RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using raloxifene and tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells.

PURPOSE: Randomized double-blinded clinical trial to compare the effectiveness of raloxifene with that of tamoxifen in preventing breast cancer in postmenopausal women.

OBJECTIVES:

• Determine whether raloxifene is more or less effective than tamoxifen in significantly reducing the incidence rate of invasive breast cancer in postmenopausal women.
• Evaluate the effects of tamoxifen and raloxifene on the incidence of intraductal carcinoma in situ, lobular carcinoma in situ, endometrial cancer, ischemic heart disease, fractures of the hip and spine, or Colles' fractures of the wrist in these participants.
• Evaluate the toxic effects of these regimens in these participants.
• Determine the effect of these regimens on the quality of life of these participants (at selected centers). (Quality of life evaluation closed to accrual effective 5/31/01.)

OUTLINE: This is a randomized, double-blind study. Participants are stratified by age (35 to 49 vs 50 to 59 vs over 59), race (black vs white vs other), history of lobular carcinoma in situ (yes vs no), prior hysterectomy (yes vs no), and estimated absolute risk of invasive breast cancer within 5 years (using the Gail model)(less than 2.0 vs 2.0-2.9 vs 3.0-4.9 vs 5.0 or greater). Participants are randomized to 1 of 2 arms.

• Arm I: Participants receive oral tamoxifen plus placebo daily for 5 years.
• Arm II: Participants receive oral raloxifene plus placebo daily for 5 years. Quality of life is assessed (at selected centers) at baseline and at 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, and 72 months. (Quality of life evaluation closed to accrual effective 5/31/01.)

Participants are followed annually after 5 years.

PROJECTED ACCRUAL: Approximately 19,000 participants will be accrued for this study within 5 years.

• Drug: raloxifene
• Drug: tamoxifen citrate

• Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther. 2009 Jan;9(1):51-60.
• Wickerham DL, Costantino JP, Vogel VG, Cronin WM, Cecchini RS, Ford LG, Wolmark N. The use of tamoxifen and raloxifene for the prevention of breast cancer. Recent Results Cancer Res. 2009;181:113-9.
• Land SR, Wickerham DL, Costantino JP, Ritter MW, Vogel VG, Lee M, Pajon ER, Wade JL 3rd, Dakhil S, Lockhart JB Jr, Wolmark N, Ganz PA. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21;295(23):2742-51. Epub 2006 Jun 5.
• Vogel VG, Costantino JP, Wickerham DL, Cronin WM, Cecchini RS, Atkins JN, Bevers TB, Fehrenbacher L, Pajon ER Jr, Wade JL 3rd, Robidoux A, Margolese RG, James J, Lippman SM, Runowicz CD, Ganz PA, Reis SE, McCaskill-Stevens W, Ford LG, Jordan VC, Wolmark N; National Surgical Adjuvant Breast and Bowel Project (NSABP). Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA. 2006 Jun 21;295(23):2727-41. Epub 2006 Jun 5. Erratum in: JAMA. 2006 Dec 27;296(24):2926.
• Land SR, Ritter MW, Costantino JP, Julian TB, Cronin WM, Haile SR, Wolmark N, Ganz PA. Compliance with patient-reported outcomes in multicenter clinical trials: methodologic and practical approaches. J Clin Oncol. 2007 Nov 10;25(32):5113-20. Review.
• Gradishar WJ, Cella D. Selective estrogen receptor modulators and prevention of invasive breast cancer. JAMA. 2006 Jun 21;295(23):2784-6. Epub 2006 Jun 5. No abstract available.

DISEASE CHARACTERISTICS:

• Postmenopausal women at increased risk for developing invasive breast cancer, who meet one of the following criteria:

  • At least 12 months since spontaneous menstrual bleeding
  • Prior documented hysterectomy and bilateral salpingo-oophorectomy
  • At least 55 years of age with prior hysterectomy with or without oophorectomy
  • Age 35 to 54 with a prior hysterectomy without oophorectomy OR with a status of ovaries unknown with documented follicle-stimulating hormone level demonstrating elevation in postmenopausal range
• Histologically confirmed lobular carcinoma in situ treated by local excision only OR at least 1.66% probability of invasive breast cancer within 5 years using Breast Cancer Risk Assessment Profile
• No clinical evidence of malignancy on physical exam within the past 180 days
• No evidence of suspicious or malignant disease on bilateral mammogram within the past year
• No bilateral or unilateral prophylactic mastectomy
• No prior invasive breast cancer or intraductal carcinoma in situ

• Hormone receptor status:

  • Not specified

PATIENT CHARACTERISTICS:

Age:

• 35 and over

Sex:

• Female

Menopausal status:

• See Disease Characteristics

Performance status:

• No restricted normal activity for a significant portion of each day

Life expectancy:

• At least 10 years

Hematopoietic:

• Granulocyte count at least 1,500/mm^3
• Complete blood count and differential normal
• Platelet count normal

Hepatic:

• SGOT or SGPT normal
• Bilirubin normal
• Alkaline phosphatase normal

Renal:

• Creatinine normal

Cardiovascular:

• No cerebral vascular accident, transient ischemic attack, atrial fibrillation, or uncontrolled hypertension
• No deep vein thrombosis

Pulmonary:

• No pulmonary embolus

Other:

• No other prior malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No concurrent nonmalignant disease that would preclude administration of tamoxifen or raloxifene
• No clinical depression, psychiatric condition, or addictive disorder
• No uncontrolled diabetes

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• Not specified

Endocrine therapy:

• At least 3 months since prior estrogen or progesterone replacement therapy, oral contraceptives, androgens, luteinizing hormone-releasing hormone analogs, prolactin inhibitors, or antiandrogens
• At least 3 months since prior tamoxifen, raloxifene, or other selective estrogen-receptor modulators of less than 3 months duration
• Concurrent Estring allowed

Radiotherapy:

• No prior breast radiotherapy

Surgery:

• See Disease Characteristics

Other:

• No prior systemic adjuvant therapy for breast cancer

• No other participation in a cancer prevention or osteoporosis prevention study involving pharmacologic intervention(s)

  • NSABP-P-1 patients who received placebo are eligible
• No concurrent warfarin or cholestyramine
• Concurrent calcitonin or nonhormonal medication (e.g., cholecalciferol, fluoride, or bisphosphonates) allowed