Efficacy and Tolerance Study of Bevacizumab in Her2- Inflammatory Breast Cancer Patients

OBJECTIVES:

Primary

• Evaluate the complete histological response rate in patients with inflammatory HER2-negative breast cancer treated with bevacizumab and concurrent chemotherapy followed by bevacizumab and concurrent hormonal therapy after surgery and radiotherapy.

Secondary

• Evaluate the progression-fee and overall survival of these patients at 3 and 5 years.
• Evaluate the tolerance of bevacizumab in these patients.
• Assess circulating metastatic disease before, during, and after treatment.
• Assess circulating endothelial cells before, during, and after treatment.
• Assess predictive factors of response by genomic and proteomic studies on frozen tumor samples and fluid samples (i.e., serum and plasma).

OUTLINE: This is a multicenter study.

• Neoadjuvant induction therapy:

• Courses 1-4: Patients receive bevacizumab IV over 30-90 minutes, fluorouracil IV, epirubicin hydrochloride IV over 10 minutes, and cyclophosphamide IV over 5 minutes on day 1.
• Courses 5-8: Patients receive bevacizumab IV over 30-90 minutes and docetaxel IV over 1 hour on day 1.

Treatment repeats every 21 days for 8 courses in the absence of disease progression or unacceptable toxicity.

• Surgery: Patients undergo surgery 4-6 weeks after completion of bevacizumab.
• Adjuvant therapy: Beginning 2-4 weeks after surgery, patients undergo radiotherapy for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes beginning 2-4 weeks after surgery, during the radiotherapy period. Treatment with bevacizumab repeats every 3 weeks for 30 weeks in the absence of disease progression or unacceptable toxicity. Patients who are estrogen receptor- or progesterone receptor-positive (≥ 10% by IHC) receive the following concurrent hormonal therapy beginning in week 7:

• Premenopausal patients: Patients receive tamoxifen citrate for 5 years.
• Postmenopausal patients: Patients receive aromatase-inhibitor therapy (or tamoxifen citrate if unable to tolerate anti-aromatase therapy) for 5 years.
• Perimenopausal patients: Patients receive tamoxifen citrate for 2-3 years and aromatase-inhibitor therapy for 2-3 years OR tamoxifen citrate for 5 years followed by aromatase-inhibitor therapy for 2-3 years (if follicle-stimulating hormone > 30 IU/L and/or estradiol < 30 ng/L).

After completion of study treatment, patients are followed for at least 3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed inflammatory breast cancer, meeting 1 of the following staging criteria:

• T4d, any N (AJCC stage IIIB or IIIC)
• Gustave-Roussy Institute (IGR) classification Poussee evolutirie (PEV; measures tumor growth over time) 2

• PEV 2: tumor with underlying breast tissue, especially skin, that is affected by subacute inflammation and edema involving < ½ of breast surface
• IGR classification PEV 3

• PEV 3: acute or subacute inflammation and edema involving > ½ of breast surface
• Biopsy-confirmed presence of tumor embolism in surface lymph nodes
• HER2-negative (HER2 0 or 1+, or HER2 2+ by IHC if FISH-negative allowed)
• No metastatic disease
• No non-inflammatory breast cancer with edema, ulceration, or satellite skin nodules
• No bilateral breast cancer
• Hormone receptor status known

PATIENT CHARACTERISTICS:

• Any menopausal status allowed
• WHO performance status 0-2
• Life expectancy ≥3 months
• LVEF normal by ECHO
• ANC >1.5 x 10^9/L
• Platelet count >100 x 10^9/L
• INR ≤1.5 (except for patients on prophylactic anticoagulants)
• aPTT ≤1.5 times upper limit of normal (ULN)
• Total bilirubin normal
• SGOT and SGPT ≤1.25 times ULN
• Alkaline phosphatase ≤2.5 times ULN
• Creatinine clearance ≥60 mL/min
• Proteinuria <2+ or 24-hour urine protein ≤1 g
• No unhealed wound, stomach ulcer, or bone fracture
• No history of thrombotic or hemorrhagic disorders
• No significant cardiovascular disease including the following:

• Cerebrovascular accident within the past 6 months
• Unstable angina
• Cardiac failure
• Myocardial infarction
• Arrhythmia requiring treatment
• No uncontrolled hypertension (i.e., systolic BP >150 mm Hg and/or diastolic BP >100 mm Hg)
• No other active infection or serious illness that would preclude patient from receiving study treatment
• No hypersensitivity to any active products or excipients of study drugs
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No social or psychologic reasons that would prevent study compliance or follow-up
• No patients who are incarcerated or on probation

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or hormonal therapy for this disease
• More than 4 weeks since prior surgery (diagnostic biopsy or installation of implant allowed)
• More than 10 days since prior chronic non-inflammatory steroids (e.g., acetylsalicylic acid >325 mg/day) or platelet anticoagulation treatment (e.g., dipyridamole, ticlopidine, clodiprogel, cilostazol)
• More than 10 days since prior oral or parenteral anticoagulant or thrombolytic drugs (preventative thrombolytic drugs allowed)
• No concurrent participation in another experimental clinical trial