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

Alternate Title

Doxorubicin and Cyclophosphamide Plus Paclitaxel With or Without Trastuzumab in Treating Women With Node-Positive Breast Cancer That Overexpresses HER2

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	Not specified	NCI	NSABP-B-31 NCT00004067

Objectives

1. Compare the cardiotoxicity of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab (Herceptin®) in women with operable, node-positive breast cancer that overexpresses HER2.
2. Compare the effect of these regimens on disease-free and overall survival of these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically proven invasive adenocarcinoma of the breast
  • Stage IIA, IIB, or IIIA
  • Confined to the breast and ipsilateral axilla (cN0-1) on clinical examination
  • At least 1 histologically positive axillary node
  • No lymph nodes clinically fixed to each other or to other structures (cN2)
  • HER2 strongly positive (3+ by immunostain OR gene amplification by fluorescent in situ hybridization)
    • Submission of tumor block required



• Must have undergone axillary dissection and either total mastectomy OR lumpectomy
  • Sentinel node dissection allowed, if followed by axillary dissection
  • No diffuse tumors by mammography in patients treated with lumpectomy
  • No more than 84 days since prior surgery for breast cancer (e.g., lumpectomy, mastectomy, axillary dissection, or re-excision of lumpectomy margins)



• No bilateral malignancy, contralateral mass, or mammographic abnormality unless histologically proven as benign



• No suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes unless histologically proven not to be involved with tumor



• No primary T4 tumors (for any reason)



• No prior breast cancer, including ductal carcinoma in situ
  • Prior lobular carcinoma in situ allowed



• Bone pain allowed provided there is no metastatic disease by x-ray, MRI, or biopsy



• Hormone receptor status:
  • Estrogen and progesterone status known

Prior/Concurrent Therapy:

Biologic therapy:

• No prior biologic therapy for this breast cancer

Chemotherapy:

• No prior chemotherapy for this breast cancer
• No prior anthracycline or taxane therapy for any cancer

Endocrine therapy:

• No prior hormonal therapy for this breast cancer
• No concurrent hormonal therapy (e.g., birth control pills or ovarian hormone replacement therapy)
• No concurrent raloxifene or other selective estrogen-receptor modulators

Radiotherapy:

• No prior radiotherapy for this breast cancer
• No concurrent radiotherapy to internal mammary nodes
• No other concurrent radiotherapy except as specified in study

Surgery:

• See Disease Characteristics

Other:

• No other concurrent investigational agents

Patient Characteristics:

Age:

• Not specified

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Not specified

Life expectancy:

• At least 10 years, excluding diagnosis of breast cancer

Hematopoietic:

• Platelet count at least 100,000/mm^3*
• Absolute neutrophil count at least 1,500/mm³ (unless determined by the investigator to be normal for ethnic or racial variation)

 [Note: *Significant underlying hematologic disorders must be excluded if above upper limit of normal (ULN)]

Hepatic:

• Bilirubin no greater than ULN
• SGOT less than 1.5 times ULN
• Alkaline phosphatase less than 2.5 times ULN
• No systemic hepatic disease that would preclude study participation

Renal:

• Creatinine normal
• No systemic renal disease that would preclude study participation

Cardiovascular:

• LVEF at least lower limit of normal by MUGA
• No cardiovascular disease that would preclude study participation
• No angina pectoris requiring treatment
• No cardiomegaly on chest x-ray
• No prior myocardial infarction by clinical diagnosis or by EKG or other test
• No prior congestive heart failure
• No prior cardiomyopathy
• No cardiac arrhythmia requiring medication
• No severe conduction abnormality
• No clinically significant valvular disease
• No poorly controlled hypertension (diastolic greater than 100 mm Hg), unless adequately controlled by medication
• No ventricular hypertrophy on EKG

Other:

• Not pregnant or nursing
• Fertile patients must use effective barrier contraception
• No other prior malignancy within the past 5 years except effectively treated carcinoma in situ of the cervix, melanoma in situ, or basal cell or squamous cell skin cancer
• No psychiatric or addictive disorders that would preclude informed consent
• No sensory or motor neuropathy grade 2 or greater
• No contraindications to corticosteroids

Expected Enrollment

A total of 2,700 patients will be accrued for this study within 4.75 years.

Outline

This is a randomized, multicenter study. Patients are stratified according to number of positive nodes (1-3 vs 4-9 vs 10 or more), administration of hormonal therapy (tamoxifen vs anastrozole vs neither), surgery/radiotherapy (lumpectomy plus breast irradiation vs lumpectomy plus breast irradiation plus regional irradiation vs mastectomy without radiotherapy vs mastectomy with radiotherapy), paclitaxel schedule (every 3 weeks vs weekly), and participating center. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive doxorubicin IV and cyclophosphamide IV over 30 minutes on day 1. Treatment repeats every 21 days for 4 courses. Approximately 3 weeks after the last course, patients receive paclitaxel IV over 3 hours every 21 days for 4 courses OR paclitaxel IV over 1 hour once weekly for 12 weeks (12 doses).



• Arm II: Patients receive chemotherapy as in arm I and trastuzumab (Herceptin®) IV over 90 minutes on day 1 of the first course of paclitaxel. Trastuzumab is then administered IV over 30 minutes weekly for 51 weeks, beginning on day 8.

All patients with estrogen or progesterone receptor-positive tumors receive hormonal therapy* for at least 5 years, beginning within 3-12 weeks after the last dose of chemotherapy. Patients who have received prior tamoxifen for prevention may be treated with additional tamoxifen for no more than 5 years at the discretion of the principal investigator (PI).

 [Note: *Other hormonal therapeutic agents are allowed in sequence with or as an alternative to tamoxifen therapy.]

All patients previously treated with lumpectomy undergo breast irradiation beginning after completion of chemotherapy and concurrently with trastuzumab (in arm II) administration. Patients previously treated with mastectomy may also receive radiotherapy. Radiotherapy is administered daily for 5-6 weeks.

Patients are followed every 6 months for 5 years and then annually thereafter.

Rastogi P, Jeong J, Geyer CE, et al.: Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab(H). [Abstract] J Clin Oncol 25 (Suppl 18): A-LBA513, 2007.

Geyer CE, Bryant JL, Romond EH, et al.: Update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab (H). [Abstract] J Clin Oncol 24 (Suppl 18): A-581, 2006.

Kim C, Bryant J, Horne Z, et al.: Trastuzumab sensitivity of breast cancer with co-amplification of HER2 and cMYC suggests pro-apoptotic function of dysregulated cMYC in vivo. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-46, 2005.

Tan-Chiu E, Yothers G, Romond E, et al.: Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23 (31): 7811-9, 2005.[PUBMED Abstract]

Geyer CE Jr, Bryant J, Romond E: Cardiac safety analysis of the first stage of NSABP B-31, a randomized trial comparing the safety and efficacy of adriamycin® and cyclophosphamide (AC) followed by taxol® to that of AC followed by taxol® plus herceptin® in patients (Pts) with operable, node-positive (N+), HER-2 overexpressing breast cancer (HER2+BC). [Abstract] Breast Cancer Res Treat 82 (Suppl 1): A-23, S13, 2003.

Paik S, Bryant J, Tan-Chiu E, et al.: Real-world performance of HER2 testing--National Surgical Adjuvant Breast and Bowel Project experience. J Natl Cancer Inst 94 (11): 852-4, 2002.[PUBMED Abstract]

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

Burstein HJ: The distinctive nature of HER2-positive breast cancers. N Engl J Med 353 (16): 1652-4, 2005.[PUBMED Abstract]

Hortobagyi GN: Trastuzumab in the treatment of breast cancer. N Engl J Med 353 (16): 1734-6, 2005.[PUBMED Abstract]

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]

Tan-Chiu E, Piccart M: Moving forward: Herceptin in the adjuvant setting. Oncology 63 (Suppl 1): 57-63, 2002.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

National Surgical Adjuvant Breast and Bowel Project

Edward Romond, MD, Protocol chair		Ph: 859-323-8043

Registry Information
Official Title		A Randomized Trial Comparing the Safety and Efficacy of Adriamycin and Cyclophosphamide Followed by Taxol (AC-T) to That of Adriamycin and Cyclophosphamide Followed by Taxol Plus Herceptin (AC-T+H) in Node-Positive Breast Cancer Patients Who Have Tumors That Overexpress HER2
Trial Start Date		2000-02-22
Registered in ClinicalTrials.gov		NCT00004067
Date Submitted to PDQ		1999-08-11
Information Last Verified		2005-02-15
NCI Grant/Contract Number		CA12027