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

A Randomized Phase III Trial of Adjuvant Therapy Comparing Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or Four Cycles of Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in Women With Node-Positive or High-Risk Node-Negative HER2-Low 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