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

• Published in: European journal of cancer (1990) Vol. 49; no. 8; pp. 1825 - 1835
• Main Authors: Harbeck, N, Schmitt, M, Meisner, C, Friedel, C, Untch, M, Schmidt, M, Sweep, C.G.J, Lisboa, B.W, Lux, M.P, Beck, T, Hasmüller, S, Kiechle, M, Jänicke, F, Thomssen, C
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.05.2013; Elsevier
• Subjects: Adjuvant chemotherapy; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer biomarker; Chemotherapy, Adjuvant; Cyclophosphamide - administration & dosage; Decision Making; Disease-Free Survival; Drug Therapy - methods; Drug Therapy - psychology; Enzyme-Linked Immunosorbent Assay; Female; Fluorouracil - administration & dosage; Hematology, Oncology and Palliative Medicine; Humans; Medical sciences; Methotrexate - administration & dosage; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Node-negative breast cancer; PAI-1; Pharmacology. Drug treatments; Plasminogen Activator Inhibitor 1 - metabolism; Prognosis; Prognostic factors; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome; Tumors; uPA; Urokinase-Type Plasminogen Activator - metabolism; United States; North America; America; Cancer biomarker; PAI-1; Adjuvant chemotherapy; Prognostic factors; Node-negative breast cancer; uPA; u-Plasminogen activator; Breast disease; Prognosis; American; Multicenter study; Adjuvant treatment; Biological marker; Early stage; Prospective; Plasminogen activator inhibitor 1; Cancerology; Node-negative breast; Clinical trial; Mammary gland; Human; Serine endopeptidases; Enzyme; Decision making; Patient; Breast cancer; Malignant tumor; Recommendation; Mammary gland diseases; Peptidases; Chemotherapy; Treatment; Breast; Hydrolases; Society; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2013.01.007

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.