RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development of cancer. Anastrozole may be effective in preventing breast cancer.

PURPOSE: This randomized clinical trial is studying how well anastrozole works in preventing breast cancer in postmenopausal women who are at increased risk for the disease.

OBJECTIVES:

Primary

• Determine the effectiveness of anastrozole in preventing breast cancer in postmenopausal women at increased risk for the disease.

Secondary

• Determine the role of this drug in preventing estrogen receptor-positive breast cancer in these participants.
• Determine the effect of this drug on breast cancer mortality in these participants.
• Determine the effect of this drug on other cancers, cardiovascular disease, fracture rates, and non-breast cancer deaths in these participants.
• Determine the tolerability and acceptability of side effects of this drug in these participants.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Participants are stratified according to participating center. Participants are randomized to 1 of 2 treatment arms.

• Arm I: Participants receive oral anastrozole daily for 5 years.
• Arm II: Participants receive an oral placebo daily for 5 years. In both arms, treatment continues in the absence of the development of breast cancer (including ductal carcinoma in situ), a drop in the T-score below minus 4, or the occurrence of a new fragility fracture.

Participants are followed for at least a further 5 years.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

ACCRUAL: A total of 3,864 participants were recruited for this study over 10 years.

DISEASE CHARACTERISTICS:

• Meets at least 1 of the relative risk factors based on age as follows:

  • 45 to 70 years of age:

    • First-degree relative who developed breast cancer at ≤ 50 years of age

    • First-degree relative who developed bilateral breast cancer

    • Two or more first- or second-degree relatives who developed breast cancer or ovarian cancer

      • Participants having both relatives who are second degree and on the opposite sides of the family must have at least one that was diagnosed at ≤ 50 years of age

    • Nulliparous (or first birth at ≥ 30 years of age) and a first-degree relative who developed breast cancer

    • Benign biopsy with proliferative disease and a first-degree relative who developed breast cancer

    • Mammographic opacity covering at least 50% of the breast in the absence of hormone replacement therapy within the past 3 months

  • 60 to 70 years of age:

    • First-degree relative with breast cancer at any age
    • Age at menopause ≥ 55 years
    • Nulliparous or age at first birth ≥ 30 years

  • 40 to 44 years of age:

    • Two or more first- or second-degree relatives who developed breast cancer or ovarian cancer at ≤ 50 years of age
    • First-degree relative with bilateral breast cancer who developed the first breast cancer at ≤ 50 years of age
    • Nulliparous (or first birth at ≥ 30 years of age) and a first-degree relative who developed breast cancer at ≤ 40 years of age
    • Benign biopsy with proliferative disease and a first-degree relative who developed breast cancer at ≤ 40 years of age

• All age groups (40 to 70 ears of age) with a 10-year risk > 5% who do not fit into the above categories are allowed

  • Clearly apparent family history AND/OR other risk factors indicating appropriate increased risk of breast cancer for age

• The following prior breast conditions are allowed (for all age groups):

  • Lobular carcinoma in situ
  • Atypical ductal or lobular hyperplasia in a benign lesion
  • Ductal carcinoma in-situ (DCIS), diagnosed within the past 6 months, and treated by mastectomy

• No evidence of breast cancer on mammogram within the past year

• Hormone receptor status:

  • For patients with prior DCIS, estrogen- or progesterone-receptor status must have been positive

    • Must have had greater than or equal to 5% positive cells

PATIENT CHARACTERISTICS:

Age

• 40 to 70

Sex

• Female

Menopausal status

• Postmenopausal, defined as at least 1 of the following:

  • Over 60 years of age
  • Bilateral oophorectomy
  • ≤ 60 years of age with a uterus and amenorrhea for at least 12 months
  • ≤ 60 years of age without a uterus and with follicle-stimulating hormone levels > 30 IU/L

Performance status

• Not specified

Life expectancy

• At least 10 years

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Psychologically and physically suitable to receive 5 years of anti-estrogen therapy

• No cancer within the past 5 years except non-melanoma skin cancer or carcinoma in situ of the cervix

• No evidence of osteoporosis or fragility fractures within the spine

  • Participants with a T-score > minus 4 and no more than 2 fragility fractures are allowed

• No concurrent severe disease that would place the participant at unusual risk or confound the results of the study

• No other medical condition that would preclude the ability to receive the study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• No prior tamoxifen, raloxifene, or other selective estrogen receptor modulator (SERM) use for more than 6 months in duration unless an IBIS-I participant (must have been off trial therapy for at least 5 years.
• No concurrent tamoxifen, raloxifene, or other SERM
• No concurrent estrogen-based hormone replacement therapy
• No concurrent systemic estrogen replacement therapy, including vaginal estrogen preparations

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics
• No prior prophylactic mastectomy
• No concurrent prophylactic mastectomy

Other

• More than 6 months since prior investigational drugs