Phase II Trial for Large ER-Negative Breast Cancers
Phase II Trial for Large ER-Negative Breast Cancers
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.
The clinical outcomes of breast cancer treatment are remarkably similar regardless of the
 regimen used, even though the individual drugs may differ substantially in mechanisms of
 action. We are interested in identifying a set of genes that may be associated with breast
 cancer cell survival following selection by chemotherapy. We intend to use two different
 selection pressures (different chemotherapy regimens with different mechanisms of action) in
 order to focus on those genes that are regulated similarly in response to either regimen.

 Neoadjuvant chemotherapy is in common use for locally advanced breast cancers. Although it
 does not yet appear to impart a survival advantage, it does enhance the likelihood of breast
 conserving surgery and also provides important prognostic information. Taxotere appears to
 add significantly to pathologic complete responses when added to doxorubicin and
 cyclophosphamide alone. The combination of capecitabine and docetaxel was superior to
 docetaxel alone in metastatic disease. Many investigators are interested in incorporating
 this regimen for the treatment of earlier stages of breast cancer.
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.