Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Study Exploring the Efficacy of Capecitabine Given Concomitantly or in Sequence to EC-Doc With or Without Trastuzumab as Neoadjuvant Treatment of Primary Breast Cancer
Brief Summary: RATIONALE: Drugs used in chemotherapy, such as epirubicin, cyclophosphamide, docetaxel, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy together with monoclonal antibodies before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving monoclonal antibodies after surgery may kill any tumor cells that remain after surgery. It is not yet known whether combination chemotherapy is more effective with or without capecitabine and/or trastuzumab in treating breast cancer.

PURPOSE: This randomized phase III trial is studying epirubicin, cyclophosphamide, and docetaxel to compare how well they work with or without capecitabine and/or trastuzumab before surgery in treating women with stage I, stage II, or stage III breast cancer.


Options:
A: Inclusion criteria:

* Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the participants for treatment and follow-up.
* Accessible for treatment and follow-up at participating centers.
* Histologically proven breast cancer with an interval between definitive surgery that included axillary lymph node involvement assessment and registration of less than or equal to 60 days. A central pathology review might be performed post randomization for confirmation of diagnosis and molecular studies. The same block used for HER2neu determination prior to randomization might be used for the central pathology review.
* Definitive surgical treatment must be either mastectomy with axillary lymph node involvement assessment, or breast conserving surgery with axillary lymph node involvement assessment for operable breast cancer (T1-3, Clinical N0-1, M0). Margins of resected specimen from definitive surgery must be histologically free of invasive adenocarcinoma and/or ductal carcinoma in situ (DCIS).
* Participants must be either lymph node positive or high risk node negative. Lymph node positive participants were to be defined as participants having invasive adenocarcinoma with at least one axillary lymph node (pN1) showing evidence of tumor among a minimum of six resected lymph nodes. High risk lymph node negative participants were to be defined as participants having invasive adenocarcinoma with either 0 (pNo) among a minimum of 6 resected lymph nodes or negative sentinel node biopsy (pNo) and at least one of the following factors: tumor size \> 2 cm, estrogen receptor (ER) and/or progesteron receptor (PR) status was negative, histologic and/or nuclear grade 2-3, or age \< 35 years.
* Tumor must show the presence of the HER2neu gene amplification by Fluorescence In-Situ Hybridization (FISH analysis) by a designated central laboratory.
* Estrogen and/or progesterone receptor analysis performed on the primary tumor prior to randomization. Results must be known at the time of randomization.
* Karnofsky Performance status index ≥ 80%.
* Normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF) (multiple-gated acquisition \[MUGA\] scan) and electrocardiogram (ECG) within 3 months prior to registration. The result of the MUGA must be equal to or above the lower limit of normal for the institution.
* Laboratory requirements: (within 14 days prior to registration)

  a) Hematology: i) Neutrophils ≥ 2.0 109/L ii) Platelets ≥ 100 109/L iii) Hemoglobin ≥ 10 g/Dl

  b) Hepatic function: i) Total bilirubin ≤ 1 UNL ii) Aspartate aminotransferase (ASAT) (Serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine amino transferase (ALAT) (Serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 2.5 UNL iii) Alkaline phosphatase ≤ 5 UNL iv) Participants with ASAT and/or ALAT \> 1.5 x UNL associated with alkaline phosphatase \> 2.5 x UNL are not eligible for the study.

  c) Renal function: i) Creatinine ≤ 175 µmol/L (2 mg/dL) ii) If creatinine was 140 - 175 μmol/L, the calculated creatinine clearance should be ≥ 60 mL/min.
* Complete staging work-up within 3 months prior to registration. All participants had bilateral mammography, chest X-ray (posterioanterior \[PA\] and lateral) and/or computerized tomography (CT) and/or magnetic resonance imaging (MRI), abdominal ultrasound and/or CT scan and/or MRI, and bone scan. In cases of positive bone scans, bone X-ray evaluation was mandatory to rule out the possibility of metastatic bone scan positivity. Other tests may be performed as clinically indicated.
* Negative pregnancy test (urine or serum) within 7 days prior to registration for all women of childbearing potential.
* An audiology assessment with normal results was to be performed within 4 weeks of registration. This was only for those centers who had selected cisplatin as their platinum salt of choice for the BCIRG 006 study.

Exclusion criteria:

* Prior systemic anticancer therapy for breast cancer (immunotherapy, hormonotherapy, chemotherapy).
* Prior anthracycline therapy, taxoids (paclitaxel, docetaxel) or platinum salts for any malignancy.
* Prior radiation therapy for breast cancer.
* Bilateral invasive breast cancer.
* Pregnant, or lactating participants. Participants of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment (chemotherapy and tamoxifen therapy) and must had negative urine or serum pregnancy test within 7 days prior to registration.
* Any T4 or N2 or known N3 or M1 breast cancer.
* Pre-existing motor or sensory neurotoxicity of a severity ≥ grade 2 by National Cancer Institute (NCI) criteria.
* Cardiac disease that would preclude the use of doxorubicin, docetaxel and Herceptin:

  1. any documented myocardial infarction
  2. angina pectoris that required the use of antianginal medication
  3. any history of documented congestive heart failure
  4. Grade 3 or Grade 4 cardiac arrhythmia (NCI Common Terminology Criteria \[CTC\], version 2.0)
  5. clinically significant valvular heart disease
  6. participants with cardiomegaly on chest x-ray or ventricular hypertrophy on ECG, unless they demonstrate by MUGA scan within the past 3 months that the LVEF was ≥ the lower limit of normal for the radiology facility;
  7. participants with poorly controlled hypertension i.e. diastolic greater than 100 mm/Hg. (Participants who were well controlled on medication were eligible for entry)
  8. participants who currently received medications (digitalis, beta-blockers, calcium channel-blockers, etc) that altered cardiac conduction, if these medications were administered for cardiac arrhythmia, angina or congestive heart failure. If these medications were administered for other reasons (ie hypertension), the participant was eligible.
* Other serious illness or medical condition:

  1. history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
  2. active uncontrolled infection
  3. active peptic ulcer, unstable diabetes mellitus
  4. impaired hearing (only for those participants treated at centers who had selected cisplatin as their platinum salt of choice)
* Past or current history of neoplasm other than breast carcinoma, except for:

  1. curatively treated non-melanoma skin cancer
  2. in situ carcinoma of the cervix
  3. other cancer curatively treated and with no evidence of disease for at least 10 years
  4. ipsilateral DCIS of the breast
  5. lobular carcinoma in-situ (LCIS) of the breast
* Current therapy with any hormonal agent such as raloxifene, tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention. Participants must had discontinued these agents prior to randomization.
* Chronic treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose (≤ 20 mg methylprednisolone or equivalent).
* Concurrent treatment with ovarian hormonal replacement therapy. Prior treatment must be stopped prior to randomization.
* Definite contraindications for the use of corticosteroids.
* Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
* Concurrent treatment with any other anti-cancer therapy.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
B: Inclusion criteria

* The patient must have a life expectancy of at least 10 years, excluding her diagnosis of breast cancer. (Comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer.)
* The interval between the last surgery for breast cancer treatment (lumpectomy, mastectomy, axillary dissection, or re-excision of lumpectomy margins) and randomization must be less than or equal to 84 days.
* All of the following staging criteria must be met:

  * Primary tumor must be T1-3 by clinical and pathologic evaluation.
  * Ipsilateral nodes must be cN0-1 by clinical evaluation.
  * Ipsilateral nodes must be pN1, pN2a, or pN3a by pathologic evaluation.
  * M0
* Patients must have undergone either a total mastectomy and an axillary dissection or a lumpectomy and an axillary dissection. Sentinel node biopsy is permitted, but must be followed by an axillary dissection.
* The tumor must be invasive adenocarcinoma on histologic examination.
* The tumor must be determined to be HER2-positive prior to randomization. Assays performed using fluorescent in situ hybridization (FISH) require gene amplification to be eligible. Assays using immunohistochemistry (IHC) must be performed at an NSABP-approved reference laboratory and require a strongly positive staining score.
* Patients must have an analysis of both estrogen and progesterone receptors performed on the primary tumor prior to randomization. "Marginal," "borderline," etc., results (i.e., those not definitely negative) will also be considered positive regardless of the methodology used.
* At the time of randomization, the patient must have had the following: history and physical exam, EKG, and PA and lateral chest x-ray within the past 3 months; and a bilateral mammogram (or unilateral if patient has had a mastectomy) and a pelvic exam (for women who have a uterus and who will be taking tamoxifen) within the past year.
* Within 3 months prior to entry, the patient must have a baseline left ventricular ejection fraction (LVEF) measured by MUGA scan equal to or greater than the lower limit of normal for the radiology facility. (If LVEF is \> 75%, the investigator should consider having the LVEF determination reviewed prior to randomization. Following randomization, the LVEF determination may be reviewed up until the time of the post-AC MUGA. Please note that if a more accurate value is obtained from the review of the baseline MUGA, the corrected value must be submitted to the NSABP Biostatistical Center before the post-AC MUGA is performed.)
* At the time of randomization:

  * The postoperative absolute neutrophil count (ANC) must be ≥ 1500/mm3 (or \<1500/mm3 if, in the opinion of the investigator, this represents an ethnic or racial variation of normal).
  * Postoperative platelet count must be ≥ 100,000/mm3. Significant underlying hematologic disorders must be excluded when the platelet count is above the upper limit of normal for the lab.
* There must be postoperative evidence of adequate hepatic function, i.e., total bilirubin must be ≤ ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation (\>ULN to ≤1.5 x ULN) due to Gilbert's disease or similar syndrome; and alkaline phosphatase must be \<2.5 times the ULN for the lab; and the serum glutamic-oxaloacetic transaminase (SGOT \[AST\]) must be \<1.5 times the ULN for the lab.
* There must be postoperative evidence of adequate renal function (serum creatinine within or less than the institution's normal range).
* Patients must have no clinical or radiologic evidence of metastatic disease. Suspicious findings must be confirmed as benign by radiologic evaluation or biopsy. A patient with skeletal pain is eligible for inclusion in the study if bone scan and/or roentgenological examination fails to disclose metastatic disease.
* Patients with a history of non-breast malignancies are eligible if they have been disease-free for 5 or more years prior to randomization and are deemed by their physician to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: carcinoma in situ of the cervix, melanoma in situ, and basal cell and squamous cell carcinoma of the skin.
* Prior to randomization, the investigator must designate whether the patients who had a lumpectomy will receive local or locoregional radiation therapy. For patients who had a mastectomy, the investigator must designate whether or not the patient will receive radiation therapy. (Pre-randomization discussion and/or consultation with a radiation oncologist is encouraged.) Note: Irradiation of any internal mammary nodes is prohibited in this trial.
* Special conditions for eligibility of lumpectomy patients: irradiation and surgery
* Patients treated by lumpectomy and axillary node dissection to be followed by breast radiation therapy must meet all the eligibility criteria in addition to the following: Generally, lumpectomy should be reserved for tumors \<5 cm. However, at the investigator's discretion, patients treated with lumpectomy for tumors ≥ 5 cm are eligible. The margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. In patients in whom pathologic examination demonstrates tumor present at the line of resection, additional operative procedures may be performed to obtain clear margins. This is permissible even if axillary dissection has been performed. Patients in whom tumor is still present at the resected margin after re-excision(s) must undergo total mastectomy to be eligible. Whole breast irradiation is required. Irradiation of regional lymph nodes is optional, but partial breast irradiation and irradiation of any internal mammary nodes are prohibited in this trial. Intent to irradiate the axilla or other regional node groups must be declared by the investigator prior to randomization for stratification purposes.
* Special conditions for eligibility of mastectomy patients: irradiation. The decision to use locoregional irradiation in patients who have undergone total mastectomy and axillary node dissection must be declared by the investigator prior to randomization for stratification purposes. Failure to adhere to the radiation therapy plan will be a protocol violation.

Exclusion criteria

* Bilateral malignancy or a mass or mammographic abnormality in the opposite breast suspicious for malignancy unless there is biopsy proof that the mass is not malignant.
* Primary tumor staged as T4 for any reason.
* Nodes staged as clinical N2 or N3 for any reason and nodes staged as pathologic pN2b, pN3b, or pN3c.
* Prior history of breast cancer, including DCIS (patients with a history of lobular carcinoma in situ \[LCIS\] are eligible).
* Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy administered for the currently diagnosed breast cancer prior to randomization. The only exception is hormonal therapy, which may have been given for up to a total of 28 days anytime after diagnosis and before randomization. In such a case, hormonal therapy must stop at or before randomization and be re-started if indicated following chemotherapy.
* Prior anthracycline or taxane therapy for any malignancy.
* Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement therapy, etc. (These patients are eligible only if this therapy is discontinued prior to randomization.)
* Therapy with any hormonal agents such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or prevention. (Patients are eligible only if these medications are discontinued prior to randomization. These medications are not permitted while on the study except for the use of tamoxifen as described in the protocol)
* Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude a patient from being subjected to any of the treatment options or would prevent prolonged follow-up.
* Cardiac disease that would preclude the use of Adriamycin, Taxol or Herceptin. This includes:
* Active cardiac disease:

  * angina pectoris that requires the use of antianginal medication;
  * cardiac arrhythmia requiring medication;
  * severe conduction abnormality;
  * clinically significant valvular disease;
  * cardiomegaly on chest x-ray;
  * ventricular hypertrophy on EKG; or
  * patients with poorly controlled hypertension, i.e., diastolic greater than 100 mm/Hg. (Patients with hypertension who are well controlled on medication are eligible for entry.)
* History of cardiac disease:

  * myocardial infarction documented as a clinical diagnosis or by EKG or any other tests;
  * documented congestive heart failure; or
  * documented cardiomyopathy.
* Psychiatric or addictive disorders that would preclude obtaining informed consent.
* Pregnancy or lactation at the time of proposed randomization. This protocol excludes pregnant or lactating women based on the fetal toxicity of both tamoxifen and Taxol which are listed as Pregnancy Category D agents. Pregnant women who received tamoxifen have experienced fetal deaths, birth defects, spontaneous abortions, and vaginal bleeding. Women of reproductive potential must agree to use an effective barrier method of contraception. Hormonal birth control methods are not permitted.
* Sensory/motor neuropathy ≥ grade 2, as defined by the NCI's Common Toxicity Criteria version 2.0.
* Contraindications to corticosteroid use which, in the opinion of the investigator, would preclude participation in this study.
* Concurrent treatment with other investigational agents.
* Sensitivity to benzyl alcohol.
* Special conditions for ineligibility of lumpectomy patients: irradiation and surgery. For patients treated by lumpectomy with axillary dissection, breast irradiation is required. Please see guidelines for radiation therapy in Appendix A. In addition, the following patients will also be ineligible:

  * Patients with diffuse tumors (as demonstrated on mammography) that would not be considered surgically amenable to lumpectomy.
  * Patients treated with lumpectomy in whom there is another clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant. Such a mass must be biopsied and demonstrated to be histologically benign prior to randomization or, if malignant, must be surgically removed with clear margins.
  * Patients in whom the margins of the resected specimen are involved with invasive tumor or ductal carcinoma in situ (DCIS). Additional surgical resections to obtain free margins are allowed. Patients in whom tumor is still present after the additional resection(s) must undergo mastectomy to be eligible.
C: DISEASE CHARACTERISTICS:

* Histologically confirmed unilateral or bilateral primary breast cancer

  * Meets 1 of the following staging criteria:

    * Clinical stage T4 or T3 disease
    * Clinical stage T1 and pathologic stage N+ by sentinel lymph node biopsy OR clinical stage T2, N+ disease AND estrogen receptor (ER) or progesterone receptor (PR) positive tumor
    * ER and PR negative tumor (T1-4, N0-3, M0)
* Disease confirmed by core biopsy

  * No fine-needle aspiration or incisional biopsy
* Bidimensionally measurable disease\*

  * Tumor lesion palpable and measures ≥ 2 cm OR tumor lesion ≥ 1 cm in maximum diameter by sonography

    * For inflammatory disease, extent of inflammation can be used as measurable lesion NOTE: \*In patients with multifocal or multicentric breast cancer, the largest lesion should be measured
* Candidate for adjuvant chemotherapy

  * No low- or moderate-risk patients who are doubtful candidates for adjuvant chemotherapy and do not fulfill the staging criteria
* Known HER-2/neu status by core biopsy

  * HER-2/neu positive tumor is defined as +3 by immunohistochemistry \[IHC\] OR positive by fluorescence in situ hybridization (FISH)
* No evidence of distant metastasis
* Hormone receptor status:

  * ER- or PR-positive tumor OR ER- and PR-negative tumor

PATIENT CHARACTERISTICS:

* No male patients
* Menopausal status not specified
* Karnofsky performance status 80-100%
* Life expectancy ≥ 10 years (disregarding diagnosis of cancer)
* Normal cardiac function confirmed by ECG
* LVEF ≥ 55% by cardiac ultrasound
* Neutrophil count ≥ 2,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin ≥ 10 g/dL
* Bilirubin normal
* AST and ALT ≤ 2.5 times upper limit of normal (ULN)
* Alkaline phosphatase (AP) ≤ 5 times ULN OR
* AP ≤ 2.5 times ULN AND AST and/or ALT ≤ 1.5 times ULN
* Creatinine ≤ 2 mg/dL
* Creatinine clearance ≥ 50 mL/min
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective nonhormonal contraception
* No motor or sensory neuropathy ≥ grade 2
* No other malignancy within the past 5 years except carcinoma in situ of the cervix or nonmelanoma skin cancer
* No New York Heart Association class II-IV congestive heart failure
* No coronary artery disease
* No history of myocardial infarction
* No uncontrolled arterial hypertension (i.e., blood pressure ≥ 160/90 mm Hg despite antihypertensive therapy)
* No rhythm abnormalities requiring permanent therapy
* No history of significant neurological or psychiatric disorders including psychotic disorders, dementia, or seizures that would preclude giving informed consent
* No active infection
* No active peptic ulcer
* No unstable diabetes mellitus or insulin-dependent type II diabetes mellitus
* No other serious illness or medical condition
* No known hypersensitivity reaction to investigational compounds or incorporated substances
* No definite contraindications for the use of corticosteroids
* No known dihydropyrimidine dehydrogenase deficiency
* Must be fit for anthracycline/taxane-containing chemotherapy

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy for any malignancy
* No prior radiation therapy for breast cancer
* No concurrent bisphosphonates during chemotherapy

  * Bisphosphonates allowed postoperatively
* No chronic treatment with corticosteroids unless it is initiated \> 6 months prior to study entry and is given at low doses (≤ 20 mg methylprednisolone or equivalent)
* No concurrent amifostine during chemotherapy
* No concurrent cardioprotectors (e.g., dexrazoxane) during chemotherapy
* No concurrent sex hormone therapy
* No concurrent virostatic agents (e.g., sorivudine or brivudine)
* No concurrent aminoglycosides
* No other concurrent experimental drugs or anticancer therapy
* At least 30 days since prior participation in another clinical trial with any investigational (not marketed) drug
D: Inclusion Criteria:

* Non-metastatic primary invasive breast cancer overexpressing HER2 (determined by immunohistochemistry 3+ or positive fluorescence in situ hybridization test) that has been histologically confirmed, adequately excised, axillary node positive or negative, and tumor size at least T1c according to Tumor/Node/Metastasis (TNM) staging
* Completion of at least 4 cycles of (neo-)adjuvant systemic chemotherapy, definitive surgery, and radiotherapy, if applicable
* Known hormone receptor status
* Baseline left ventricular ejection fraction (LVEF) greater than or equal to (≥) 55 percent (%)

Exclusion Criteria:

* Prior invasive breast carcinoma
* Other malignancies except for curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix
* Clinical T4 tumors
* Cumulative doxorubicin exposure greater than (\>) 360 milligrams per meter-squared (mg/m\^2) or epirubicin \>720 mg/m\^2 or any prior anthracyclines unrelated to the present breast cancer
* Peripheral stem cell or bone marrow stem cell support
* Prior mediastinal irradiation except for internal mammary node irradiation for the present breast cancer
* Non-irradiated internal mammary nodes or supraclavicular lymph node involvement
* Prior anti-HER2 therapy for any other reason or other prior biologic or immunotherapy for breast cancer
* Concurrent anti-cancer treatment in another investigational trial
* Serious cardiac or pulmonary conditions/illness, or any other conditions that could interfere with planned treatment
* Poor hematologic, hepatic, or renal function
* Pregnancy or lactation
* Women of childbearing potential or less than 1 year post-menopause unwilling to use adequate contraceptive measures

Answer: C