Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer
Letrozole or Tamoxifen in Treating Postmenopausal Women With Breast Cancer
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.
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