Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer
Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer
This randomized phase III trial studies doxorubicin hydrochloride, cyclophosphamide,
 paclitaxel, and trastuzumab to see how well they work compared to combination chemotherapy
 alone in treating women with breast cancer that is human epidermal growth factor receptor 2
 (HER2)-positive and has spread to the lymph nodes or high-risk and has not spread to the
 lymph nodes. Drugs used in chemotherapy use different ways to stop tumor cells from dividing
 so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells
 and either kill them or deliver tumor-killing substances to them without harming normal
 cells. It is not yet known whether combination chemotherapy is more effective with or without
 trastuzumab in treating breast cancer.
PRIMARY OBJECTIVES:

 I. To compare the combination of doxorubicin hydrochloride and cyclophosphamide (AC) followed
 by weekly paclitaxel with the combination of AC followed by the combination of weekly
 paclitaxel and trastuzumab in terms of disease free survival (DFS). (Stage I) II. To compare
 the combination of AC followed by weekly paclitaxel with the combination of AC followed by
 the combination of weekly paclitaxel and trastuzumab in terms of the rate of cardiac events.
 (Stage I) III. To compare the combination AC followed by weekly paclitaxel with the
 sequential schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of
 DFS. (Stage II) IV. To compare the sequential schedule of the combination of AC, weekly
 paclitaxel, and trastuzumab with the combination of AC followed by the combination of weekly
 paclitaxel and trastuzumab in terms of DFS. (Stage II) V. To compare the combination AC
 followed by weekly paclitaxel with the sequential schedule of the combination of AC, weekly
 paclitaxel, and trastuzumab in terms of the rate of cardiac events. (Stage II)

 SECONDARY OBJECTIVES:

 I. To compare the combination of AC followed by weekly paclitaxel with the sequential
 schedule of the combination of AC, weekly paclitaxel, and trastuzumab in terms of overall
 survival (OS).

 II. To compare the combination AC followed by weekly paclitaxel with the combination of AC
 followed by the combination of weekly paclitaxel and trastuzumab in terms of OS.

 III. To compare the sequential schedule of the combination AC, weekly paclitaxel, and
 trastuzumab with the combination of AC followed by the combination of weekly paclitaxel and
 trastuzumab in terms of OS.

 TERTIARY OBJECTIVES:

 I. To determine whether higher levels of shed ECD (extracellular domain) or autoantibodies to
 human epidermal growth factor receptor (HER)-2 and HER-1 measured in the serum prior to
 treatment are prognostic for DFS and survival.

 II. To determine the concordance of central review of HER-2 overexpression as measured by the
 HercepTest (DAKO) and Vysis fluorescence in situ hybridization (FISH).

 III. For each treatment arm, levels of brain natriuretic peptide (BNP), troponin-T (TnT),
 troponin-I (cTnI), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and
 interleukin-6 (IL-6), CD40 ligand, and troponin levels will be compared and contrasted.

 IV. To determine whether genetic markers are prognostic for cardiac adverse events associated
 with treatment.

 OUTLINE: Patients are randomized to 1 of 3 treatment arms.

 ARM I*: Patients receive doxorubicin hydrochloride intravenously (IV) and cyclophosphamide IV
 over 20-30 minutes on day 1. Treatment repeats every 3 weeks for 4 courses. Patients then
 receive paclitaxel IV over 1 hour beginning on day 1 of week 13 and continuing weekly for 12
 courses in the absence of disease progression or unacceptable toxicity. NOTE: *Patients who
 completed paclitaxel on or after October 25, 2004 may receive trastuzumab for a maximum of 52
 weeks either concurrently with paclitaxel or following completion of paclitaxel treatment.

 ARM II*: Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in
 arm I. Patients then receive trastuzumab IV over 30-90 minutes beginning on day 1 of week 25
 and continuing weekly for 52 courses in the absence of disease progression or unacceptable
 toxicity. NOTE: *Patients who completed paclitaxel on or after October 25, 2004 may receive
 trastuzumab for a maximum of 52 weeks either concurrently with paclitaxel or following
 completion of paclitaxel treatment.

 ARM III: Patients receive doxorubicin hydrochloride and cyclophosphamide as in arm I.
 Patients then receive paclitaxel IV over 1 hour and trastuzumab IV over 30-90 minutes
 beginning on day 1 of week 13 and continuing weekly for 12 courses. Patients then receive
 trastuzumab IV over 30 minutes beginning on day 1 of week 25 and continuing weekly for 40
 courses in the absence of disease progression or unacceptable toxicity.

 Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All
 postmenopausal estrogen receptor (ER)- or progesterone receptor (PR)-positive patients
 receive oral tamoxifen or an aromatase inhibitor once daily for 5 years beginning no later
 than 5 weeks after the last dose of paclitaxel. Patients may also receive an aromatase
 inhibitor once daily for 5 years after 5 years of daily tamoxifen. Patients who receive
 tamoxifen once daily for less than 4.5 years may receive an aromatase inhibitor daily until
 they have received a total of 5 years of adjuvant hormonal therapy.

 After completion of study treatment, patients are followed up every 3 months for 1 year,
 every 6 months for 4 years, and then annually for 15 years or until disease progression.
Inclusion Criteria:

 -  Required tumor parameters for node positive disease: NOTE: This study will continue to
 use the American Joint Committee on Cancer (AJCC) 5th edition for TNM classification
 and staging

 -  Operable, histologically confirmed adenocarcinoma of the female breast and
 positive lymph nodes

 -  Node positivity may be determined by either an axillary node dissection or a
 positive sentinel node finding by hematoxylin and eosin (H&E)

 -  NOTE: Positive nodes refers to H&E visible nodal metastases;
 immunohistochemistry (IHC) positive only cells in lymph nodes will not
 be considered positive nodes

 -  One or more positive lymph nodes whose tumors are T1-3, pN1-2, M0 are
 eligible

 -  cN2 disease is not eligible

 -  pN2 disease is eligible

 -  One positive lymph node by sentinel node biopsy or at least 6 axillary nodes
 must be examined on axillary node dissection with at least one positive
 lymph node

 -  Metaplastic carcinoma is eligible

 -  ER/PgR determination

 -  HER-2 positive (pre-entry requirement for registration)

 -  FISH must show gene amplification OR

 -  IHC assay must show a strong positive (3+) staining score

 -  NOTE: ductal carcinoma in situ (DCIS) components should not be counted
 in the determination of degree of IHC staining or FISH amplification

 -  Required tumor parameters for high-risk node-negative disease; NOTE: This study will
 continue to use the AJCC 5th edition for TNM classification and staging

 -  Operable, histologically confirmed adenocarcinoma of the female breast and
 negative lymph nodes

 -  Node status may be determined by either axillary node dissection or sentinel
 node biopsy with H&E staining; to be considered node negative, either of the
 following must be true: 1) negative sentinel node biopsy or 2) no positive
 lymph nodes found among at least 6 axillary nodes examined on axillary node
 dissection

 -  NOTE: IHC positive only cells in lymph nodes will not be considered positive
 nodes

 -  Tumors > 2.0 cm (irrespective of hormonal receptor status) or > 1.0 cm if
 ER-negative and PR-negative disease

 -  ER/PgR determination

 -  HER-2 positive (pre-entry requirement for registration)

 -  FISH must show gene amplification OR

 -  IHC assay must show a strong positive (3+) staining score

 -  NOTE: DCIS components should not be counted in the determination of
 degree of IHC staining or FISH amplification

 -  =< 84 days from mastectomy or =< 84 days from axillary dissection or sentinel node
 detection if the patient's most extensive breast surgery was a breast sparing
 procedure; (This timing is per a decision by the Breast Intergroup)

 -  Surgical resection margins. All tumor should be removed by either a modified radical
 mastectomy or a segmental mastectomy with axillary node dissection

 -  Mastectomy: There will be no evidence of gross or microscopic tumor (invasive or
 DCIS) at the surgical resection margins noted in the final surgery or pathology
 reports; patients with close margins are eligible

 -  Segmental mastectomy (lumpectomy): Margins must be clear of invasive cancer and
 DCIS

 -  Axillary dissection or sentinel node dissection: There will be no gross residual
 adenopathy

 -  TAM therapy

 -  May have received up to four weeks of TAM therapy, or any other hormonal agent,
 for this malignancy

 -  May have received TAM or raloxifene for purposes of chemoprevention (e.g., Breast
 Cancer Prevention Trial) or for other indications (including previous breast
 cancer if lobular carcinoma in situ [LCIS]) but must be discontinued before
 registration on this study

 -  May never have received TAM, raloxifene, or any other hormonal agent

 -  Absolute neutrophil count (ANC) >= 1500/mm^3

 -  Platelets (PLT) >= 100,000/mm^3

 -  Total bilirubin =< 1.5 x upper normal limit (UNL)

 -  Aspartate aminotransferase (AST) =< 2.0 x UNL

 -  Left ventricular ejection fraction (LVEF) within institutional normal range; if LVEF
 is > 75%, the investigator should consider performing a second review of the
 multigated acquisition (MUGA)/echocardiogram or performing a repeat
 MUGA/echocardiogram prior to registration; such re-reviews or repeat
 MUGA/echocardiogram are not permitted after registration

 -  Willingness to discontinue sex hormonal therapy, e.g., birth control pills, ovarian
 hormonal replacement therapy, etc., prior to registration and while on study

 -  Willingness to discontinue any hormonal agent such as raloxifene (Evista) prior to
 registration and while on study

 -  Non-breast malignancies that have not recurred within the last 5 years and are deemed
 to be at low risk for recurrence

 EXCEPTIONS: These non-breast malignancies are eligible even if diagnosed =< 5 years prior
 to registration:

 -  Squamous or basal cell carcinoma of the skin that has been effectively treated

 -  Carcinoma in situ of the cervix that has been treated by surgery only

 -  Lobular carcinoma in situ (LCIS) of the ipsilateral or contralateral breast treated by
 surgery and/or tamoxifen only

 -  Patients undergoing breast conservation therapy (i.e., lumpectomy and axillary
 dissection) must have plans to receive radiation therapy to the breast +/-
 regional lymphatics following completion of the chemotherapy; for patients
 treated with mastectomy, the use of radiation therapy is required for 4 or more
 positive lymph nodes and must be started after completion of chemotherapy; the
 use of radiation therapy is at the discretion of the investigator for 0-3
 positive lymph nodes but, if used, must be started after the completion of
 chemotherapy

 -  Prior to registration, the physician must designate if it is planned for the
 patient to receive radiation therapy (for adjuvant radiation therapy
 post-mastectomy or, less commonly, post-conservative therapy but not primary
 breast radiation as part of breast conserving treatment)

 -  Willing and able to sign an informed consent

 -  Gene amplified by FISH or strong positivity (3+) by HercepTest on central review;
 Note: The patient registers based on community HER-2 testing using FISH or IHC,
 AC chemotherapy is initiated; the tumor block or slides must be received =< 2
 weeks from time of registration to the North Central Cancer Treatment Group
 (NCCTG) Operations Office for central HER-2 testing

 Exclusion Criteria:

 -  Any of the following:

 -  Pregnant women

 -  Nursing women

 -  Women of childbearing potential or their sexual partners who are unwilling to
 employ adequate contraception (condoms, diaphragm, intrauterine device [IUD],
 surgical sterilization, or abstinence, etc.); hormonal birth control methods are
 not permitted

 -  Locally advanced tumors (classification T4) at diagnosis including tumors fixed to
 chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes
 (diffuse brawny cutaneous induration with an erysipeloid edge)

 -  Prior history of breast cancer, except LCIS

 -  Bilateral invasive carcinoma, either metachronous or synchronous (EXCEPTION: Patients
 diagnosed with unilateral invasive carcinoma and metachronous or synchronous DCIS of
 the contralateral breast treated with mastectomy are eligible)

 -  Prior chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer

 -  Active, unresolved infection

 -  Active cardiac disease

 -  Any prior myocardial infarction

 -  History of documented congestive heart failure (CHF)

 -  Current use of digitalis or beta-blockers for CHF

 -  Any prior history of arrhythmia or cardiac valvular disease requiring medications
 or clinically significant

 -  Current use of medications for treatment of arrhythmias or angina pectoris

 -  Current uncontrolled hypertension (diastolic > 100 mmHg or systolic > 200 mmHg)

 -  Clinically significant pericardial effusion

 -  Prior anthracycline or taxane therapy for any malignancy

 -  Sensitivity to benzyl alcohol

 -  Neurology/Neuropathy-Sensory >= grade 2 per the National Cancer Institute's (NCI's)
 Common Toxicity Criteria Version 2.0; EXCEPTION: Any chronic neurologic disorder will
 be looked at on a case-by-case basis by the study chair