Phase II Trial for Large ER-Negative Breast Cancers
Condition: Malignant Neoplasm of Female Breast
MeSH terms: Neoplasms
Intervention: Epirubicin; Cyclophosphamide; Docetaxel; Capecitabine; Radiation Therapy
Intervention description: Epirubicin 90 mg/m2 d1 q3w; Cyclophosphamide 600 mg/m2 d1 q3w; Docetaxel 75 mg/m2 d1 q3w; Capecitabine 1000 mg/m2/dose bid x 14d q3w; Standard dosing, fields depending on clinical findings
Intervention MeSH terms: Cyclophosphamide; Docetaxel; Capecitabine; Epirubicin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: randomized sequence of therapy.
Masking: None (Open Label)
Enrollment: 72.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Malignant; Neoplasm; Cancer; Female; Breast; Stage II; Stage III

Summary:

      A primary objective of this study is to evaluate the in vivo response of tumor to
      chemotherapy through gene microarray analysis. Neoadjuvant treatment allows the unique
      opportunity to observe the in vivo effects of cytotoxic therapy on gene expression in tumor
      tissue. The investigators plan to evaluate several different questions by comparing gene
      profiles in different phases of treatment in this study. These are outlined below.

      Hypotheses

        1. Chemotherapy enriches for tumor cell populations that have enhanced resistance and
           survival mechanisms. These mechanisms will in part be identifiable through changes in
           gene expression profiles pre vs. post treatment.

        2. Use of two distinct chemotherapy selection pressures, for example a DNA-damaging regimen
           (epirubicin and cyclophosphamide) or a mitotic spindle/metabolic targeted regimen
           (docetaxel and capecitabine), will allow for the identification of a smaller set of
           genes associated to resistance and survival mechanisms of broad importance.

        3. Genes associated with enrichment for resistance and survival mechanisms will not be
           present in large amounts pretreatment in tumors destined for complete pathologic
           response.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Written informed consent

          -  The diagnosis of breast cancer can be made by fine-needle aspiration (FNA), core, or
             tru-cut biopsy. Biopsy must demonstrate invasive adenocarcinoma.

          -  Patients must have a life expectancy of at least 1 year, excluding their diagnosis of
             cancer.

          -  Patients must have a mass on clinical or radiological examination of >1 cm and must be
             confined to either the breast or to the breast and ipsilateral axilla. Multiple masses
             permitted, provided one of them is >1cm.

          -  Patients may enter prior to ER or Her2 status being known, however if Her2 is
             positive, then the patient is withdrawn from the treatment phase of the trial.

          -  Patients with palpable mass with distant metastasis and/or palpable supraclavicular
             lymphadenopathy allowed if definitive local treatment is judged to be necessary.

          -  Patients may have inflammatory breast cancer.

          -  Prior to time of entry, patients must have had the following:

          -  history and physical exam

          -  blood tests

          -  chest imaging within the last 3 months (chest x-ray, CT scan, PET/CT)

          -  bilateral mammogram

          -  Ultrasound of tumor with placement of clip to localize tumor should it respond
             completely to chemotherapy is recommended

          -  Bone scan and MRI of the breast as clinically indicated.

          -  Patients with clinically palpable lymph nodes are recommended to have a FNA biopsy to
             document the lymph node status. Patients may undergo a sentinel node biopsy procedure
             prior to preoperative chemotherapy.

          -  At time of entry

          -  White blood cell count (WBC) > 3,000

          -  platelet count > 100,000

          -  bilirubin, serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate
             oxaloacetate transaminase (SGPT), alkaline phosphatase, and serum creatinine must all
             be < 1.2 x upper limit of normal (ULN)

          -  calculated creatinine clearance [Cockcroft-Gault] > 50 ml/min. normalized to a 1.73 m2
             body surface area (BSA). Patients with benign hyperbilirubinemia are also excluded.

          -  Patients with bone pain are eligible for inclusion if bone scan and/or
             roentgenological exam fail to disclose metastatic disease, or if metastatic disease is
             found, definitive local treatment is to be performed.

          -  Patients with non-breast malignancies are eligible if they have not received prior
             chemotherapy, or extensive radiation therapy, and are free from disease for at least
             two years. Patients with squamous or basal carcinoma of the skin that has been
             effectively treated, carcinoma in situ of the cervix that has been treated by surgery
             only are eligible. Patients with prior or simultaneous lobular or ductal carcinoma in
             situ of the ipsilateral or contralateral breast are also eligible. Patients with
             bilateral breast cancer for which at least one of the breast cancers meet the
             eligibility requirements are also eligible.

          -  Has a negative serum or urine pregnancy test within 7 days prior to initiation of
             chemotherapy (female patients of childbearing potential).

        Exclusion Criteria:

          -  Patients with Her2 positive breast cancer

          -  Pregnancy or breast feeding at the time of proposed randomization. Women of
             childbearing potential with either a positive or no pregnancy test at baseline. Woman
             of childbearing potential not using a reliable and appropriate contraceptive method.
             (Postmenopausal woman must have been amenorrheic for at least 12 months to be
             considered of non-childbearing potential). Patients will agree to continue
             contraception for 30 days from the date of the last study drug administration.

          -  Participation in any investigational drug study within 4 weeks preceding the start of
             study treatment.

          -  Prior unanticipated severe reaction to fluoropyrimidine therapy, or known sensitivity
             to 5-fluorouracil.

          -  Prior therapy for this breast cancer.

          -  Prior chemotherapy for a different breast cancer. Patients who have received prior
             anthracycline therapy for any malignancy are not eligible.

          -  Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
             preclude the patient from being subjected to any of the treatment options or surgery
             or would prevent prolonged follow-up.

          -  Active cardiac disease that would preclude the use of epirubicin. This includes:

          -  Any documented myocardial infarction or unstable angina;

          -  Any history of documented congestive heart failure;

          -  Valvular disease with documented cardiac function compromise;

          -  Patients with cardiomegaly on chest X-ray, or ventricular hypertrophy on EKG, unless
             they demonstrate adequate left ventricular ejection fraction (LVEF) > 45% by MUltiple
             Gated Acquisition (MUGA) or echocardiogram.

          -  Patients with a cardiac arrhythmia are eligible, provided the arrhythmia is not
             associated with concomitant heart failure or cardiac dysfunction.

          -  History of uncontrolled seizures, central nervous system disorders or psychiatric
             disability judged by the investigator to be clinically significant, precluding
             informed consent, or interfering with compliance of oral drug intake.

          -  Lack of physical integrity of the upper gastrointestinal tract or malabsorption
             syndrome.

          -  Known, existing uncontrolled coagulopathy

          -  Unwillingness to give written informed consent.

          -  Unwillingness to participate or inability to comply with the protocol for the duration
             of the study.