RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Anastrozole may fight breast cancer by blocking the production of estrogen by the tumor cells. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. It is not yet known whether anastrozole is more effective with or without trastuzumab in treating metastatic breast cancer.

PURPOSE: Randomized phase II/III trial to compare the effectiveness of anastrozole plus trastuzumab with that of anastrozole alone in treating postmenopausal women who have metastatic breast cancer.

Condition	Treatment or Intervention	Phase
stage IV breast cancer recurrent breast cancer	Drug: anastrozole  Drug: trastuzumab  Procedure: antibody therapy  Procedure: aromatase inhibition  Procedure: biological response modifier therapy  Procedure: endocrine therapy  Procedure: hormone therapy  Procedure: monoclonal antibody therapy	Phase II Phase III

OBJECTIVES:

• Compare the efficacy of anastrozole with or without trastuzumab (Herceptin), in terms of progression-free survival, in postmenopausal women with hormone-receptor positive HER2-overexpressing metastatic breast cancer.
• Compare the safety profile of these regimens in these patients.
• Compare the overall clinical-benefit rate in patients treated with these regimens.
• Compare the overall survival, duration of response, and 2-year survival of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to presence of liver metastases (yes vs no), tumor assessment (measurable disease vs evaluable disease), relapse after prior adjuvant tamoxifen therapy (no prior adjuvant tamoxifen therapy vs relapse at least 12 months after therapy vs relapse during or fewer than 12 months after therapy), and concurrent bisphosphonate therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral anastrozole once daily and trastuzumab (Herceptin) IV over 30-90 minutes once weekly.
• Arm II: Patients receive anastrozole as in arm I. In both arms, treatment continues for at least 2 years in the absence of disease progression or unacceptable toxicity. Patients in either arm who do not develop disease progression may continue receiving treatment, in the arm to which they were originally randomized, during the extension phase of this study. Patients in arm II who develop disease progression may receive treatment in arm I during the extension phase in the absence of further disease progression.

Patients are followed at 28 days.

PROJECTED ACCRUAL: A total of 202 patients (101 per treatment arm) will be accrued for this study within 2 years.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic breast cancer
• HER2 overexpression (3+) by immunohistochemistry OR
• Any degree of erbB-2 amplification (at least 2 fold) by FISH
• Measurable or evaluable disease
• Postmenopausal as defined by any of the following:
• At least 60 years of age
• Under 60 years of age and amenorrheic for at least 12 months
• Under 60 years of age, without a uterus, and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) values within postmenopausal range
• Menopausal age (under 60), amenorrheic for 12 months or less, and LH and FSH values within postmenopausal range
• Prior bilateral oophorectomy
• Prior radiation castration with amenorrhea for at least 6 months
• No clinical or radiological evidence of CNS metastases
• Hormone receptor status:
• Estrogen-receptor positive AND/OR
• Progesterone-receptor positive

PATIENT CHARACTERISTICS: Age:

• See Disease Characteristics
• 18 and over

Sex:

• Female

Menopausal status:

• See Disease Characteristics

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• WBC greater than 3,000/mm^3
• Neutrophil count greater than 1,500/mm^3
• Platelet count greater than 100,000/mm^3
• Hemoglobin greater than 9 g/dL

Hepatic:

• Transaminases less than 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases present)

Renal:

• Creatinine less than 1.5 times ULN

Cardiovascular:

• LVEF greater than 50% by echocardiogram or MUGA
• No uncontrolled cardiac disease
• No angina
• No arrhythmias
• No hypertension
• No prior congestive heart failure
• No myocardial infarction within the past 6 months

Pulmonary:

• No severe dyspnea at rest due to complications of advanced malignancy
• No requirement for supplementary oxygen

Other:

• No concurrent uncontrolled serious illness
• No other prior malignancy that would preclude study compliance
• Patients with prior nonmelanoma skin cancer, carcinoma in situ of the cervix, or other curatively treated malignancy allowed if disease free for more than 5 years
• No clinical disease that requires immediate cytotoxic chemotherapy
• No known allergy to Chinese hamster ovary cell proteins, murine proteins, or to any excipients of trastuzumab (Herceptin) formulation (e.g., l-histidine, trehalose dihydrate, or polysorbate 20) or preparation (e.g., benzyl alcohol)
• Not pregnant or nursing
• Negative pregnancy test

PRIOR CONCURRENT THERAPY: Biologic therapy:

• No prior anti-HER2 therapy
• No other concurrent anticancer immunotherapy

Chemotherapy:

• At least 6 months since prior adjuvant chemotherapy
• No prior chemotherapy for metastatic disease
• No concurrent anticancer chemotherapy

Endocrine therapy:

• Prior first-line tamoxifen for metastatic disease allowed if partial or complete response or stable disease for more than 6 months
• At least 1 day since prior tamoxifen
• No more than 4 weeks (duration) of prior anastrozole
• No concurrent steroid treatment for cancer
• No concurrent hormone replacement therapy
• No other concurrent anticancer hormonal therapy

Radiotherapy:

• See Disease Characteristics
• No prior radiotherapy to indicator lesion, unless objective disease recurrence or progression within radiation portal since completion of radiotherapy
• No concurrent radiotherapy to only known site of disease
• Concurrent palliative radiotherapy allowed

Surgery:

• See Disease Characteristics
• No concurrent resection of only known site of disease
• Concurrent palliative surgery allowed

Other:

• At least 30 days since prior investigational drugs
• Prior or concurrent bisphosphonate therapy allowed
• No other concurrent specific anticancer therapy

Arkansas
      Arkansas Cancer Research Center at University of Arkansas for Medical Sciences, Little Rock,  Arkansas,  72205,  United States; Recruiting
California
      Kaiser Permanente Medical Center - Vallejo, Vallejo,  California,  94589,  United States; Recruiting
Florida
      Cancer Research Network Inc., Plantation,  Florida,  33324,  United States; Recruiting
Maine
      Maine Center for Cancer Medicine and Blood Disorders - Scarborough, Scarborough,  Maine,  04074,  United States; Recruiting
Michigan
      Josephine Ford Cancer Center at Henry Ford Hospital, Detroit,  Michigan,  48202,  United States; Recruiting
Ohio
      Charles M. Barrett Cancer Center at University Hospital, Cincinnati,  Ohio,  45267-0501,  United States; Recruiting
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5055,  United States; Recruiting

Study chairs or principal investigators

Bernd Langer, PhD,  Study Chair,  F. Hoffmann - La Roche, Ltd.   

Study ID Numbers:  CDR0000068841; ROCHE-BO16216; CWRU-030118; GENENTECH-H2223g; ROCHE-1100; ROCHE-B016216E
Record last reviewed:  December 2002
Record first received:  August 10, 2001
ClinicalTrials.gov Identifier:  NCT00022672
Health Authority: Unspecified
ClinicalTrials.gov processed this record on 2004-10-29