title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Brustzentrum, Frauenklinik Maistrasse, Universitaet München, 80337 Munich, Germany. nadia.harbeck@med.uni-muenchen.de
authors.forename: N
authors.initials: N
authors.lastname: Harbeck
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.forename: C
authors.initials: C
authors.lastname: Meisner
authors.forename: C
authors.initials: C
authors.lastname: Friedel
authors.forename: M
authors.initials: M
authors.lastname: Untch
authors.forename: M
authors.initials: M
authors.lastname: Schmidt
authors.forename: C G J
authors.initials: CG
authors.lastname: Sweep
authors.forename: B W
authors.initials: BW
authors.lastname: Lisboa
authors.forename: M P
authors.initials: MP
authors.lastname: Lux
authors.forename: T
authors.initials: T
authors.lastname: Beck
authors.forename: S
authors.initials: S
authors.lastname: Hasmüller
authors.forename: M
authors.initials: M
authors.lastname: Kiechle
authors.forename: F
authors.initials: F
authors.lastname: Jänicke
authors.forename: C
authors.initials: C
authors.lastname: Thomssen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage; D003657:Decision Making; D018572:Disease-Free Survival; D004358:Drug Therapy / Q000379:methods / Q000523:psychology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D003520:Cyclophosphamide; D014568:Urokinase-Type Plasminogen Activator; D005472:Fluorouracil; D008727:Methotrexate