Letrozole in Treating Women With Primary Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy

• Incidence of contralateral breast cancer [ Time Frame: 8 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: 8 years ] [ Designated as safety issue: No ]
• Long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality, changes in bone mineral density, incidence of all bone fractures, and common toxicities [ Time Frame: 8 years ] [ Designated as safety issue: Yes ]
• Quality of life (QOL) as assessed by SF-36 Health Survey and the Menopause-Specific QOL Questionnaire (NCIC CTG participating centers) [ Time Frame: 8 years ] [ Designated as safety issue: No ]

• Incidence of contralateral breast cancer [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality, changes in bone mineral density, incidence of all bone fractures, and common toxicities [ Designated as safety issue: Yes ]
• Quality of life (QOL) as assessed by SF-36 Health Survey and the Menopause-Specific QOL Questionnaire (NCIC CTG participating centers) [ Designated as safety issue: No ]

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using letrozole may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether letrozole is more effective than a placebo in treating in women with breast cancer who have already received 5 years of aromatase inhibitor therapy.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy.

OBJECTIVES:

Primary

• To compare the disease-free survival of women with primary breast cancer treated with letrozole vs placebo after completing approximately 5 years (i.e., 4½ - 6 years) of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane).

Secondary

• To compare the effect of these drugs on overall (all cause specific) mortality of these patients.
• To compare the incidence of contralateral breast cancer in patients treated with these drugs.
• To evaluate the long-term clinical and laboratory safety of aromatase inhibitor therapy, particularly cardiovascular morbidity and mortality (e.g., significant coronary artery disease, including myocardial infarction and angina requiring percutaneous transluminal coronary angioplasty or coronary artery bypass graft, fatal and nonfatal strokes, and all vascular deaths); incidence of all bone fractures (with particular emphasis on hip and wrist fractures as indicators of osteoporosis); changes in bone density; and common toxicities.
• To compare overall quality of life (QOL) and menopausal-specific QOL of patients treated with these drugs.

OUTLINE: This is a multicenter study. Patients are stratified according to lymph node status at diagnosis (negative vs positive vs unknown), prior adjuvant chemotherapy (yes vs no), interval between last dose of aromatase inhibitor therapy and study randomization (< 6 months vs 6 months to 2 years), and duration of prior tamoxifen citrate use (0 vs < 2 years vs 2 - 4½ years vs > 4½ years). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
• Arm II: Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.

Patients undergo bone mineral density measurement by DEXA scan at baseline (if not done within 12 months of study entry), at 24 and 48 months during study therapy, and at the completion of study therapy. Some patients also complete quality-of-life questionnaires at baseline and at 12, 24, 36, 48, and 60 months.

After completion of study therapy, patients are followed annually.

• Drug: letrozole
  Given orally
  Other Name: femara
• Other: placebo
  Given orally
  Other Name: sugar pill

• Experimental: Arm I
  Patients receive oral letrozole once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
  Intervention: Drug: letrozole
• Placebo Comparator: Arm II
  Patients receive oral placebo once daily for up to 5 years in the absence of unacceptable toxicity, disease recurrence, or development of a second malignancy.
  Intervention: Other: placebo

DISEASE CHARACTERISTICS:

• Previously diagnosed with primary breast cancer

• Must have received 4½ - 6 years of aromatase inhibitor therapy (e.g., letrozole, anastrozole, or exemestane), either as initial therapy or after prior tamoxifen citrate, including treatment received as part of clinical trial CAN-NCIC-MA17

  • Completed aromatase inhibitor therapy ≤ 2 years ago

• No metastatic or recurrent disease, contralateral breast cancer, or ductal carcinoma in situ in either breast, as determined by the following:

  • Clinical examination of the breast area, axillae, and neck within the past 60 days
  • Mammogram within the past 12 months*
  • Chest x-ray within the past 60 days
  • Bone scan, if alkaline phosphatase > 2 times normal and/or there are symptoms of metastatic disease AND confirmatory x-ray, if bone scan results are questionable, within the past 60 days
  • Abdominal ultrasound, liver scan, or CT scan of the abdomen within the past 60 days, if ALT, AST, or alkaline phosphatase > 2 times normal NOTE: *A baseline mammogram is not required for patients who have undergone bilateral complete mastectomy

• Hormone-receptor status:

  • Estrogen receptor positive (ER+) and/or progesterone receptor positive (PR+) primary tumor at the time of diagnosis, defined as a tumor receptor content of > 10 fmol/mg protein or receptor positive by immunocytochemical assay (for patients not previously enrolled on clinical trial CAN-NCIC-MA17)
  • ER+ and/or PR+ primary tumor OR hormone receptor status of primary tumor unknown (for patients previously enrolled on clinical trial CAN-NCIC-MA17)

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-2
• Life expectancy ≥ 5 years
• WBC > 3.0 x 10^9/L OR granulocyte count (polymorphs + bands) ≥ 1.5 times 10^9/L
• Platelet count > 100 x 10^9/L
• AST and/or ALT < 2 times upper limit of normal (ULN)*
• Alkaline phosphatase < 2 times ULN*

• Able (i.e. sufficiently fluent) and willing to complete quality-of-life questionnaires in either English or French (NCIC CTG participating centers)

  • Inability to complete questionnaires due to illiteracy in English or French, loss of sight, or other equivalent reason allowed
• Accessible for treatment and follow-up
• No other prior or concurrent malignancy except adequately treated, superficial squamous cell or basal cell skin cancer, carcinoma in situ of the cervix, or other cancer treated > 5 years ago that is presumed cured NOTE: *Elevated levels allowed provided imaging examinations have ruled out metastatic disease

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No concurrent selective estrogen receptor modulator (e.g., raloxifene, idoxifene)
• No other concurrent anticancer therapy

• Eastern Cooperative Oncology Group
• North Central Cancer Treatment Group
• Southwestern Oncology Group (SWOG)
• Cancer and Leukemia Group B