Doxorubicin Hydrochloride, Cyclophosphamide, and Pacltaxel With or Without Trastuzumab in Treating Women With HER2-Positive Node-Positive or High-Risk Node-Negative Breast Cancer

August 13, 2020 updated by: National Cancer Institute (NCI)

Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Over-Expressing or Amplified 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

3436

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Saskatchewan
      • Saskatoon, Saskatchewan, Canada, S7N 4H4
        • Saskatoon Cancer Centre
  • Peru
      • Lima, Peru, Lima 34
        • Instituto Nacional de Enfermedades Neoplasicas
  • South Africa
      • Pretoria, South Africa, 0002
        • University of Pretoria
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35233
        • University of Alabama at Birmingham Cancer Center
    • Arizona
      • Phoenix, Arizona, United States, 85006
        • Western Regional CCOP
      • Scottsdale, Arizona, United States, 85259
        • Mayo Clinic in Arizona
      • Tucson, Arizona, United States, 85719
        • Banner University Medical Center - Tucson
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • University of Arkansas for Medical Sciences
    • California
      • Clovis, California, United States, 93611
        • Community Cancer Institute
      • Duarte, California, United States, 91010
        • City of Hope Comprehensive Cancer Center
      • Fremont, California, United States, 94538
        • Washington Hospital
      • Glendale, California, United States, 91204
        • Glendale Memorial Hospital and Health Center
      • Los Angeles, California, United States, 90033
        • USC / Norris Comprehensive Cancer Center
      • Modesto, California, United States, 95355
        • Memorial Medical Center
      • Monterey, California, United States, 93940
        • Community Hospital of Monterey Peninsula
      • Orange, California, United States, 92868
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
      • Palo Alto, California, United States, 94304
        • Stanford Cancer Institute Palo Alto
      • Sacramento, California, United States, 95817
        • University of California Davis Comprehensive Cancer Center
      • Salinas, California, United States, 93901
        • Salinas Valley Memorial
      • San Diego, California, United States, 92134
        • Naval Medical Center -San Diego
      • San Diego, California, United States, 92103
        • University of California San Diego
      • San Francisco, California, United States, 94115
        • UCSF Medical Center-Mount Zion
      • Santa Monica, California, United States, 90404
        • The Angeles Clinic and Research Institute - Santa Monica Office
      • Santa Rosa, California, United States, 95405
        • Santa Rosa Memorial Hospital
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Hospital
    • District of Columbia
      • Washington, District of Columbia, United States, 20007
        • MedStar Georgetown University Hospital
    • Florida
      • Jacksonville, Florida, United States, 32224-9980
        • Mayo Clinic in Florida
      • Orlando, Florida, United States, 32803
        • AdventHealth Orlando
      • Tampa, Florida, United States, 33612
        • Moffitt Cancer Center
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University Hospital/Winship Cancer Institute
      • Atlanta, Georgia, United States, 30342
        • Atlanta Regional CCOP
      • Gainesville, Georgia, United States, 30501
        • Northeast Georgia Medical Center-Gainesville
      • Savannah, Georgia, United States, 31404
        • Memorial Health University Medical Center
    • Hawaii
      • Honolulu, Hawaii, United States, 96813
        • University of Hawaii Cancer Center
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern University
      • Chicago, Illinois, United States, 60612
        • Rush University Medical Center
      • Chicago, Illinois, United States, 60637
        • University of Chicago Comprehensive Cancer Center
      • Chicago, Illinois, United States, 60612
        • University of Illinois
      • Decatur, Illinois, United States, 62526
        • Heartland Cancer Research NCORP
      • Maywood, Illinois, United States, 60153
        • Loyola University Medical Center
      • Urbana, Illinois, United States, 61801
        • Carle Cancer Center
    • Indiana
      • Indianapolis, Indiana, United States, 46202
        • Indiana University/Melvin and Bren Simon Cancer Center
      • South Bend, Indiana, United States, 46628
        • Northern Indiana Cancer Research Consortium
    • Iowa
      • Des Moines, Iowa, United States, 50309
        • Iowa-Wide Oncology Research Coalition NCORP
      • Iowa City, Iowa, United States, 52242
        • University of Iowa/Holden Comprehensive Cancer Center
      • Sioux City, Iowa, United States, 51101
        • Siouxland Regional Cancer Center
    • Kansas
      • Pittsburg, Kansas, United States, 66762
        • Via Christi Hospital-Pittsburg
      • Prairie Village, Kansas, United States, 66208
        • Kansas City NCI Community Oncology Research Program
      • Salina, Kansas, United States, 67401
        • Salina Regional Health Center
      • Topeka, Kansas, United States, 66606
        • Cotton O'Neil Cancer Center / Stormont Vail Health
      • Topeka, Kansas, United States, 66606
        • Saint Francis Hospital and Medical Center - Topeka
      • Wichita, Kansas, United States, 67214
        • Wichita NCI Community Oncology Research Program
    • Louisiana
      • New Orleans, Louisiana, United States, 70121
        • Ochsner Medical Center Jefferson
      • New Orleans, Louisiana, United States, 70112
        • Tulane University Health Sciences Center
      • Shreveport, Louisiana, United States, 71103
        • Louisiana State University Health Sciences Center Shreveport
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University/Sidney Kimmel Cancer Center
      • Baltimore, Maryland, United States, 21201
        • University of Maryland/Greenebaum Cancer Center
      • Bethesda, Maryland, United States, 20889-5600
        • Walter Reed National Military Medical Center
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Beth Israel Deaconess Medical Center
      • Boston, Massachusetts, United States, 02215
        • Dana-Farber Cancer Institute
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center
      • Boston, Massachusetts, United States, 02118
        • Boston Medical Center
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital Cancer Center
      • Milford, Massachusetts, United States, 01757
        • Milford Regional Medical Center
      • Worcester, Massachusetts, United States, 01655
        • University of Massachusetts Medical School
      • Worcester, Massachusetts, United States, 01608
        • Saint Vincent Hospital/Reliant Medical Group
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan Comprehensive Cancer Center
      • Ann Arbor, Michigan, United States, 48106
        • Michigan Cancer Research Consortium NCORP
      • Detroit, Michigan, United States, 48202
        • Henry Ford Hospital
      • Detroit, Michigan, United States, 48201
        • Wayne State University/Karmanos Cancer Institute
      • Grand Rapids, Michigan, United States, 49503
        • Cancer Research Consortium of West Michigan NCORP
      • Kalamazoo, Michigan, United States, 49008
        • Kalamazoo Center for Medical Studies
      • Southfield, Michigan, United States, 48075
        • Ascension Providence Hospitals - Southfield
    • Minnesota
      • Duluth, Minnesota, United States, 55805
        • Essentia Health Cancer Center
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota/Masonic Cancer Center
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
      • Saint Cloud, Minnesota, United States, 56303
        • Coborn Cancer Center at Saint Cloud Hospital
      • Saint Louis Park, Minnesota, United States, 55416
        • Metro Minnesota Community Oncology Research Consortium
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • University of Mississippi Medical Center
    • Missouri
      • Columbia, Missouri, United States, 65212
        • University of Missouri - Ellis Fischel
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine
      • Saint Louis, Missouri, United States, 63131
        • Missouri Baptist Medical Center
      • Saint Louis, Missouri, United States, 63141
        • Saint Louis-Cape Girardeau CCOP
      • Saint Louis, Missouri, United States, 63110
        • Washington University - Jewish
      • Springfield, Missouri, United States, 65804
        • Cancer Research for the Ozarks NCORP
    • Montana
      • Billings, Montana, United States, 59102
        • Montana Cancer Consortium NCORP
    • Nebraska
      • Kearney, Nebraska, United States, 68847
        • CHI Health Good Samaritan
      • Omaha, Nebraska, United States, 68198
        • University of Nebraska Medical Center
      • Omaha, Nebraska, United States, 68106
        • Missouri Valley Cancer Consortium
    • Nevada
      • Las Vegas, Nevada, United States, 89102
        • University Medical Center of Southern Nevada
    • New Hampshire
      • Hooksett, New Hampshire, United States, 03106
        • New Hampshire Oncology Hematology PA-Hooksett
      • Lebanon, New Hampshire, United States, 03756
        • Dartmouth Hitchcock Medical Center
    • New Jersey
      • Englewood, New Jersey, United States, 07631
        • Englewood Hospital and Medical Center
      • Hackensack, New Jersey, United States, 07601
        • Hackensack University Medical Center
      • New Brunswick, New Jersey, United States, 08903
        • Rutgers Cancer Institute of New Jersey
    • New York
      • Bronx, New York, United States, 10461
        • Montefiore Medical Center-Weiler Hospital
      • Buffalo, New York, United States, 14263
        • Roswell Park Cancer Institute
      • Manhasset, New York, United States, 11030
        • North Shore University Hospital
      • New Hyde Park, New York, United States, 11040
        • Long Island Jewish Medical Center
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
      • New York, New York, United States, 10029
        • Mount Sinai Hospital
      • New York, New York, United States, 10032
        • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
      • New York, New York, United States, 10065
        • NYP/Weill Cornell Medical Center
      • New York, New York, United States, 10016
        • Laura and Isaac Perlmutter Cancer Center at NYU Langone
      • Rochester, New York, United States, 14642
        • University of Rochester
      • Syracuse, New York, United States, 13210
        • State University of New York Upstate Medical University
      • Syracuse, New York, United States, 13215
        • SUNY Upstate Medical Center-Community Campus
    • North Carolina
      • Asheville, North Carolina, United States, 28801
        • Mission Hospital Inc-Memorial Campus
      • Chapel Hill, North Carolina, United States, 27599
        • UNC Lineberger Comprehensive Cancer Center
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center
      • Greensboro, North Carolina, United States, 27403
        • Cone Health Cancer Center
      • Wilson, North Carolina, United States, 27893
        • Wilson Medical Center
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Health Sciences
      • Winston-Salem, North Carolina, United States, 27103
        • Novant Health Forsyth Medical Center
      • Winston-Salem, North Carolina, United States, 27104
        • Southeast Clinical Oncology Research (SCOR) Consortium NCORP
    • North Dakota
      • Bismarck, North Dakota, United States, 58501
        • Sanford Bismarck Medical Center
      • Fargo, North Dakota, United States, 58122
        • Sanford Broadway Medical Center
      • Grand Forks, North Dakota, United States, 58201
        • Altru Cancer Center
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati/Barrett Cancer Center
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Foundation
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer Center
      • Toledo, Ohio, United States, 43617
        • Toledo Community Hospital Oncology Program CCOP
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • University of Oklahoma Health Sciences Center
    • Oregon
      • Eugene, Oregon, United States, 97403-1217
        • University of Oregon
      • Portland, Oregon, United States, 97213
        • Providence Portland Medical Center
    • Pennsylvania
      • Danville, Pennsylvania, United States, 17822
        • Geisinger Medical Center
      • Hershey, Pennsylvania, United States, 17033-0850
        • Penn State Milton S Hershey Medical Center
      • Philadelphia, Pennsylvania, United States, 19111
        • Fox Chase Cancer Center
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania/Abramson Cancer Center
      • Pittsburgh, Pennsylvania, United States, 15224
        • West Penn Hospital
      • Pittsburgh, Pennsylvania, United States, 15232
        • University of Pittsburgh Cancer Institute (UPCI)
      • Wynnewood, Pennsylvania, United States, 19096
        • Lankenau Medical Center
    • Rhode Island
      • Pawtucket, Rhode Island, United States, 02860
        • Memorial Hospital of Rhode Island
      • Providence, Rhode Island, United States, 02903
        • Rhode Island Hospital
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Medical University of South Carolina
      • Charleston, South Carolina, United States, 29401
        • Roper Hospital
    • South Dakota
      • Rapid City, South Dakota, United States, 57701
        • Rapid City Regional Hospital
      • Sioux Falls, South Dakota, United States, 57104
        • Sanford NCI Community Oncology Research Program of the North Central Plains
    • Tennessee
      • Kingsport, Tennessee, United States, 37660
        • Wellmont Holston Valley Hospital and Medical Center
      • Knoxville, Tennessee, United States, 37916
        • Thompson Cancer Survival Center
      • Knoxville, Tennessee, United States, 37920
        • University of Tennessee - Knoxville
      • Memphis, Tennessee, United States, 38163
        • University of Tennessee Health Science Center
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt University/Ingram Cancer Center
    • Texas
      • Amarillo, Texas, United States, 79106
        • The Don and Sybil Harrington Cancer Center
      • Fort Sam Houston, Texas, United States, 78234
        • Brooke Army Medical Center
      • Galveston, Texas, United States, 77555-0565
        • University of Texas Medical Branch
      • San Antonio, Texas, United States, 78229
        • University of Texas Health Science Center at San Antonio
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Huntsman Cancer Institute/University of Utah
    • Vermont
      • Bennington, Vermont, United States, 05201
        • Southwestern Vermont Medical Center
      • Burlington, Vermont, United States, 05405
        • University of Vermont and State Agricultural College
    • Virginia
      • Charlottesville, Virginia, United States, 22901
        • Sentara Martha Jefferson Hospital
    • Washington
      • Seattle, Washington, United States, 98101
        • Virginia Mason Medical Center
      • Seattle, Washington, United States, 98112
        • Kaiser Permanente Washington
      • Tacoma, Washington, United States, 98405
        • Northwest NCI Community Oncology Research Program
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin Hospital and Clinics
      • Milwaukee, Wisconsin, United States, 53226
        • Froedtert and the Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm I (AC, paclitaxel, tamoxifen, aromatase inhibitor)
Patients receive doxorubicin hydrochloride 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. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Paclitaxel
Given IV
Other Names:
  • Taxol
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol Konzentrat
Drug: Cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • CTX
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • Adriamycin
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin HCl
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Drug: Aromatase Inhibition Therapy
Given orally
Other Names:
  • Aromatase Inhibition
Drug: Tamoxifen Citrate
Given orally
Other Names:
  • Nolvadex
  • TAM
  • Soltamox
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide
Experimental: Arm II (AC, paclitaxel, trastuzumab, tamoxifen)
Patients receive doxorubicin hydrochloride, cyclophosphamide, and paclitaxel as in arm I. Patients then receive trastuzumab (Herceptin®) 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. Within 5 weeks after completion of paclitaxel, patients may undergo radiotherapy. All postmenopausal ER- or 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Trastuzumab
Given IV
Other Names:
  • Herceptin
  • ABP 980
  • ALT02
  • Anti-c-ERB-2
  • Anti-c-erbB2 Monoclonal Antibody
  • Anti-ERB-2
  • Anti-erbB-2
  • Anti-erbB2 Monoclonal Antibody
  • Anti-HER2/c-erbB2 Monoclonal Antibody
  • Anti-p185-HER2
  • c-erb-2 Monoclonal Antibody
  • HER2 Monoclonal Antibody
  • Herceptin Biosimilar PF-05280014
  • Herceptin Trastuzumab Biosimilar PF-05280014
  • Herzuma
  • MoAb HER2
  • Monoclonal Antibody c-erb-2
  • Monoclonal Antibody HER2
  • Ogivri
  • Ontruzant
  • PF-05280014
  • rhuMAb HER2
  • RO0452317
  • Trastuzumab Biosimilar ABP 980
  • Trastuzumab Biosimilar ALT02
  • trastuzumab biosimilar EG12014
  • Trastuzumab Biosimilar HLX02
  • Trastuzumab Biosimilar PF-05280014
  • Trastuzumab-dkst
  • Trastuzumab-pkrb
  • Trastuzumab-QYYP
  • Trazimera
  • Trastuzumab-DTTB
Drug: Paclitaxel
Given IV
Other Names:
  • Taxol
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol Konzentrat
Drug: Cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • CTX
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • Adriamycin
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin HCl
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Drug: Aromatase Inhibition Therapy
Given orally
Other Names:
  • Aromatase Inhibition
Drug: Tamoxifen Citrate
Given orally
Other Names:
  • Nolvadex
  • TAM
  • Soltamox
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide
Experimental: Arm III (AC, paclitaxel, trastuzumab, tamoxifen)

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 ER- or 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Trastuzumab
Given IV
Other Names:
  • Herceptin
  • ABP 980
  • ALT02
  • Anti-c-ERB-2
  • Anti-c-erbB2 Monoclonal Antibody
  • Anti-ERB-2
  • Anti-erbB-2
  • Anti-erbB2 Monoclonal Antibody
  • Anti-HER2/c-erbB2 Monoclonal Antibody
  • Anti-p185-HER2
  • c-erb-2 Monoclonal Antibody
  • HER2 Monoclonal Antibody
  • Herceptin Biosimilar PF-05280014
  • Herceptin Trastuzumab Biosimilar PF-05280014
  • Herzuma
  • MoAb HER2
  • Monoclonal Antibody c-erb-2
  • Monoclonal Antibody HER2
  • Ogivri
  • Ontruzant
  • PF-05280014
  • rhuMAb HER2
  • RO0452317
  • Trastuzumab Biosimilar ABP 980
  • Trastuzumab Biosimilar ALT02
  • trastuzumab biosimilar EG12014
  • Trastuzumab Biosimilar HLX02
  • Trastuzumab Biosimilar PF-05280014
  • Trastuzumab-dkst
  • Trastuzumab-pkrb
  • Trastuzumab-QYYP
  • Trazimera
  • Trastuzumab-DTTB
Drug: Paclitaxel
Given IV
Other Names:
  • Taxol
  • Anzatax
  • Asotax
  • Bristaxol
  • Praxel
  • Taxol Konzentrat
Drug: Cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • CTX
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • Adriamycin
  • 5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI)
  • ADM
  • Adriacin
  • Adriamycin Hydrochloride
  • Adriamycin PFS
  • Adriamycin RDF
  • ADRIAMYCIN, HYDROCHLORIDE
  • Adriamycine
  • Adriblastina
  • Adriblastine
  • Adrimedac
  • Chloridrato de Doxorrubicina
  • DOX
  • DOXO-CELL
  • Doxolem
  • Doxorubicin HCl
  • Doxorubicin.HCl
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Drug: Aromatase Inhibition Therapy
Given orally
Other Names:
  • Aromatase Inhibition
Drug: Tamoxifen Citrate
Given orally
Other Names:
  • Nolvadex
  • TAM
  • Soltamox
  • Apo-Tamox
  • Clonoxifen
  • Dignotamoxi
  • Ebefen
  • Emblon
  • Estroxyn
  • Fentamox
  • Gen-Tamoxifen
  • Genox
  • ICI 46,474
  • ICI-46474
  • Jenoxifen
  • Kessar
  • Ledertam
  • Lesporene
  • Nolgen
  • Noltam
  • Nolvadex-D
  • Nourytam
  • Novo-Tamoxifen
  • Novofen
  • Noxitem
  • Oestrifen
  • Oncotam
  • PMS-Tamoxifen
  • Tamax
  • Tamaxin
  • Tamifen
  • Tamizam
  • Tamofen
  • Tamoxasta
  • Tamoxifeni Citras
  • Zemide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Duration of DFS
Time Frame: Time from registration to first adverse event, assessed up to 15 years
Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether DFS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for DFS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.
Time from registration to first adverse event, assessed up to 15 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival
Time Frame: Time from registration to death due to any cause, assessed up to 15 years
Will be estimated using the Kaplan-Meier method. A stratified log-rank test will be used to assess whether OS differs with respect to the addition of trastuzumab to a chemotherapy regimen including AC and paclitaxel. Ninety-five percent confidence intervals will be reported for relative risks, for OS at the 5-year point, and for absolute benefit as defined by differences in DFS and OS.
Time from registration to death due to any cause, assessed up to 15 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Collaborators

Eastern Cooperative Oncology Group
Canadian Cancer Trials Group
Southwest Oncology Group
Cancer and Leukemia Group B

Investigators

  • Principal Investigator: Edith A Perez, Alliance for Clinical Trials in Oncology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 19, 2000

Primary Completion (Actual)

April 25, 2005

Study Completion (Actual)

January 27, 2010

Study Registration Dates

First Submitted

July 5, 2000

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Actual)

August 14, 2020

Last Update Submitted That Met QC Criteria

August 13, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2012-01849 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • U10CA180821 (U.S. NIH Grant/Contract)
  • U10CA025224 (U.S. NIH Grant/Contract)
  • 9343 (CTEP)
  • ECOG-N9831
  • CAN-NCIC-MA28
  • SWOG-N9831
  • MA.28
  • NCCTG-N9831
  • CALGB-49909
  • CDR0000067953
  • GUMC-00224
  • N9831 (Other Identifier: CTEP)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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