Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1

J Natl Cancer Inst. 2001 Jun 20;93(12):913-20. doi: 10.1093/jnci/93.12.913.


Background: Most patients with lymph node-negative breast cancer are cured by locoregional treatment; however, about 30% relapse. Because traditional histomorphologic and clinical factors fail to identify the high-risk patients who may benefit from adjuvant chemotherapy, other prognostic factors are needed. In a unicenter study, we have found that levels of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) in the primary tumor are predictive of disease recurrence. Thus, we designed the Chemo N(0) prospective randomized multicenter therapy trial to investigate further whether uPA and PAI-1 are such prognostic factors and whether high-risk patients identified by these factors benefit from adjuvant chemotherapy. After 4.5 years, we present results of the first interim analysis.

Methods: We studied 556 patients with lymph node-negative breast cancer. The median follow-up was 32 months. All patients with low tumor levels of uPA (< or = 3 ng/mg of protein) and of PAI-1 (< or = 14 ng/mg of protein) were observed. Patients with high tumor levels of uPA (> 3 ng/mg of protein) and/or of PAI-1 (> 14 ng/mg of protein) were randomly assigned to combination chemotherapy or subjected to observation only. All statistical tests were two-sided.

Results: A total of 241 patients had low levels of uPA and PAI-1, and 315 had elevated levels of uPA and/or PAI-1. The estimated 3-year recurrence rate for patients with low tumor levels of uPA and PAI-1 (low-risk group) was 6.7% (95% confidence interval [CI] = 2.5% to 10.8%). This rate for patients with high tumor levels of uPA and/or PAI-1 (high-risk group) was 14.7% (95% CI = 8.5% to 20.9%) (P = 0.006). First interim analysis suggests that high-risk patients in the chemotherapy group benefit, with a 43.8% lower estimated probability of disease recurrence at 3 years than high-risk patients in the observation group (intention-to-treat analysis: relative risk = 0.56; 95% CI = 0.25 to 1.28), but further follow-up is needed for confirmation.

Conclusions: Using uPA and PAI-1, we have been able to classify about half of the patients with lymph node-negative breast cancer as low risk, for whom adjuvant chemotherapy may be avoided, and half as high risk, who appear to benefit from adjuvant chemotherapy.

Publication types

  • Clinical Trial
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery*
  • Chemotherapy, Adjuvant
  • Cyclophosphamide / administration & dosage
  • Disease-Free Survival
  • Female
  • Fluorouracil / administration & dosage
  • Humans
  • Lymph Nodes / pathology
  • Menopause
  • Methotrexate / administration & dosage
  • Middle Aged
  • Neoplasm Staging
  • Plasminogen Activator Inhibitor 1 / adverse effects
  • Plasminogen Activator Inhibitor 1 / blood
  • Plasminogen Activator Inhibitor 1 / therapeutic use*
  • Plasminogen Activators / adverse effects
  • Plasminogen Activators / blood
  • Plasminogen Activators / therapeutic use*
  • Predictive Value of Tests
  • Prognosis
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Urokinase-Type Plasminogen Activator / adverse effects
  • Urokinase-Type Plasminogen Activator / blood
  • Urokinase-Type Plasminogen Activator / therapeutic use*


  • Plasminogen Activator Inhibitor 1
  • Cyclophosphamide
  • Plasminogen Activators
  • Urokinase-Type Plasminogen Activator
  • Fluorouracil
  • Methotrexate

Supplementary concepts

  • CMF regimen