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Clinical Trials (PDQ®)

Phase III Randomized Comparison of Adjuvant Therapy with TMX Alone vs TMX plus Sequential MTX/5-FU vs TMX plus Conventional CMF (CTX/MTX/5-FU) Following Curative Resection of ER-Positive Carcinoma of the Breast with Negative Nodes

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

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted18 and overNCINSABP-B-20
MAOP-1388, NCOG-NSABP-B-20

Objectives

I.  Compare survival and disease-free survival of patients who have undergone 
curative resection of ER-positive carcinoma of the breast with negative nodes 
randomly assigned to adjuvant postoperative treatment with tamoxifen alone vs. 
tamoxifen plus sequential methotrexate-fluorouracil followed by leucovorin vs. 
tamoxifen plus conventional CMF (cyclophosphamide/methotrexate/fluorouracil).

II.  Correlate tumor cell ploidy, kinetics, and pathological variables of 
tumor differentiation (e.g., nuclear grade) to clinical outcome.

Entry Criteria

Disease Characteristics:


Pathologically documented invasive, node-negative carcinoma of
the breast that has been potentially curatively resected within
35 days of entry by:

  Total mastectomy with axillary dissection
  Segmental mastectomy with axillary dissection to be followed
   on protocol with radiotherapy

Tumor confined to breast on clinical exam and movable in
relation to overlying skin and to underlying muscle and chest
wall

No inflammatory breast cancer, ulceration, erythema, peau
d'orange of any magnitude, parasternal nodules, edema of the
arm, or infiltration of the skin
  Tethering or dimpling of the skin or nipple inversion is not
  considered infiltration; patients with these are eligible

All axillary nodes histologically negative for tumor
  Preoperatively palpable ipsilateral axillary nodes allowed if
  histologically negative

Palpable contralateral axillary or palpable supraclavicular or
infraclavicular nodes must be histologically free of tumor on
biopsy

No satellite breast nodules (suspected satellite foci of tumor
involving the skin must be histologically proven to be tumor
free)

Bone pain allowed only if bone scan and/or radiographic exam
reveals no evidence of metastatic disease

No bilateral breast cancer any contralateral breast mass must
be proven nonmalignant on biopsy

Segmental mastectomy patients must also satisfy the following
requirements:

  Tumor 5 cm or less in greatest diameter on clinical exam

  Breast of sufficient size to allow cosmetically acceptable
  resection

  Resection margins histologically negative (1 additional
  surgical procedure allowed to obtain negative margins; if
  margins are positive after the second surgical procedure, a
  total mastectomy is required)

  No diffuse tumor (on xeroradiography or mammography) that
  would preclude segmental mastectomy

  No second dominant mass in the same breast unless
  histologically proven to be benign

Hormone receptor status:
  ER+ (at least 10 fmol/mg cytosol protein), any Pr
  ER- patients are eligible for protocol NSABP-B-23


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 (including
     radiation castration or oophorectomy)
  Current hormonal therapy (e.g., birth control pills,
     replacement therapy) must be discontinued while on
     protocol until first recurrence

Radiotherapy:
  No prior radiation castration
  No breast irradiation prior to randomization

Surgery:
  No more than 4 weeks between establishment of histologic
   diagnosis (excisional, incisional, or needle biopsy and
   aspiration cytology) and definitive surgery
  Prior oophorectomy for reasons other than breast cancer
  treatment allowed


Patient Characteristics:


Age:
  18 and over

Sex:
  Women only

Menopausal status:
  Not specified

Performance status:
  Not specified

Life expectancy:
  At least 10 years exclusive of breast cancer

Hematopoietic:
  WBC at least 4,000 postoperatively
  Platelets at least 100,000 postoperatively

Hepatic:
  Bilirubin no greater than 1.5 mg/dl postoperatively
  SGOT no greater than 60 IU/ml postoperatively
  No hepatic disease that would preclude protocol therapy

Renal:
  Creatinine no greater than 1.5 mg/dl postoperatively
  Creatinine clearance at least 60 ml/min postoperatively
  No renal disease that would preclude protocol therapy

Cardiovascular:
  No cardiovascular disease that would preclude protocol
  therapy

Other:
  No other nonmalignant systemic disease that would preclude
     protocol therapy
  No psychiatric or addictive disorders that would preclude
     informed consent
  No second malignancy except:
     Effectively treated nonmelanomatous skin cancer
     Operatively treated in situ carcinoma of the cervix
  No pregnant women


Expected Enrollment

2,340 patients will be entered over about 3 years.

Outline

Randomized study.  Patients on all arms who have undergone segmental resection 
receive breast irradiation as described under Regimen A concurrently with 
adjuvant therapy.

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

Arm II:  Antiestrogen Therapy plus 2-Drug Sequential Combination Chemotherapy 
plus Leucovorin Rescue.  TMX; plus Methotrexate, MTX, NSC-740; followed by 
Fluorouracil, 5-FU, NSC-19893; plus Leucovorin calcium, CF, NSC-3590.

Arm III:  Antiestrogen Therapy plus 3-Drug Combination Chemotherapy.  TMX; 
plus CMF:  Cyclophosphamide, CTX, NSC-26271; MTX; 5-FU.

Regimen A:  Radiotherapy.  Irradiation of the remaining ipsilateral breast 
tissue with Co60 or linear accelerator equipment.

Published Results

Ross DT, Kim C, Tang G, et al.: Chemosensitivity and stratification by a five monoclonal antibody IHC test in the NSABP B20 trial. [Abstract] J Clin Oncol 25 (Suppl 18): A-529, 2007.

Paik S, Tang G, Shak S, et al.: Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24 (23): 3726-34, 2006.[PUBMED Abstract]

Fisher B, Dignam J, DeCillis A, et al.: The worth of chemotherapy and tamoxifen (TAM) over TAM alone in node-negative patients with estrogen-receptor (ER) positive invasive breast cancer (BC). [Abstract] Proceedings of the American Society of Clinical Oncology 16 : A1, 1997.

Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 89 (22): 1673-82, 1997.[PUBMED Abstract]

Related Publications

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]

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.

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.: 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.

Trial Contact Information

Trial Lead Organizations

National Surgical Adjuvant Breast and Bowel Project

Norman Wolmark, MD, Protocol chair
Ph: 412-359-3336; 866-680-0004

Clinical Research Program - Northern California Cancer Center

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

Mid-Atlantic Oncology Program

James Ahlgren, MD, Protocol chair
Ph: 202-741-2478
Email: w4rx@alum.mit.edu

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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