RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using anastrozole and fulvestrant may fight breast cancer by blocking the use of estrogen. Gefitinib may stop the growth of cancer cells by blocking the enzymes necessary for their growth. It is not yet known whether gefitinib is more effective when combined with anastrozole or fulvestrant in treating breast cancer.

PURPOSE: This randomized phase II trial is studying how well giving gefitinib together with anastrozole works compared to giving gefitinib together with fulvestrant in treating postmenopausal women with recurrent or metastatic breast cancer.

OBJECTIVES:

• Compare the antitumor activity of anastrozole and gefitinib vs fulvestrant and gefitinib in postmenopausal women with recurrent or metastatic hormone receptor-positive breast cancer.
• Compare the safety of these regimens in these patients.
• Compare the interaction of biological predictors of response in patients treated with these regimens.

OUTLINE: This is a randomized, open-label study. Patients are stratified according to prior hormonal therapy (yes vs no) and dominant site of disease (soft tissue/lymph nodes vs bone vs visceral). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral anastrozole and oral gefitinib once daily on days 1-28.
• Arm II: Patients receive fulvestrant intramuscularly on day 1 and oral gefitinib once daily on days 1-28.

Courses in both arms repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 1 year.

PROJECTED ACCRUAL: A total of 148 patients (74 per treatment arm) will be accrued for this study within 2 years.

• Drug: anastrozole
• Drug: fulvestrant
• Drug: gefitinib

• Experimental: Patients receive oral anastrozole and oral gefitinib once daily on days 1-28.
• Experimental: Patients receive fulvestrant intramuscularly on day 1 and oral gefitinib once daily on days 1-28.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

  • Recurrent or metastatic disease
• Measurable disease
• Patients with available tissue blocks from either the primary or metastatic site must submit the tissue for epidermal growth factor receptor analysis
• No history of CNS metastasis

• Hormone receptor status:

  • Estrogen and/or progesterone receptor positive

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Postmenopausal* defined by 1 of the following:

  • Prior bilateral oophorectomy or bilateral ovarian irradiation
  • No menstrual period for at least 12 months NOTE: *If age 55 and under and on tamoxifen within the past 6 months, must have an estradiol level in the postmenopausal range

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 1.25 times upper limit of normal (ULN)
• ALT and AST no greater than 2.5 times ULN (5 times ULN if liver metastases are present)
• INR, PT, and PTT normal

Renal

• Creatinine clearance at least 30 mL/min

Other

• Not pregnant or nursing
• No untreated ocular inflammation or infection
• No medical or psychiatric condition that would preclude study compliance, ability to give informed consent, or assessment of response or anticipated toxic effects
• No other invasive malignancies within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No contraindication to intramuscular injections

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 3 weeks since prior trastuzumab (Herceptin®)
• No concurrent trastuzumab

Chemotherapy

• More than 3 weeks since prior chemotherapy
• No more than 2 prior chemotherapy regimens for metastatic disease
• No concurrent chemotherapy

Endocrine therapy

• More than 3 months since prior luteinizing hormone-releasing hormone agonists or antagonists (patients 55 years old and under)
• No prior hormonal therapy for metastatic disease
• No prior estrogen receptor down-regulators (e.g., fulvestrant) in the adjuvant setting
• No prior aromatase inhibitors (e.g., anastrozole, letrozole, exemestane, or aminoglutethimide) in the adjuvant setting
• No other concurrent hormonal therapy

Radiotherapy

• Recovered from prior radiotherapy

• Concurrent radiotherapy to painful sites of bony disease or areas of impending fracture is allowed provided the following conditions are met:

  • Therapy was initiated prior to study entry
  • Sites of measurable disease outside the radiotherapy port are available for disease evaluation

Surgery

• Not specified

Other

• No prior agents that target epidermal growth factor receptors
• No concurrent CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, or verapamil)
• No concurrent anticoagulants, except for thrombotic events in patients in arm I
• No concurrent medications that would alter the pharmacokinetics of gefitinib (e.g., phenytoin, carbamazepine, phenobarbital, rifampin, Hypericum perforatum [St. John's wort], oxcarbazepine, rifapentine, modafinil, and griseofulvin)
• Concurrent bisphosphonates for hypercalcemia or bone metastases are allowed