Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)-recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients

N. Harbeck, M. Schmitt, C. Meisner, C. Friedel, M. Untch, M. Schmidt, C. G.J. Sweep, B. W. Lisboa, M. P. Lux, T. Beck, S. Hasmüller, M. Kiechle, F. Jänicke, C. Thomssen

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130 Scopus citations

Abstract

Aim: Final 10-year analysis of the prospective randomised Chemo-N0 trial is presented. Based on the Chemo-N0 interim results and an European Organisation for Research and Treatment of Cancer (EORTC) pooled analysis (n = 8377), American Society of Clinical Oncology (ASCO) and Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines recommend invasion and metastasis markers urokinase-type plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) for risk assessment and treatment decision in node-negative (N0) breast cancer (BC). Methods: The final Chemo-N0 trial analysis (recruitment 1993-1998; n = 647; 12 centres) comprises 113 (5-167) months of median follow-up. Patients with low-uPA and PAI-1 tumour tissue levels (n = 283) were observed. External quality assurance guaranteed uPA/PAI-1 enzyme-linked immunosorbent assay (ELISA) standardisation. Of 364 high uPA and/or PAI-1 patients, 242 agreed to randomisation for CMF chemotherapy (n = 117) versus observation (n = 125). Results: Actuarial 10-year recurrence rate (without any adjuvant systemic therapy) for high-uPA/PAI-1 observation group patients (randomised and non-randomised) was 23.0%, in contrast to only 12.9% for low-uPA/PAI-1 patients (plog-rank = 0.011). High-risk patients randomised to cyclophosphamide-methotrexate-5-fluorouracil (CMF) therapy had a 26.0% lower estimated probability of disease recurrence than those randomised for observation (intention-to-treat (ITT)-analysis: hazard ratio (HR) 0.74 (0.44-1.27); plog-rank = 0.28). Per-protocol analysis demonstrated significant treatment benefit: HR 0.48 (0.26-0.88), p = 0.019, disease-free survival (DFS) Cox regression, adjusted for tumour stage and grade. Conclusions: Chemo-N0 is the first prospective biomarker-based therapy trial in early BC defining patients reaching good long-term DFS without adjuvant systemic therapy. Using a standardised uPA/PAI-1 ELISA, almost half of N0-patients could be spared chemotherapy, while high-risk patients benefit from adjuvant chemotherapy. These 10-year results validate the long-term prognostic impact of uPA/PAI-1 and the benefit from adjuvant chemotherapy in the high-uPA/PAI-1 group at highest level of evidence. They thus support the guideline-based routine use of uPA/PAI-1 for risk-adapted individualised therapy decisions in N0 breast cancer.

Original languageEnglish
Pages (from-to)1825-1835
Number of pages11
JournalEuropean Journal of Cancer
Volume49
Issue number8
DOIs
StatePublished - May 2013
Externally publishedYes

Keywords

  • Adjuvant chemotherapy
  • Cancer biomarker
  • Node-negative breast cancer
  • PAI-1
  • Prognostic factors
  • uPA

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