Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (n = 3424).
Risk assessment and prediction of response to treatment are prerequisites for individualized adjuvant therapy decisions in breast cancer. The strong prognostic impact of the two invasion factors urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor type 1 (PAI-1), in breast cancer has recently been validated at level-I evidence. This article considers the predictive impact of uPA/PAI-1 on response to adjuvant chemo- and endocrine therapy in 3424 primary breast cancer patients from two different data sets. uPA and PAI-1 antigen levels were measured by ELISA in primary tumor tissue extracts. After a median follow-up of 83 months, uPA/PAI-1 has a significant impact on disease-free survival in Cox multivariate analysis (P < 0.001; hazard ratio, 2.0; 95% confidence interval, 1.8-2.3). Patients with high uPA/PAI-1 levels benefit more strongly from adjuvant chemotherapy than those with low levels. This effect is seen as a significant interaction between chemotherapy and uPA/PAI-1 for the entire collective (P < 0.003; hazard ratio, 0.68; 95% confidence interval, 0.53-0.88) and separately within nodal subgroups. This enhanced benefit in the high uPA/PAI-1 patients occurs over and above the significant impact of both therapies in all patients. We find no corresponding significant interaction between endocrine therapy and uPA/PAI-1; i.e., no significant difference in benefit between patients with high and low uPA/PAI-1. In conclusion, uPA and PAI-1 levels in primary tumor tissue provide clinically relevant information on relapse risk and treatment response that will help to tailor adjuvant therapy concepts in breast cancer, accounting for individual biological tumor characteristics.
Department of Obstetrics and Gynecology, Technical University, D-81675 Munich, Germany. nadia.harbeck@lrz.tum.de
Nadia
N
Harbeck
Ronald E
RE
Kates
Maxime P
MP
Look
Marion E
ME
Meijer-Van Gelder
Jan G M
JG
Klijn
Achim
A
Krüger
Marion
M
Kiechle
Fritz
F
Jänicke
Manfred
M
Schmitt
John A
JA
Foekens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013629:Tamoxifen / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D018943:Anthracyclines; D018931:Antineoplastic Agents, Hormonal; D017395:Plasminogen Activator Inhibitor 1; D013629:Tamoxifen; D014568:Urokinase-Type Plasminogen Activator