Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer

• Disease-free survival [ Time Frame: Up to 10 years ] [ Designated as safety issue: No ]
• Breast cancer-free survival [ Time Frame: From randomization until local recurrence, or death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
• Recurrence-free interval (RFI) [ Time Frame: From randomization until invasive local, regional, or distant recurrence, or death from breast cancer, assessed up to 10 years ] [ Designated as safety issue: No ]
• Distant recurrence-free interval (DRFI) [ Time Frame: From randomization until the first diagnosis of distant metastasis or death from breast cancer, assessed up to 10 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: From randomization to death from any cause, assessed up to 10 years ] [ Designated as safety issue: No ]
• Frequencies of adverse events using the NCI CTCAE v4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
  The occurrence of adverse events, including toxicities and deaths, will be monitored.
• Change in HER2 mRNA level [ Time Frame: From baseline to 24 months ] [ Designated as safety issue: No ]
  The interaction between treatment effect and HER2 mRNA level will be evaluated in the proportional hazards model, which would include an indicator for treatment group and the HER2 mRNA level as a continuous variable, and the corresponding interaction term. The log-hazard ratio plot for the interaction term with 95% confidence intervals will be used to determine the cut-off of the HER2 mRNA level that would determine a subset of the patients who would benefit from the adjuvant trastuzumab therapy.
• Fcγ receptor polymorphism [ Time Frame: From baseline to up to 24 months ] [ Designated as safety issue: No ]
  The polymorphism of the Fcγ 158 receptor gene will be dichotomized as V/V (valine) vs. other genotypes and the polymorphism of the Fcγ 131 receptor gene will be dichotomized as H/H (histidine) vs. other genotypes to evaluate an interaction between treatment group and Fcγ polymorphism. The Kaplan-Meier method105 will be used to estimate the distribution of the primary endpoints stratified by the dichotomized subgroups, and the log-rank test106 will be used to statistically compare the time-to-event distributions.

• Disease-free survival [ Designated as safety issue: No ]
• Breast cancer-free survival [ Designated as safety issue: No ]
• Recurrence-free interval [ Designated as safety issue: No ]
• Distant recurrence-free interval [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Frequencies of adverse events using the NCI CTCAE v4.0 [ Designated as safety issue: Yes ]

This randomized phase III clinical trial is studying 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 or by stopping them from dividing. 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 cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-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) of 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 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.

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 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 ASCO/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 Fcγ 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: This is a multicenter study. Patients are stratified according to IHC score (1+ vs 2+), number of positive nodes (0-3 vs 4-9 vs 10+), hormone receptor status (estrogen [ER]-positive and/or progesterone receptor [PgR]-positive vs ER- and PgR-negative), and intended chemotherapy regimen* (docetaxel and cyclophosphamide vs doxorubicin hydrochloride and cyclophosphamide followed by paclitaxel). Patients are randomized to 1 of 2 treatment arms.

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

ARM I:

GROUP A: Patients receive docetaxel intravenously (IV) over 60 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 courses.

GROUP B: Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1.

Treatment repeats every 2 or 3 weeks (at the investigator's discretion) for 4 courses. Patients then receive paclitaxel IV over 60 minutes once weekly for 12 doses.

ARM II:

GROUP A: Patients receive chemotherapy as in arm IA. Patients also receive trastuzumab IV over 30-90 minutes on day 1. Trastuzumab treatment repeats every 3 weeks for 11 courses.

GROUP B: Patients receive chemotherapy as in arm IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses. After completion of paclitaxel, patients receive trastuzumab IV over 30-90 minutes on day 1.

Treatment repeats every 3 weeks for 13 courses. Tumor and blood samples may be collected periodically during study treatment for correlative studies.

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

• Estrogen Receptor-negative Breast Cancer
• Estrogen Receptor-positive Breast Cancer
• HER2-positive Breast Cancer
• Progesterone Receptor-negative Breast Cancer
• Progesterone Receptor-positive Breast Cancer
• Recurrent Breast Cancer
• Stage IA Breast Cancer
• Stage IB Breast Cancer
• Stage II Breast Cancer
• Stage IIIA Breast Cancer
• Stage IIIC Breast Cancer

• Drug: doxorubicin hydrochloride
  Given IV
  Other Names:

  • ADM
  • ADR
  • Adria
  • Adriamycin PFS
  • Adriamycin RDF
• Drug: docetaxel
  Given IV
  Other Names:

  • RP 56976
  • Taxotere
  • TXT
• Drug: cyclophosphamide
  Given IV
  Other Names:

  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
• Biological: trastuzumab
  Given IV
  Other Names:

  • anti-c-erB-2
  • Herceptin
  • MOAB HER2
• Drug: paclitaxel
  Given IV
  Other Names:

  • Anzatax
  • Asotax
  • TAX
  • Taxol
• Other: laboratory biomarker analysis
  Correlative studies

• Experimental: Arm IA (docetaxel, cyclophosphamide)
  Patients receive docetaxel IV over 60 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 courses.
  Interventions:

  • Drug: docetaxel
  • Drug: cyclophosphamide
  • Other: laboratory biomarker analysis
• Experimental: Arm IB (doxorubicin hydrochloride, cyclophosphamide)
  Patients receive doxorubicin hydrochloride IV over 15 minutes and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 2 or 3 weeks (at the investigator's discretion) for 4 courses. Patients then receive paclitaxel IV over 60 minutes once weekly for 12 doses.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: cyclophosphamide
  • Drug: paclitaxel
  • Other: laboratory biomarker analysis
• Experimental: Arm IIA (docetaxel, cyclophosphamide, trastuzumab)
  Patients receive chemotherapy as in arm IA. Patients also receive trastuzumab IV over 30-90 minutes on day 1. Trastuzumab treatment repeats every 3 weeks for 11 courses.
  Interventions:

  • Drug: docetaxel
  • Drug: cyclophosphamide
  • Biological: trastuzumab
  • Other: laboratory biomarker analysis
• Experimental: Arm IIB (chemotherapy, trastuzumab)
  Patients receive chemotherapy as in arm IB. Patients also receive trastuzumab IV over 30-90 minutes weekly for 12 doses. After completion of paclitaxel, patients receive trastuzumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks for 13 courses.
  Interventions:

  • Drug: doxorubicin hydrochloride
  • Drug: cyclophosphamide
  • Biological: trastuzumab
  • Drug: paclitaxel
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• 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
      • pT2 and ER positive (PgR status may be positive or negative) and either grade 3histology or Oncotype DX Recurrence Score of >= 25; or
      • pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX Recurrence Score
• No T4 tumors including inflammatory breast cancer

• No 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
• No synchronous or previous contralateral invasive breast cancer (patients with synchronous and/or previous contralateral DCIS or lobular carcinoma in situ [LCIS] are eligible)
• No previous ipsilateral invasive breast cancer or ipsilateral DCIS (patients with synchronous or previous ipsilateral LCIS are eligible)

• 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 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

• No 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

• 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 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 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 RT of the chest wall will be administered)
  • 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 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
  • Axillary lymphadenectomy with or without SN isolation procedures
• 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
• Pre- or postmenopausal
• Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1
• 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 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 (CT, MRI, 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, positron emission tomography (PET)-computed tomography (CT) scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease
• The most recent post operative serum creatinine performed within 6 weeks prior to randomization must be =< ULN for the lab
• Not pregnant or nursing
• Negative pregnancy test

• Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; LVEF assessment performed by 2-dimensional (D) echo cardiogram 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
• No 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

• No cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens, including, but not limited 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

• No 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 OR 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
• No active hepatitis B or hepatitis C with abnormal liver function tests
• No intrinsic lung disease resulting in dyspnea
• No poorly controlled diabetes mellitus
• No active infection or chronic infection requiring chronic suppressive antibiotics
• No nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) v4.0
• No conditions that would prohibit administration of corticosteroids
• No known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor EL
• No other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up
• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
• Concurrent participation in NSABP-B-39 allowed
• No previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy
• No chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization
• No whole-breast radiation therapy (RT) prior to randomization or partial-breast RT that cannot be completed on or before the date of randomization
• No use of any investigational product within 30 days prior to randomization
• No continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor (patients are eligible if these medications are discontinued prior to randomization)
• No 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)
• No chronic daily treatment with corticosteroids with a dose of >= 10 mg/day methylprednisol one equivalent (excluding inhaled steroids)
• No other concurrent chemotherapy
• No other concurrent targeted therapy for malignancy
• No partial-breast irradiation following randomization