Letrozole in Treating Postmenopausal Women Who Have Received Hormone Therapy for Hormone Receptor-Positive Breast Cancer

• Overall survival [ Time Frame: Time from randomization to any death ] [ Designated as safety issue: No ]
• Breast cancer-free interval [ Time Frame: Time from randomization to recurrence or contralateral second primary cancer ] [ Designated as safety issue: No ]
• Distant recurrence [ Time Frame: Time from randomization to distant recurrence of breast cancer. ] [ Designated as safety issue: No ]
• Osteoporotic-related fractures [ Time Frame: Incidence of osteoporotic-related fractures (Colles', hip, and spine). ] [ Designated as safety issue: Yes ]
• Arterial thrombotic events [ Time Frame: Incidence of arterial thrombotic events (CTCAE v. 3.0 grades 3, 4, or 5 cardiac ischemia/infarction, CNS cerebrovascular ischemia, peripheral arterial ischemia, and visceral arterial ischemia [nonmyocardial]) ] [ Designated as safety issue: Yes ]

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 patients with hormone receptor-positive breast cancer.

PURPOSE: This randomized phase III trial is studying letrozole to see how well it works compared with a placebo in treating postmenopausal women who have received hormone therapy for hormone receptor-positive breast cancer.

OBJECTIVES:

Primary

• Determine whether or not prolonged adjuvant hormonal therapy comprising letrozole vs placebo will improve disease-free survival of postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive breast cancer who have completed 5 years of hormonal therapy with 5 years of an aromatase inhibitor (AI) or 5 years of a combination of up to 3 years of tamoxifen citrate followed by an AI.
• Compare the disease-free survival of patients treated with these regimens.

Secondary

• Compare overall survival of patients treated with these regimens.
• Compare breast cancer-free interval of patients treated with these regimens.
• Compare distant recurrence in patients treated with these regimens.
• Compare the incidence of osteoporotic-related fractures (e.g., Colles', hip, and spine) in these patients treated with these regimens.
• Compare the incidence of arterial thrombotic events in patients treated with these regimens.

OUTLINE: This is a double-blind, multicenter, placebo-controlled, randomized study. Patients are stratified according to pathologic nodal status (negative vs positive), adjuvant tamoxifen citrate therapy (yes vs no), and lowest bone mineral density T score for lumbosacral spine, total hip, or femoral neck (> -2.0 vs ≤ -2.0 standard deviation). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral letrozole once daily.
• Arm II: Patients receive oral placebo once daily. In both arms, treatment continues for up to 5 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed annually.

PROJECTED ACCRUAL: A total of 3,840 patients will be accrued for this study.

• Drug: Letrozole
  Letrozole 2.5 mg taken orally once daily for 5 years
• Other: Placebo
  Placebo tablet taken orally once daily for 5 years

• Experimental: Arm I
  Patients receive oral letrozole once daily for up to 5 years.
  Intervention: Drug: Letrozole
• Placebo Comparator: Arm II
  Patients receive oral placebo once daily for up to 5 years.
  Intervention: Other: Placebo

DISEASE CHARACTERISTICS:

• Histologically confirmed invasive carcinoma of the breast by core needle or final pathological evaluation of the surgical specimen

  • Clinical stage I, II, or IIIA primary tumor for patients who received neoadjuvant chemotherapy
  • Primary tumor t1-3 on pathologic evaluation and ipsilateral nodes pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b for patients who received adjuvant chemotherapy

• Received adjuvant hormonal therapy after breast cancer diagnosis for a duration of 57-63 months from the first dose (regardless of the number of missed doses) with 1 of the following:

  • Aromatase inhibitor* (AI)

  • Combination of up to 3 years of tamoxifen citrate followed by an AI for a total of 5 years

    • No tamoxifen citrate during years 4 and 5 of 5-year adjuvant hormonal therapy NOTE: *Adjuvant AI therapy must be discontinued at the time of randomization
• Must have completed adjuvant hormonal therapy within the past 6 months

• Must have undergone a bilateral mammogram within the past year (unilateral if patient had a mastectomy)

  • Mammogram not required if patient has a prophylactic contralateral mastectomy
• Must have undergone a bone mineral density test within the past year

• Must have undergone a lumpectomy with axillary nodal staging followed by breast radiotherapy OR a total mastectomy with axillary nodal staging

  • Nodal staging with sentinel node biopsy alone is allowed provided sentinel nodes were negative on H&E staining
• No evidence of recurrent breast cancer by history and physical within the past 3 months
• No diagnosis of bilateral breast cancer, including ductal carcinoma in situ (synchronous or metachronous)

• Estrogen receptor (ER)-positive and/or progesterone receptor-positive tumor

  • Patients with a tumor considered to be borderline hormone receptor-positive that was treated with tamoxifen citrate and/or AI are allowed

PATIENT CHARACTERISTICS:

• Female

• Postmenopausal as defined by any of the following criteria:

  • Age ≥ 56 years with no spontaneous menses for ≥ 12 months prior to study entry
  • Age ≤ 55 years with no spontaneous menses for ≥ 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) AND a documented estradiol level in the postmenopausal range
  • Prior documented bilateral oophorectomy
• ECOG performance status 0 or 1

• Cholesterol ≤ grade 1 (with or without cholesterol-lowering therapy) meeting 1 of the following criteria:

  • Criteria must be met within the past year if patient has any of the following:

    • History of hypercholesterolemia controlled with cholesterol-lowering therapy and/or therapeutic lifestyle changes

    • History of ≥ 1 of the following risk factors for cardiovascular events:

      • Diabetes
      • Hypertension
      • Obesity
      • Tobacco use
      • Hypertriglyceridemia
      • Documented coronary artery disease
      • Family history of premature coronary heart disease
  • Criteria must be met within the past 2 years for all other patients
• Not pregnant or nursing
• No history of nontraumatic osteoporotic fracture of the wrist, hip, or spine
• No other malignancies unless disease-free for ≥ 5 years and, in the opinion of the investigator, at low risk for recurrence

• No other prior malignancy within the past 5 years except for the following:

  • Carcinoma in situ of the cervix
  • Colon carcinoma in situ
  • Melanoma in situ
  • Basal cell or squamous cell carcinoma of the skin

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No other investigational agent within the past 30 days
• No other concurrent anticancer therapy
• No concurrent participation in any other hormonal therapy or placebo-controlled supportive therapy clinical trial

• No other concurrent hormonal therapy, including any of the following:

  • Hormonal agent for management of osteoporosis (e.g., raloxifene)
  • Selective estrogen receptor modulators (e.g., raloxifene)
  • Sex hormonal therapy (e.g., estrogen- or progesterone-replacement therapy, including low-dose estrogen in the form of vaginal cream) or oral contraceptives
  • Luteinizing hormone-releasing hormone agonists/antagonists (e.g., goserelin)

  • Estradiol acetate

    • Conjugated estrogen ring or estradiol hemihydrate vaginal tab allowed
  • Other aromatase inhibitors
• Concurrent bisphosphonates allowed provided dose is as recommended for bone protection, not anticancer therapy

• National Cancer Institute (NCI)
• Novartis