Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	NCCTG-N9831 CALGB-49909, ECOG-N9831, SWOG-N9831, GUMC-00224, N9831, NCT00005970, CAN-NCIC-MA28, MA28

Objectives

Primary

1. Compare the disease-free survival of women with HER-2-overexpressing node-positive or high-risk node-negative breast cancer treated with doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin®).
2. Compare the cardiotoxic effects of these regimens in these patients.

Secondary

1. Compare the overall survival of patients treated with these regimens.

Tertiary

1. Determine whether higher levels of shed extracellular domain or autoantibodies to HER-2 and HER-1 measured in the serum prior to treatment are prognostic for disease-free and overall survival in these patients.
2. Determine whether the concordance of HER-2 overexpression is associated with disease-free and overall survival in this patient population.

Entry Criteria

Disease Characteristics:

• Histologically confirmed operable adenocarcinoma of the breast, meeting 1 of the following criteria:
  • Node-positive disease, meeting the following criteria:
    • One or more positive lymph nodes (T1-3, pN1-2, M0)
    • No cN2 disease
    • pN2 disease allowed
    • One positive lymph node by sentinel node biopsy or at least 6 axillary nodes must be examined on axillary node dissection with at least 1 positive lymph node
    • Metaplastic carcinoma allowed
  • High-risk node-negative disease, meeting the following criteria:
    • Node-negative as determined by 1 of the following:
      • Negative sentinel node biopsy
      • No positive lymph nodes found among at least 6 axillary nodes examined on axillary node dissection
    • Tumor must be greater than 2.0 cm if estrogen-receptor (ER)- and progesterone-receptor (PR)-positive disease is present OR greater than 1.0 cm if ER and PR negative

   [Note: Lymph nodes positive by immunohistochemistry (IHC) only are not considered positive nodes]




• HER-2 positive
  • Fluorescent in situ hybridization (FISH) must show gene amplification

    OR

  • IHC assay must show a strong positive (3+) staining score
  • Ductal carcinoma in situ (DCIS) components must not be counted in determination of the degree of IHC staining or FISH amplification



• No locally advanced (T4) tumors at diagnosis, including:
  • Tumors fixed to chest wall
  • Peau d'orange
  • Skin ulcerations/nodules
  • Clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)



• No bilateral invasive carcinoma or DCIS (metachronous or synchronous)
  • Unilateral invasive carcinoma and previous metachronous or synchronous DCIS of the contralateral breast treated with mastectomy allowed



• No prior breast cancer except lobular carcinoma in situ (LCIS)



• No more than 84 days since prior mastectomy or axillary or sentinel node dissection
  • No gross or microscopic disease at margins



• No significant pericardial effusion



• Hormone receptor status:
  • ER/PR status known

Prior/Concurrent Therapy:

Biologic therapy:

• No prior biologic therapy or immunotherapy for breast cancer

Chemotherapy:

• No prior chemotherapy for breast cancer
• No prior anthracycline or taxane

Endocrine therapy:

• Prior tamoxifen or any other hormonal therapy for breast cancer allowed if administered for no more than 4 weeks
• Prior tamoxifen or raloxifene for chemoprevention (e.g., Breast Cancer Prevention Trial) or for other indications (e.g., prior LCIS) allowed
• No concurrent tamoxifen or raloxifene
• No concurrent hormonal therapy (e.g., birth control pills or hormone replacement therapy)

Radiotherapy:

• No prior radiotherapy for breast cancer

Surgery:

• See Disease Characteristics

Other:

• No concurrent digitalis or beta-blockers for congestive heart failure
• No concurrent medications for cardiac arrhythmias or angina pectoris
• No concurrent cardioprotective drugs

Patient Characteristics:

Age:

• 18 and over

Sex:

• Female

Menopausal status:

• Any status

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST no greater than 2 times ULN

Renal:

• Not specified

Cardiovascular:

• LVEF normal
• No prior myocardial infarction or congestive heart failure
• No prior arrhythmia or cardiovalvular disease that requires medications or is clinically significant
• No uncontrolled hypertension (diastolic blood pressure [BP] greater than 100 mm Hg and systolic BP greater than 200 mm Hg)

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for 2 months after study participation
• No active unresolved infection
• No known sensitivity to benzyl alcohol
• No grade 2 or greater neuropathy
• No other prior malignancy within the past 5 years except:
  • Effectively treated squamous cell or basal cell skin cancer
  • Carcinoma in situ of the cervix treated with surgery only
  • LCIS of the ipsilateral or contralateral breast treated with surgery and/or tamoxifen only

Expected Enrollment

A total of 3,700 patients (at least 1,150 for arms I and II and at least 1,000 for arm III) will be accrued for this study within approximately 5.75 years.

Outline

This is a randomized, multicenter study. Patients are stratified according to nodal status (0 vs 1-3 positive nodes by axillary nodal dissection vs 4-9 positive nodes by axillary nodal dissection vs at least 10 positive nodes by axillary nodal dissection vs positive sentinel node with no or negative axillary nodal dissection vs negative sentinel node with no axillary nodal dissection vs node negative by axillary nodal dissection) and receptor status (estrogen receptor [ER] or progesterone receptor [PR] positive vs other). Patients are randomized to 1 of 3 treatment arms.

• Arm I*: Patients receive doxorubicin 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, 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.

   [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 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.

Patients are followed every 3 months for 1 year, every 6 months for 4 years, and then annually for 15 years or until disease progression.

Halyard MY, Pisansky TM, Dueck AC, et al.: Radiotherapy and Adjuvant Trastuzumab in Operable Breast Cancer: Tolerability and Adverse Event Data From the NCCTG Phase III Trial N9831. J Clin Oncol : , 2009.[PUBMED Abstract]

Moreno-Aspitia A, Dueck AC, Lingle WL, et al.: Serum HER2 (sHER2) levels in early-stage HER2 neu (+) breast cancer (HER2+BC): results from the NCCTG adjuvant Intergroup trial N9831. [Abstract] J Clin Oncol 26 (Suppl 15): A-529, 2008.

Perez EA, Reinholz MM, Dueck AC, et al.: c-MYC amplification and correlation with patient outcome in early stage HER2+ breast cancer from the NCCTG adjuvant intergroup trial N9831. [Abstract] 31st Annual San Antonio Breast Cancer Symposium, December 10-14, 2008, San Antonio, Texas. A-56, 2008.

Perez EA, Suman VJ, Davidson NE, et al.: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 26 (8): 1231-8, 2008.[PUBMED Abstract]

Kutteh LA, Hobday T, Jaffe A, et al.: A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): A-579, 2007.

Reinholz MM, Jenkins RB, Hillman D, et al.: The clinical significance of polysomy 17 in the HER2+ N9831 intergroup adjuvant trastuzumab trial. [Abstract] Breast Cancer Res Treat 106 (1): A-36, S11, 2007.

Halyard MY, Pisansky TM, Solin LJ, et al.: Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: toxicity data from North Central Cancer Treatment Group phase III trial N9831. [Abstract] J Clin Oncol 24 (Suppl 18): A-523, 2006.

Perez EA, Suman VJ, Davidson NE, et al.: HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 24 (19): 3032-8, 2006.[PUBMED Abstract]

Miller DV, Jenkins RB, Lingle WL, et al.: Focal HER2/neu amplified clones partially account for discordance between immunohistochemistry and fluorescence in-situ hybridization results: data from NCCTG N9831 intergroup adjuvant trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-568, 19s, 2004.

Perez EA, Suman VJ, Davidson NE, et al.: HER2 testing by local, central, and reference laboratories in the NCCTG N9831 intergroup adjuvant trial. [Abstract] J Clin Oncol 22 (Suppl 14): A-567, 19s, 2004.

Perez EA, Suman VJ, Davidson NE, et al.: Effect of doxorubicin plus cyclophosphamide on left ventricular ejection fraction in patients with breast cancer in the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. J Clin Oncol 22 (18): 3700-4, 2004.[PUBMED Abstract]

Perez EA, Suman VJ, Davidson NE, et al.: Effect of doxorubicin plus cyclophosphamide (AC) on left ventricular ejection fraction (LVEF) in the NCCTG N9831 intergroup adjuvant trial. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-75, 19, 2003.

Roche PC, Suman VJ, Jenkins RB, et al.: Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 94 (11): 855-7, 2002.[PUBMED Abstract]

Jahanzeb M: Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer 8 (4): 324-33, 2008.[PUBMED Abstract]

Partridge AH, Wolff AC, Marcom PK, et al.: The impact of sharing results of a randomized breast cancer clinical trial with study participants. Breast Cancer Res Treat : , 2008.[PUBMED Abstract]

Reinholz MM, Dueck AC, Lingle WL, et al.: The concordance between NCCTG's and NSABP's C-myc FISH assays. [Abstract] J Clin Oncol 26 (Suppl 15): A-22110, 2008.

Garrison LP Jr, Lubeck D, Lalla D, et al.: Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer. Cancer 110 (3): 489-98, 2007.[PUBMED Abstract]

Kurian AW, Thompson RN, Gaw AF, et al.: A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu-positive breast cancer. J Clin Oncol 25 (6): 634-41, 2007.[PUBMED Abstract]

Liberato NL, Marchetti M, Barosi G: Cost effectiveness of adjuvant trastuzumab in human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 25 (6): 625-33, 2007.[PUBMED Abstract]

Perez E, Romond E, Suman V, et al.: Updated results of the combined analysis of NCCTG N9831 and NSABP B-31 adjuvant chemotherapy with/without trastuzumab in patiens with HER2-positive breast cancer. [Abstract] J Clin Oncol 25 (Suppl 18): 512, 6s, 2007.

Telli ML, Hunt SA, Carlson RW, et al.: Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 25 (23): 3525-33, 2007.[PUBMED Abstract]

Baselga J, Perez EA, Pienkowski T, et al.: Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist 11 (Suppl 1): 4-12, 2006.[PUBMED Abstract]

Garrison LP, Perez EA, Dueck A, et al.: Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2+ breast cancer. [Abstract] J Clin Oncol 24 (Suppl 18): A-6023, 306s, 2006.

Gupta AK, Mekan SF, Eckman MH: Trastuzumab for all? A decision analysis examining tradeoffs between efficacy and cardiac toxicity of adjuvant therapy in HER2 positive breast cancer. [Abstract] J Clin Oncol 24 (Suppl 18): A-6022, 306s, 2006.

Romond EH, Perez EA, Bryant J, et al.: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353 (16): 1673-84, 2005.[PUBMED Abstract]

Perez EA, Rodeheffer R: Clinical cardiac tolerability of trastuzumab. J Clin Oncol 22 (2): 322-9, 2004.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Edith Perez, MD, Protocol chair		Ph: 904-953-7283 Email: perez.edith@mayo.edu

Eastern Cooperative Oncology Group

Nancy Davidson, MD, Protocol chair		Ph: 410-955-8489

Cancer and Leukemia Group B

Peter Kaufman, MD, Protocol chair		Ph: 603-650-6700; 800-639-6918 Email: peter.a.kaufman@hitchcock.org

Southwest Oncology Group

Silvana Martino, DO, Protocol chair		Ph: 310-582-7900 Email: martinos@jwci.org

NCIC-Clinical Trials Group

Karen Gelmon, MD, Protocol chair		Ph: 604-877-6000 ext. 2445; 800-663-3333 Email: kgelmon@bccancer.bc.ca

Registry Information
Official Title		Phase III Trial of Doxorubicin and Cyclophosphamide (AC) Followed by Weekly Paclitaxel With or Without Trastuzumab as Adjuvant Treatment for Women With HER-2 Overexpressing Node Positive or High-Risk Node Negative Breast Cancer
Trial Start Date		2000-05-19
Registered in ClinicalTrials.gov		NCT00005970
Date Submitted to PDQ		2000-05-04
Information Last Verified		2006-01-18
NCI Grant/Contract Number		CA25224