Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer

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.

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