Efficacy of Anastrozole and Fulvestrant in Patients With ER Positive, HER2 Negative, Operable Breast Cancer

OBJECTIVES:

Primary

• To compare the clinical response rates (complete and partial responses) at 6 months in postmenopausal women with operable stage II or III breast cancer treated with neoadjuvant anastrozole vs fulvestrant.

Secondary

• To compare the breast surgery conservation rate in patients treated with these drugs.
• To correlate imaging findings by mammography, ultrasonography, and MRI with histological and clinical response in these patients and with sensitivity profile to these drugs.
• To compare histological response in patients treated with these drugs.
• To define criteria appropriate for neoadjuvant hormonal therapy.
• To correlate baseline molecular characteristics and modifications during treatment with response in these patients.
• To compare the tolerability of these drugs in these patients.
• To compare the serum proteomic profile of patients treated with these drugs.
• To correlate 3-year event-free and overall survival rates with clinical and histological response in these patients.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral anastrozole once daily for 4-6 months in the absence of clinical progression.
• Arm II: Patients receive fulvestrant intramuscularly on days 1, 15, and 29 in the first month and then every 28 days in each subsequent month. Treatment continues for 4-6 months in the absence of clinical progression.

Patients in both arms then undergo surgery and radiotherapy according to institutional guidelines. Patients then receive adjuvant hormonal therapy for at least 5 years.

After completion of study therapy, patients are followed periodically for up to 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed infiltrating breast adenocarcinoma

• Large, operable tumor
• Stage T2 (≥ 3 cm) or T3-T4 (excluding inflammatory disease), N0-N3, M0 disease

• No bilateral inflammatory breast tumors (T4d [PEV-2 or PEV-3])
• Elston-Ellis grade I or II and mitotic index 1 or 2 (if < 65 years of age)
• At least 1 embedded and 1 frozen biopsy sample available
• No multifocal or multicentric tumors for which breast conservation cannot be envisaged
• No ErbB2-overexpressing tumors (HER2 3+ by IHC OR HER2 2+ by IHC and FISH positive)
• Hormone receptor status:

• Estrogen receptor and/or progesterone receptor positive tumor (> 10%) as assessed by IHC

PATIENT CHARACTERISTICS:

• Female
• Postmenopausal
• ECOG performance status 0-2
• ANC ≥ 2,000/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Total bilirubin ≤ 1.25 times ULN
• AST and ALT ≤ 1.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN
• No other cancer within the past 10 years, except basal cell skin cancer or previously treated carcinoma in situ of the cervix
• No uncontrolled cardiac pathology, including any of the following:

• Angina pectoris
• Congestive cardiac insufficiency
• Myocardial infarction within the past 3 months
• No known history of hemorrhagic diathesis
• No known allergy to the study drugs or their excipients
• No congenital galactosemia, glucose malabsorption syndrome, or lactase deficiency
• No chronic somatic or psychiatric illness with pejorative prognosis
• No geographical, social, or psychiatric condition that would preclude study compliance and follow-up schedule
• No individual deprived of liberty or placed under the authority of a tutor

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, hormonal therapy, or any targeted treatment for the breast tumor
• At least 2 weeks since prior hormone replacement therapy for menopause
• No concurrent long-term anticoagulation treatment
• No concurrent participation on another therapeutic trial involving an experimental molecule