S0800, Nab-Paclitaxel, Doxorubicin, Cyclophosphamide, and Pegfilgrastim With or Without Bevacizumab in Treating Women With Inflammatory or Locally Advanced Breast Cancer

OBJECTIVES:

• To compare the pathologic complete response rates in women with HER2/neu-negative inflammatory or locally advanced breast cancer treated with paclitaxel albumin-stabilized nanoparticle formulation, doxorubicin hydrochloride, cyclophosphamide, and pegfilgrastim with vs without bevacizumab.
• To compare the overall survival of patients treated with these regimens.
• To assess whether there is a correlation between bevacizumab and stratification factors (type of disease and hormone receptor status).
• To compare the toxicities of these regimens.
• To explore the molecular biomarkers related to the biology and outcome of inflammatory breast cancer.
• To explore potential molecular biomarkers that predict response to therapy and drug sensitivity.
• To evaluate biomarkers with respect to the sequence of paclitaxel albumin-stabilized nanoparticle formulation and doxorubicin hydrochloride/cyclophosphamide/pegfilgrastim administration in patients not receiving bevacizumab.
• To explore residual cancer burden and correlate it with outcome.
• To evaluate the time to treatment failure prior to surgery.
• To evaluate disease-free survival from the time of surgery in patients undergoing definitive surgery.

OUTLINE: This is a multicenter study. Patients are stratified according to type of disease (inflammatory vs locally advanced breast cancer) and hormone receptor status (positive [estrogen receptor (ER)+ and/or progesterone receptor (PgR)+] vs negative [ER- and PgR-]). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1 and bevacizumab IV over 30- to 90-minutes on day 1 of weeks 1-12. Patients then receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2 of weeks 14, 16, 18, 20, 22, and 24.
• Arm II: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1 of weeks 1-12. Patients then receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2 of weeks 14, 16, 18, 20, 22, and 24.
• Arm III: Patients receive doxorubicin hydrochloride IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2 of weeks 1, 3, 5, 7, 9, and 11. Patients then receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1 of weeks 14-25.

In all arms, patients with stable or responding disease undergo surgery 3-6 weeks after completion of chemotherapy. Patients may then undergo radiotherapy 5 days a week for 6 weeks.

Serum, whole blood, and tissue samples are collected periodically for biomarker analysis, circulating endothelial cell analysis, and pharmacogenomic studies, respectively.

After completion of study treatment, patients are followed every 6 months for 1 year and then annually for 4 years.

DISEASE CHARACTERISTICS:

• Histologically or pathologically confirmed breast cancer meeting one of the following criteria:

• Locally advanced disease (stage IIIB disease, stage IIB/IIIA, or stage IIIC disease)
• Inflammatory disease meeting the following two clinicopathologic criteria:

• Diffuse erythema AND edema (peau d'orange) of the breast involving the majority of the skin of the breast, i.e., more than 50%
• A biopsy demonstrating cancer either within the dermal lymphatics OR in the breast parenchyma itself
• HER2/neu-negative tumor as demonstrated by 0 or 1+ (weak or no staining) by DAKO, IHC, or equivalent test OR no gene amplification by FISH*

• 2+ by DAKO or IHC allowed provided FISH* negative
• NOTE: *A negative FISH test ratio is < 1.8 or FISH HER2 gene copy < 4.0; if only a positive or negative result is available from the FISH test, a negative result is acceptable for study entry
• Hormone receptor status known

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• Zubrod performance status 0-2
• Granulocyte count > 1,500/mm^3
• ANC ≥ 1,500/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin 9.0 g/dL
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 3 times ULN
• Alkaline phosphatase ≤ 2.5 ULN (unless bone metastasis is present in the absence of liver metastasis)
• Urine protein:creatinine ratio ≤ 0.5 OR urine protein < 1,000 mg on 24-hour urine collection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Able to take oral medications (e.g., no uncontrolled nausea, vomiting, or diarrhea, lack of physical integrity of the upper gastrointestinal tract, or malabsorption syndrome)
• QTc < 500 msec by EKG
• LVEF normal by MUGA or ECHO (for patients with hypertension or for patients > 60 years of age)
• NYHA class II cardiac function by baseline ECHO/MUGA (for patients who have received central thoracic radiotherapy that included the heart in the radiotherapy port, or for patients who have a history of class II heart failure but are asymptomatic on treatment are eligible)
• No history of stroke (cerebrovascular accident), transient ischemic attack, or cardiac event within the past 12 months, including any of the following:

• Myocardial infarction (including severe/unstable angina)
• Coronary/peripheral artery bypass graft
• Symptomatic congestive heart failure
• Pulmonary embolism
• No poorly controlled hypertension, defined as recurrent or persistent (≥ 24 hours) elevated blood pressure (i.e., systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg)
• No other malignancy within the past 5 years except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
• Peripheral neuropathy < grade 2

PRIOR CONCURRENT THERAPY:

• No prior tyrosine kinase inhibitors
• More than 5 years since prior chemotherapy, radiotherapy, or biologic therapy (e.g., trastuzumab or bevacizumab) for invasive breast cancer
• At least 7 days since prior hormonal therapy
• At least 7 days since prior and no concurrent strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) or grapefruit juice
• No concurrent CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's wort)
• No other concurrent therapy for the treatment of breast cancer except for bisphosphonates
• No concurrent brachytherapy