Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer
Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer
This randomized phase III clinical trial studies chemotherapy with or without trastuzumab
 after surgery to see how well they work in treating women with invasive breast cancer. Drugs
 used in chemotherapy work in different ways to stop the growth of tumor cells, either by
 killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving
 more than one drug (combination chemotherapy) and giving chemotherapy after surgery may kill
 more tumor cells. Monoclonal antibodies, such as trastuzumab, can block cancer growth in
 different ways. Some block the ability of tumor cells to grow and spread. Others find tumor
 cells and help kill them or carry tumor-killing substances to them. It is not yet known
 whether combination chemotherapy is more effective with trastuzumab in treating breast
 cancer.
PRIMARY OBJECTIVES:

 I. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves
 invasive disease-free survival (IDFS) in women with resected node-positive or high-risk
 node-negative breast cancer which is reported as human epidermal growth factor receptor
 (HER)2-low by all HER2 testing performed.

 SECONDARY OBJECTIVES:

 I. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves
 disease-free survival (DFS)-ductal carcinoma in situ (DCIS) in women with resected
 node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all
 HER2 testing performed.

 II. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves
 breast cancer-free survival (BCFS) in women with resected node-positive or high-risk
 node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

 III. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves
 recurrence-free interval (RFI) in women with resected node-positive or high-risk
 node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

 IV. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves
 distant recurrence-free interval (DRFI) in women with resected node-positive or high-risk
 node-negative breast cancer which is reported as HER2-low by all HER2 testing performed.

 V. To determine whether the addition of trastuzumab to chemotherapy (TC or AC→WP) improves
 overall survival (OS) in women with resected node-positive or high-risk node-negative breast
 cancer which is reported as HER2-low by all HER2 testing performed.

 VI. To evaluate the associations between amenorrhea and circulating reproductive hormone
 levels, and the associations between chemotherapy regimen, amenorrhea, and IDFS benefit in
 premenopausal women eligible at baseline for the menstrual history assessments.

 VII. To evaluate the toxicity associated with each of the regimens. VIII. To test the
 hypothesis that the HER2 messenger ribonucleic acid (mRNA) level is the predictor of the
 degree of benefit from trastuzumab and the threshold for benefit in the adjuvant setting is
 lower than defined by current American Society of Clinical Oncology (ASCO)/College of
 American Pathologists (CAP) Guidelines for HER2 assays (immunohistochemistry [IHC] and
 fluorescent in situ hybridization [FISH]).

 IX. To identify and/or validate molecular predictors of the degree of benefit from the
 addition of trastuzumab to chemotherapy (TC or AC→WP).

 X. To test the alternative hypothesis that the main determinant of trastuzumab response in
 the adjuvant setting of HER2-low breast cancer is through antibody-dependent cellular
 cytotoxicity (ADCC) by demonstrating that the polymorphism of the Fcgamma receptor gene is
 predictive of the degree of benefit from the addition of trastuzumab to chemotherapy (TC or
 AC→WP).

 XI. To examine the relationship between behavioral host factors (obesity, tobacco, alcohol)
 and comorbid conditions that may influence systemic inflammation and breast cancer outcomes,
 controlling for tumor/stage characteristics and treatment assignment.

 XII. To examine the relationship between medication exposures that may influence systemic
 inflammation and breast cancer outcomes, controlling for tumor/stage characteristics and
 treatment assignment.

 XIII. To examine the relationship between comorbid conditions, medication exposures, and
 behavioral host factors together and breast cancer outcomes, controlling for tumor/stage
 characteristics and treatment assignment.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 NOTE: *Chemotherapy regimen is based on the investigator's preference.

 ARM I:

 GROUP IA: Patients receive docetaxel intravenously (IV) over 60 minutes and cyclophosphamide
 IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 cycles in the absence of
 disease progression or unacceptable toxicity.

 GROUP IB: Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide
 IV over 30 minutes on day 1. Treatment repeats every 2 or 3 weeks for 4 cycles in the absence
 of disease progression or unacceptable toxicity. Beginning 2-3 weeks after last dose of
 doxorubicin hydrochloride and cyclophosphamide, patients also receive paclitaxel IV over 60
 minutes once weekly for 12 doses in the absence of disease progression or unacceptable
 toxicity.

 ARM II:

 GROUP IIA: Patients receive docetaxel and cyclophosphamide as in Group IA. Patients also
 receive trastuzumab IV over 30-90 minutes on day 1. Courses repeat every 3 weeks for 1 year
 in the absence of disease progression or unacceptable toxicity.

 GROUP IIB: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in
 Group IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses and
 then every 3 weeks for subsequent doses. Treatment repeats every 3 weeks for 1 year in the
 absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 6 months for 5 years and
 then every 12 months for 5 years.
Inclusion Criteria:

 -  Patients should have a life expectancy of at least 10 years, excluding their diagnosis
 of breast cancer; (comorbid conditions should be taken into consideration, but not the
 diagnosis of breast cancer)

 -  Women of reproductive potential must agree to use an effective non-hormonal method of
 contraception (for example condoms, some intrauterine devices, diaphragms, tubal
 ligation, vasectomized partner, or abstinence) during therapy and for at least 6
 months (Arm 1 patients) and for at least 7 months (Arm 2 patients) after the last dose
 of study therapy (chemotherapy or trastuzumab)

 -  Submission of tumor samples from the breast surgery is required for all patients;
 therefore, the local pathology department policy regarding release of tumor samples
 must be considered in the screening process; patients whose tumor samples are located
 in a pathology department that by policy will not submit any samples for research
 purposes should not be approached for participation in the B-47 trial

 -  The patient must have signed and dated an Institutional Review Board (IRB)-approved
 consent form that conforms to federal and institutional guidelines

 -  Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1

 -  The tumor must be unilateral invasive adenocarcinoma of the breast on histologic
 examination

 -  All of the following staging criteria (according to the 7th edition of the American
 Joint Committee on Cancer [AJCC] Cancer Staging Manual) must be met:

 -  By pathologic evaluation, primary tumor must be pT1-3

 -  By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b,
 pN1c), pN2a, pN2b, pN3a, or pN3b

 -  If pN0, one of the following criteria must be met:

 -  pT2 and estrogen receptor (ER) negative and progesterone receptor (PgR)
 negative; or

 -  pT2 and ER positive (PgR status may be positive or negative) and either
 grade 3 histology or Oncotype DX Recurrence Score of >= 25; or

 -  pT3 regardless of hormone receptor status, histologic grade, and
 Oncotype DX Recurrence Score

 -  HER2 status of the primary tumor must be evaluated prior to randomization; all testing
 performed must indicate that the tumor is HER2-low as defined below

 -  IHC must be performed and the IHC staining results must indicate a score of 1+
 (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be
 performed and must indicate that the tumor is HER2-low as described below)

 -  If ISH testing is performed, test results must be as follows and IHC must be 1+
 or 2+: the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be < 2.0
 or, if a ratio was not performed, the HER2 gene copy number must be < 4 per
 nucleus

 -  Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+
 to 2+, the higher intensity score in the range should be used to determine
 eligibility

 -  The patient must have undergone either a total mastectomy or breast-conserving surgery
 (lumpectomy); (patients who have had a nipple-sparing mastectomy are eligible)

 -  For patients who undergo lumpectomy, the margins of the resected specimen must be
 histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as
 determined by the local pathologist; if pathologic examination demonstrates tumor at
 the line of resection, additional operative procedures may be performed to obtain
 clear margins; if tumor is still present at the resected margin after re-excision(s),
 the patient must undergo total mastectomy to be eligible; (patients with margins
 positive for lobular carcinoma in situ [LCIS] are eligible without additional
 resection)

 -  For patients who undergo mastectomy, margins must be free of gross residual tumor;
 (patients with microscopic positive margins are eligible as long as post-mastectomy
 radiation therapy [RT] of the chest wall will be administered)

 -  The patient must have completed one of the procedures for evaluation of pathologic
 nodal status listed below:

 -  Sentinel lymphadenectomy alone:

 -  If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b

 -  If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or
 pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the
 nodal involvement must be limited to 1 or 2 positive nodes

 -  Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph
 nodes if the sentinel node (SN) is positive; or

 -  Axillary lymphadenectomy with or without SN isolation procedures

 -  The interval between the last surgery for breast cancer (treatment or staging) and
 randomization must be no more than 84 days

 -  The patient must have ER analysis performed on the primary tumor prior to
 randomization; if ER analysis is negative, then PgR analysis must also be performed
 (either the core biopsy or surgical resection specimen can be used for ER/PgR
 testing); patients with a primary tumor that is hormone receptor-positive or
 receptor-negative are eligible

 -  Absolute neutrophil count (ANC) must be >= 1,200/mm^3

 -  Platelet count must be >= 100,000/mm^3

 -  Hemoglobin must be >= 10 g/dL

 -  Total bilirubin must be =< upper limit of normal (ULN) for the lab unless the patient
 has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert disease or similar
 syndrome involving slow conjugation of bilirubin

 -  Alkaline phosphatase must be =< 2.5 x ULN for the lab

 -  Aspartate aminotransferase (AST) must be =< 1.5 x ULN for the lab (if alanine
 aminotransferase [ALT] is performed instead of AST [per institution's standard
 practice], the alanine aminotransferase [ALT] value must be =< 1.5 x ULN; if both were
 performed, the AST must be =< 1.5 x ULN)

 -  Alkaline phosphatase and AST may not both be > the ULN

 -  Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the
 study if liver imaging (computed tomography [CT], magnetic resonance imaging [MRI],
 positron emission tomography [PET]-CT, or PET scan) performed within 90 days prior to
 randomization does not demonstrate metastatic disease and the above requirements are
 met

 -  Patients with alkaline phosphatase that is > ULN but =< 2.5 x ULN or unexplained bone
 pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan
 performed within 90 days prior to randomization does not demonstrate metastatic
 disease

 -  The most recent postoperative serum creatinine performed within 6 weeks prior to
 randomization must be =< ULN for the lab

 -  Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days
 prior to randomization; LVEF assessment performed by 2-dimensional (D) echocardiogram
 is preferred, however, multi-gated acquisition (MUGA) scan maybe substituted based on
 institutional preferences

 -  For patients who will receive the TC chemotherapy regimen, the LVEF must be >=
 50% regardless of the cardiac imaging facility's lower limit of normal

 -  For patients who will receive the AC-->WP chemotherapy regimen, the LVEF must be
 >= 55% regardless of the cardiac imaging facility's lower limit of normal

 -  NOTE: Since the pre-entry LVEF serves as the baseline for comparing subsequent
 LVEF assessments, it is critical that this baseline study be an accurate
 assessment; if the baseline LVEF is > 70%, the investigator is encouraged to have
 the accuracy of the initial LVEF result confirmed and repeat the test if the
 accuracy is uncertain

 Exclusion Criteria:

 -  Primary tumor with any of the following HER2 testing results:

 -  IHC staining intensity:

 -  0 on all evaluations of specimens

 -  3+ on evaluation of any specimen

 -  ISH with a ratio of HER2 to CEP17 >= 2.0 on evaluation of any specimen

 -  ISH result indicating HER2 gene copy number >= 4 per nucleus on evaluation of any
 specimen

 -  T4 tumors including inflammatory breast cancer

 -  Definitive clinical or radiologic evidence of metastatic disease

 -  NOTE: Chest imaging (mandatory for all patients) and other imaging (if required)
 must have been performed within 90 days prior to randomization

 -  Synchronous or previous contralateral invasive breast cancer (patients with
 synchronous and/or previous contralateral DCIS or LCIS are eligible)

 -  Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS;
 (patients with synchronous or previous ipsilateral LCIS are eligible)

 -  History of non-breast malignancies (except for in situ cancers treated only by local
 excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior
 to randomization

 -  Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy

 -  Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast
 cancer prior to randomization

 -  Whole-breast RT prior to randomization or partial-breast RT that cannot be completed
 on or before the date of randomization

 -  Continued endocrine therapy such as raloxifene or tamoxifen (or other selective
 estrogen receptor modulator [SERM]) or an aromatase inhibitor; patients are eligible
 if these medications are discontinued prior to randomization

 -  Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone
 replacement therapy; patients are eligible if these medications are discontinued prior
 to randomization

 -  Cardiac disease (history of and/or active disease) that would preclude the use of the
 drugs included in the treatment regimens; this includes but is not confined to:

 -  Active cardiac disease:

 -  Angina pectoris that requires the current use of anti-anginal medication

 -  Ventricular arrhythmias except for benign premature ventricular contractions

 -  Supraventricular and nodal arrhythmias requiring a pacemaker or not
 controlled with medication

 -  Conduction abnormality requiring a pacemaker

 -  Valvular disease with documented compromise in cardiac function

 -  Symptomatic pericarditis

 -  History of cardiac disease:

 -  Myocardial infarction documented by elevated cardiac enzymes or persistent
 regional wall abnormalities on assessment of left ventricle (LV) function

 -  History of documented congestive heart failure (CHF)

 -  Documented cardiomyopathy

 -  Hypertension defined according to the following ineligibility criteria:

 -  For patients who will receive TC (regardless of the patient's age): uncontrolled
 hypertension defined as sustained systolic blood pressure (BP) > 150 mm Hg or
 diastolic BP > 90 mm Hg; (patients with initial BP elevations are eligible if
 initiation or adjustment of BP medication lowers pressure to meet entry criteria)

 -  For patients < 50 years old who will receive AC-->WP: uncontrolled hypertension
 defined as sustained systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg; patients
 with initial BP elevations are eligible if initiation or adjustment of BP
 medication lowers pressure to meet entry criteria

 -  For patients >= 50 years old who will receive AC-->WP:

 -  Uncontrolled hypertension defined as sustained systolic BP > 150 mm Hg or
 diastolic BP > 90 mm Hg

 -  Controlled hypertension (systolic BP =< 150 mm Hg and diastolic BP =< 90
 mmHg), if anti-hypertensive medication(s) are needed

 -  NOTE: Patients who are not eligible based on the AC-WP regimen BP criteria but
 who meet the TC regimen BP criteria are eligible for B-47, if the intended
 chemotherapy regimen is changed to TC

 -  Active hepatitis B or hepatitis C with abnormal liver function tests

 -  Intrinsic lung disease resulting in dyspnea

 -  Poorly controlled diabetes mellitus

 -  Active infection or chronic infection requiring chronic suppressive antibiotics

 -  Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral
 sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events
 (CTCAE) version (v)4.0

 -  Conditions that would prohibit administration of corticosteroids

 -  Chronic daily treatment with corticosteroids with a dose of >= 10 mg/day
 methylprednisol one equivalent (excluding inhaled steroids)

 -  Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80
 and Cremophor EL

 -  Pregnancy or lactation at the time of study entry; (Note: pregnancy testing must be
 performed within 2 weeks prior to randomization according to institutional standards
 for women of childbearing potential)

 -  Other non-malignant systemic disease that would preclude the patient from receiving
 study treatment or would prevent required follow-up

 -  Psychiatric or addictive disorders or other conditions that, in the opinion of the
 investigator, would preclude the patient from meeting the study requirements

 -  Use of any investigational product within 30 days prior to randomization