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 HER 2 Low Invasive Breast Cancer. NSABP B 47
This trial will determine whether the addition of trastuzumab to standard chemotherapy regimens improves invasive disease-free survival relative to chemotherapy alone. Secondary aims include determining whether the addition of trastuzumab to chemotherapy improves disease-free survival, breast cancer-free survival, recurrence-free interval, distant recurrence-free interval, and overall survival relative to chemotherapy alone. additionally, the toxicities of the regimens will be compared.
The investigator must indicate at the time of study entry which of the two B-47 chemotherapy regimens the patient will receive. The non-anthracycline regimen (for patients in Groups 1a and 2a) is TC (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) administered iV every 3 weeks for 6 cycles. The anthracycline regimen (for patients in Groups 1B and 2B) is aC---WP (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered iV either every 3 weeks or every 2 weeks [per investigator discretion] for 4 cycles followed by paclitaxel 80 mg/m2 iV
administered weekly for 12 doses).
Patients will be randomized to receive chemotherapy with or without trastuzumab therapy. For patients receiving the TC chemotherapy regimen, trastuzumab will be given every 3 weeks during and following chemotherapy until 1 year after the first trastuzumab dose (8 mg/kg loading dose; 6 mg/kg for the remaining doses). For patients receiving the aC---WP chemotherapy regimen, trastuzumab will begin with the first dose of weekly paclitaxel and will be given weekly for 12 doses (4 mg/kg loading dose; 2 mg/kg for the remaining weekly doses). Following completion
of WP, trastuzumab will continue with 6 mg/kg doses given every 3 weeks for a total of 1 year of trastuzumab therapy. Patients will also receive adjuvant radiation therapy and endocrine therapy, as clinically indicated.
Menopausal status will be determined at baseline for all patients. Women who have had a menstrual period within 12 months before randomization (and have not had a hysterectomy) will have menstrual history information collected at 3 and 6 months and then every 6 months until 3 years after randomization. additionally, women in this menstrual history cohort will also be asked to consent to blood sample collection at baseline and follow-up time points until 2 years after randomization. Samples will be assayed for estradiol and FSH to provide biological correlates of amenorrhea and to examine the interaction of chemotherapy regimens, trastuzumab, and endocrine therapies with menstrual status as determined by biological evaluation and menstrual history data. in addition, blood samples will be prepared and isolated into Dna, Rna, plasma, and serum for future research studies on those women who became amenorrheic with therapy versus those who did not to better inform potential biological and hormonal factors that may be responsible for the beneficial effects of amenorrhea.
in addition, other host factors that may influence the risk for cancer recurrence will be examined in the entire B-47 study population, including comorbid conditions, medications that may have systemic effects on inflammatory processes (e.g., metformin, beta blockers, aRBs, aCe inhibitors, and aspirin), weight and weight gain, and tobacco and alcohol use. For all B-47 patients (who consented to submission of optional blood samples), plasma C-reactive protein will be assessed at baseline (pre-treatment) and at one year after randomization.
A patient cannot be considered eligible for this study unless all of the following conditions are met.
1 The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.
2 The patient must be female.
3 The patient must be >= 18 years old.
4 The patient must have an ECOG performance status of 0 or 1 (see Appendix A).
5 The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
6 All of the following staging criteria (according to the 7th edition of the 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 ER negative and PgR negative; or
- pT2 and ER positive (PgR status may be positive or negative) and either grade 3
histology or Oncotype DX(RegisteredTM) Recurrence Score of <25; or
- pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX(RegisteredTM)
7 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.
8 The patient must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy). (Patients who have had a nipple-sparing mastectomy are eligible.)
9 For patients who undergo lumpectomy, the margins of the resected specimen must be istologically 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
10 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.)
11 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 procedure.
12 The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days.
13 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
14 The most recent postoperative blood counts, performed within 6 weeks prior to randomization, must meet the following criteria:
* ANC must be >= 1200/mm3;
* Platelet count must be >= 100,000/mm3
* Hemoglobin must be >= 10 g/dL.
15 The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests performed within 6 weeks prior to randomization:
* total bilirubin must be <= ULN for the lab unless the patient has a bilirubin elevation
> ULN to 1.5 x ULN due to Gilbert[Single Quote]s disease or similar syndrome involving slow
conjugation of bilirubin
* alkaline phosphatase must be <= 2.5 x ULN for the lab
* AST must be <= 1.5 x ULN for the lab.
* Alkaline phosphatase and AST may not both be > the ULN. For example, if the alkaline phosphatase is > the ULN but <= 2.5 x ULN, the AST must be
<= the ULN. If the AST is
> the ULN but
<= 1.5 x ULN, the alkaline phosphatase must be
Note: If 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.
16 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 requirements in criterion
15 are met.
17 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.
18 The most recent postoperative serum creatinine performed within 6 weeks prior to
randomization must be
<= ULN for the lab.
19 LVEF assessment must be performed within 90 days prior to randomization. LVEF
assessment performed by 2-D echocardiogram is preferred; however, MUGA scan may
be 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. (See Sections 5.2
and 5.3 for LVEF instructions.)