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Phase III Comparison of Adjuvant Therapy with TMX vs Placebo in Patients with Negative Axillary Nodes Following Mastectomy for ER-Positive Breast Cancer

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted18 to 70NCINSABP-B-14
MAOP-1584, NCOG-NSABP-B-14

Objectives

I.  Compare disease-free interval and survival of patients with negative 
axillary nodes following mastectomy for ER-positive breast cancer who are 
randomly assigned to adjuvant tamoxifen therapy vs. placebo.

II.  In conjunction with the results of NSABP-B-13, evaluate whether treatment 
failure and survival correlate with ER level in postmastectomy, node-negative 
patients who receive no further treatment.

III.  Evaluate the influence of both hormone receptor status and the 
interaction of radiotherapy and tamoxifen on the rate of local breast 
recurrence in patients who have undergone segmental mastectomy and axillary 
node dissection for their disease.

Entry Criteria

Disease Characteristics:


Histologically proven invasive carcinoma of the breast
definitively removed by either:
  Total mastectomy with axillary node dissection
  Segmental mastectomy with axillary node dissection

No more than 35 days between mastectomy and randomization, with
radiotherapy planned on study

No more than 4 weeks between diagnosis and mastectomy

Histology established by excisional, incisional, or needle
biopsy and aspiration cytology

Tumor confined to the breast clinically, i.e., movable relative
to the underlying muscle, chest wall, and skin

Histologic proof of negative axillary nodes required
  Preoperatively palpable ipsilateral axillary nodes allowed
  if free of tumor

Palpable contralateral axillary nodes or palpable
supraclavicular or infraclavicular nodes must be biopsy-proven
benign

Hormone receptor status:
  ER-positive, i.e., at least 10 fmol/mg cytosol protein
  Quantitative PgR status required
  Receptor statuses must be known prior to randomization

The following exclude:
  Ulceration
  Erythema
  Infiltration of the skin
  Peau d'orange or any degree of skin edema
  Satellite breast nodules
  Parasternal nodules
  Edema of the arm
  Infiltration of the skin
     Tethering, skin dimpling, and nipple inversion are
     not to be interpreted as skin infiltration and
     patients with these conditions are eligible
  Inflammatory carcinoma
  Histologies other than carcinoma
  Bilateral breast cancer
     Any mass in the contralateral breast must be biopsy-
     proven benign
  Metastatic disease
     Patients with bone pain with negative bone scan
     and/or x-rays are eligible

Segmental mastectomy patients must additionally meet the
following criteria:
  Tumor clinically no greater than 4 cm in greatest diameter
     Mammography preferred

  No diffuse tumor on xeroradiography or mammography
  considered surgically unsuited for lumpectomy

  No more than 1 malignant mass in the breast
     Other masses must be biopsy-proven benign

  No requirement for removal of nipple

  Breast is of a size to allow a cosmetically acceptable
  resection

  Breast sufficiently small to permit satisfactory irradiation

  No breast irradiation prior to randomization


Prior/Concurrent Therapy:


Biologic therapy:
  No prior immunotherapy for breast cancer

Chemotherapy:
  No prior chemotherapy for breast cancer

Endocrine therapy:
  No  prior hormonal therapy for breast cancer
  No prior oophorectomy for malignancy (oophorectomy for other
     reasons allowed)
  No prior radiation castration
  Hormonal therapy other than that stipulated by protocol
     (e.g., birth control, replacement therapy) must be
     discontinued on entry

Radiotherapy:
  No prior radiotherapy for breast cancer

Surgery:
  See Disease Characteristics


Patient Characteristics:


Age:
  Under 71

Sex:
  Female only

Menopausal status:
  Any status

Performance status:
  Not specified

Hematopoietic:
  (obtained postoperatively)
  WBC greater than 4,000
  Platelets at least 100,000

Hepatic:
  (obtained postoperatively)
  Bilirubin no greater than 1.5 mg/dl
  SGOT no greater than 60 IU/ml

Renal:
  No nonmalignant systemic renal disease that would preclude
  any protocol therapy or prolonged follow-up

Cardiovascular:
  No nonmalignant systemic cardiovascular disease that would
  preclude any protocol therapy or prolonged follow-up

Other:
  No psychiatric or addictive disorder that would preclude
     informed consent
  No nonmalignant systemic disease that would preclude any
     protocol therapy or prolonged follow-up
  No second malignancy except:
     Curatively treated nonmelanomatous skin cancer
     In situ cervical cancer treated by surgery only
  No pregnancy


Expected Enrollment

A 3-year accrual of 2,320 patients will be required.

Outline

Randomized, double-blind study.  All patients are randomized on Arms I and II; 
segmental mastectomy patients are also treated on Regimen A.  Patients who are 
disease-free following 5 years of treatment on Arm I may be randomized a 
second time on Arms III and IV.

Arm I:  Antiestrogen Therapy.  Tamoxifen, TMX, NSC-180973.

Arm II:  Placebo.

Regimen A:  Radiotherapy.  Breast irradiation using Co60 or linear accelerator 
x-rays.

Arm III:  Antiestrogen Therapy.  TMX.

Arm IV:  Placebo.

Published Results

Paik S, Shak S, Tang G, et al.: Expression of the 21 genes in the Recurrence Score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen receptor positive breast cancer. [Abstract] J Clin Oncol 23 (Suppl 16): A-510, 6s, 2005.

Fisher B, Jeong JH, Bryant J, et al.: Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet 364 (9437): 858-68, 2004.[PUBMED Abstract]

Paik S, Shak S, Tang G, et al.: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351 (27): 2817-26, 2004.[PUBMED Abstract]

Dignam JJ, Wieand K, Johnson KA, et al.: Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer. J Natl Cancer Inst 95 (19): 1467-76, 2003.[PUBMED Abstract]

Fisher B, Dignam J, Bryant J, et al.: Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93 (9): 684-90, 2001.[PUBMED Abstract]

Bryant J, Fisher B, Gündüz N, et al.: S-phase fraction combined with other patient and tumor characteristics for the prognosis of node-negative, estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 51 (3): 239-53, 1998.[PUBMED Abstract]

Dignam JJ, Bryant J, Wieand HS, et al.: Early stopping of a clinical trial when there is evidence of no treatment benefit: protocol B-14 of the National Surgical Adjuvant Breast and Bowel Project. Control Clin Trials 19 (6): 575-88, 1998.[PUBMED Abstract]

Costantino JP, Kuller LH, Ives DG, et al.: Coronary heart disease mortality and adjuvant tamoxifen therapy. J Natl Cancer Inst 89 (11): 776-82, 1997.[PUBMED Abstract]

Fisher B, Dignam J, Bryant J, et al.: Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88 (21): 1529-42, 1996.[PUBMED Abstract]

Costantino J, Fisher B, Gunduz N, et al.: Tumor size, ploidy, S-phase, and erb B-2 markers in patients with node-negative, ER-positive tumors: finding from NSABP B-14. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-59, 64, 1994.

Fisher B, Costantino J, Wickerham L, et al.: Adjuvant therapy for node-negative breast cancer: an update of NSABP findings. [Abstract] Proceedings of the American Society of Clinical Oncology 12: A-79, 69, 1993.

Fisher B, Costantino J, Redmond C, et al.: A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 320 (8): 479-84, 1989.[PUBMED Abstract]

Fisher B, Redmond C, Brown A, et al.: Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol 4 (4): 459-71, 1986.[PUBMED Abstract]

Related Publications

Kim C, Tang G, Pogue-Geile KL, et al.: Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol 29 (31): 4160-7, 2011.[PUBMED Abstract]

Tang G, Shak S, Paik S, et al.: Comparison of the prognostic and predictive utilities of the 21-gene Recurrence Score assay and Adjuvant! for women with node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. Breast Cancer Res Treat 127 (1): 133-42, 2011.[PUBMED Abstract]

Mamounas EP, Tang G, Fisher B, et al.: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor-positive breast cancer: results from NSABP B-14 and NSABP B-20. J Clin Oncol 28 (10): 1677-83, 2010.[PUBMED Abstract]

Anderson SJ, Wapnir I, Dignam JJ, et al.: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five national surgical adjuvant breast and bowel project protocols of node-negative breast cancer. J Clin Oncol 27 (15): 2466-73, 2009.[PUBMED Abstract]

Ross DT, Kim CY, Tang G, et al.: Chemosensitivity and stratification by a five monoclonal antibody immunohistochemistry test in the NSABP B14 and B20 trials. Clin Cancer Res 14 (20): 6602-9, 2008.[PUBMED Abstract]

Lyman GH, Cosler LE, Kuderer NM, et al.: Impact of a 21-gene RT-PCR assay on treatment decisions in early-stage breast cancer: an economic analysis based on prognostic and predictive validation studies. Cancer 109 (6): 1011-8, 2007.[PUBMED Abstract]

Ross DT, Kim C, Tang G, et al.: Prognosis and chemosensitivity using a five monoclonal antibody IHC test in node-negative, tamoxifen-treated, ER+ breast cancer: NSABP B14 and B20 trials. [Abstract] American Society of Clinical Oncology 2007 Breast Cancer Symposium, 7-8 September 2007, San Francisco, California A-28, 2007.

Ross DT, Kim C, Tang G, et al.: Validation of the prognostic algorithm based on five monoclonal antibody immunohistochemistry test in node negative ER+ breast cancer NSABP B14 and B20 studies. [Abstract] 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, Texas. A-3149, 2006.

Taghian AG, Jeong JH, Mamounas EP, et al.: Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol 24 (24): 3927-32, 2006.[PUBMED Abstract]

Hornberger J, Cosler LE, Lyman GH: Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogen-receptor-positive, early-stage breast cancer. Am J Manag Care 11 (5): 313-24, 2005.[PUBMED Abstract]

Mamounas E, Tang G, Bryant J, et al.: Association between the 21-gene recurrence score assay (RS) and risk of locoregional failure in node-negative, ER-positive breast cancer: results from NSABP B-14 and NSABP B-20. [Abstract] Breast Cancer Research and Treatment 94 (Suppl 1): A-29, 2005.

Paik S, Shak S, Tang G, et al.: Expression of the 21 genes in the Recurrence Score assay and prediction of clinical benefit from tamoxifen in NSABP study B-14 and chemotherapy in NSABP study B-20. [Abstract] Breast Cancer Res Treat 88 (Suppl 1): A-24, 2004.

Paik S, Shak S, Tang G, et al.: Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients: NSABP studies B-20 and B-14. [Abstract] Breast Cancer Res Treat 82 (Suppl 1): A-16, S10, 2003.

Wickerham L: Tamoxifen--an update on current data and where it can now be used. Breast Cancer Res Treat 75 (Suppl 1): S7-12; discussion S33-5, 2002.[PUBMED Abstract]

Fisher B, Dignam J, Tan-Chiu E, et al.: Prognosis and treatment of patients with breast tumors of one centimeter or less and negative axillary lymph nodes. J Natl Cancer Inst 93 (2): 112-20, 2001.[PUBMED Abstract]

Fisher B, Jeong JH, Dignam J, et al.: Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer. J Natl Cancer Inst Monogr (30): 62-6, 2001.[PUBMED Abstract]

McCaskill-Stevens W, Bryant J, Costantino J, et al.: Incidence of contralateral breast cancer (CBC), endometrial cancer (EC), and thromboembolic events (TE) in African American (AA) women receiving tamoxifen for treatment of primary breast cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A269, 2000.

Fisher B, Dignam J, Mamounas EP, et al.: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 14 (7): 1982-92, 1996.[PUBMED Abstract]

Fisher ER, Kenny JP, Sass R, et al.: Medullary cancer of the breast revisited. Breast Cancer Res Treat 16 (3): 215-29, 1990.[PUBMED Abstract]

Fisher B, Redmond C, Wickerham DL, et al.: Systemic therapy in patients with node-negative breast cancer. A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials. Ann Intern Med 111 (9): 703-12, 1989.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

National Surgical Adjuvant Breast and Bowel Project

Norman Wolmark, MD, Protocol chair (Contact information may not be current)
Ph: 412-623-3205

Mid-Atlantic Oncology Program

Patrick Byrne, MD, Protocol chair (Contact information may not be current)
Ph: 703-560-3205

Clinical Research Program - Northern California Cancer Center

Robert Carlson, MD, Protocol chair
Ph: 650-725-6457; 800-756-9000

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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