal breast carcinoma, lobular breast carcinoma in situ