A Pharmacogenomics Study for Breast Cancer Patients Undergoing Adjuvant Chemotherapy With Doxorubicin (A)/Cyclophosphamide ©) and/or Weekly Paclitaxel

OBJECTIVES:

Primary

• Determine the pharmacogenomics of adjuvant chemotherapy comprising doxorubicin and cyclophosphamide and/or paclitaxel in women with nonmetastatic invasive breast cancer.
• Determine treatment-induced myelosuppression (e.g., neutropenia) in patients treated with adjuvant doxorubicin and cyclophosphamide who have polymorphisms in drug activation and metabolism genes.
• Correlate the incidence of peripheral neuropathy with pharmacogenomic analysis in patients treated with paclitaxel.

Secondary

• Determine response (i.e., relapse in the adjuvant setting) during a 10-year follow-up period in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients receive treatment on The Cancer and Leukemia Group B study(CALGB) CALGB-40101 OR are assigned to receive 1 of 2 treatment regimens on this study.

• Regimen 1: Patients receive doxorubicin IV over 10 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses.
• Regimen 2: Patients receive doxorubicin and cyclophosphamide as in regimen 1. Patients then receive paclitaxel IV over 1 hour once weekly for 12 weeks.

After completion of study treatment, patients are followed at 3, 6, and 12 months and then annually for up to 10 years.

PROJECTED ACCRUAL: A total of 500 patients (300 treated with doxorubicin and cyclophosphamide and 200 treated with paclitaxel) will be accrued for this study within 3-4 years.

Eligibility Criteria

• Histologically confirmed invasive breast cancer
• node negative stage > T1c or T1b with poor prognostic features (high grade, Her2/neu FISH positive, ER negative) or stage 2 (T2, N0) or
• enrolled on CALGB 40101, CALGB 49909, or the National Cancer Institute of Canada study MA-21 or
• any node positive patient or locally advanced undergoing neoadjuvant chemotherapy with either AC or paclitaxel
• Age greater than or equal to 18 years.
• >/=2 weeks from major surgery (wide excision / lumpectomy / mastectomy)
• No evidence of systemic metastasis
• Undergoing adjuvant treatment with standard dose AC or AC followed by weekly Paclitaxel at 80mg/m2
• Adequate bone marrow, hepatic and renal functions (absolute neutrophil count >1,500/ μl, platelet count > 100,000/ μl, serum creatinine <2.0 mg/dl, total Bilirubin <2.0 x the upper limit of normal (ULN)
• Ability to answer and understand study surveillance questionnaires
• No concurrent drug therapy (within 2 weeks) with agents that are known inducers or inhibitors of Cytochrome P450 (CYP450).

Exclusion criteria

• Other anticancer cytotoxic or endocrine therapy, immunotherapy, or biologic response modifiers,Study Drugs or other concomitant medications known to cause myelosuppression especially neutropenia and neuropathy
• Eastern Cooperative Oncology Group Performance Status(ECOG) functional status > 2.
• Serious co-morbidities including poorly controlled diabetes mellitus, ischaemic heart disease,uncontrolled hypertension or active infection.
• Pregnancy
• Use of growth factor during cycle 1 of chemotherapy (AC) under pharmacokinetic evaluation
• Grade >/=2 peripheral neuropathy symptoms based on National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) Scale. Exception: a chronic neurologic disorder will be reviewed on a case by case basis by the study PI.
• Prior treatment with weekly paclitaxelDISEASE CHARACTERISTICS:

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

• Node negative disease AND meets 1 of the following stage criteria:

• Primary tumor > T1c
• Primary tumor > T1b AND poor prognostic features, defined as the following:

• High-grade disease
• Human Epidermal Growth Factor Receptor 2 (HER2)/neu-positive disease by fluorescence in situ hybridization
• Estrogen receptor-negative disease
• Stage II disease (T2, N0)
• Node positive nonmetastatic disease
• Locally advanced disease AND receiving neoadjuvant chemotherapy comprising doxorubicin and cyclophosphamide OR paclitaxel
• Enrolled in clinical trial CALGB-40101
• No evidence of systemic metastasis
• Hormone receptor status:

• Not specified