Prognostic impact of proteolytic factors (urokinase-type plasminogen activator, plasminogen activator inhibitor 1, and cathepsins B, D, and L) in primary breast cancer reflects effects of adjuvant systemic therapy.
OBJECTIVE
Prognostic and predictive impact of five proteolytic factors associated with tumor invasion and metastasis in primary breast cancer were evaluated after long-term follow-up.


METHODS
Antigen levels of urokinase-type plasminogen activator, plasminogen activator inhibitor-1 (PAI-1), Cathepsins B, D, and L were determined using immunochemical assays in primary tumor tissue of 276 patients.


RESULTS
During follow-up (median 109 months), 119 (43%) patients relapsed, and 117 (42%) died. In the whole collective, lymph node status (P < 0.001; RR 3.8), Cathepsin L (P < 0.001; RR 2.6), and PAI-1 (P = 0.027; RR 1.7) were the only independent significant factors in multivariate analysis for disease-free survival (DFS). For overall survival (OS), lymph node status (P < 0.001; RR 2.9), Cathepsin L (P = 0.017; RR 1.9), PAI-1 (P = 0.01; RR 1.9), and grading (P = 0.026; RR 1.7) were significant. In the node-negative subgroup, PAI-1 was the only significant factor for DFS (P = 0.004; RR 3.7) and the strongest factor (P = 0.004; RR 3.7) for OS next to grading (P = 0.017; RR 3.1). In node-positive patients, Cathepsin L was the only significant factor for both DFS (P < 0.001; RR 3.2) and OS (P = 0.003; RR 2.5). For all proteolytic factors but Cathepsin L, the univariate prognostic impact on DFS was substantial in patients without adjuvant systemic therapy but was diminished if adjuvant therapy had been administered. Cathepsin L maintained its strong prognostic impact on DFS even in patients with adjuvant endocrine therapy (P = 0.01; RR 2.8).


CONCLUSIONS
The observed effect of adjuvant systemic therapy on their prognostic strength suggests that the assessed proteolytic factors supply predictive information on therapy response.
Harbeck
N
N
Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, D-81675 Munich, Germany. nadia.harbeck@lrz.tum.de
Alt
U
U
Berger
U
U
Krüger
A
A
Thomssen
C
C
Jänicke
F
F
Höfler
H
H
Kates
R E
RE
Schmitt
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002401:Cathepsin B / Q000032:analysis; D002402:Cathepsin D / Q000032:analysis; D056668:Cathepsin L; D002403:Cathepsins / Q000032:analysis; D017024:Chemotherapy, Adjuvant; D003546:Cysteine Endopeptidases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007118:Immunoassay; D008875:Middle Aged; D015999:Multivariate Analysis; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis; D011379:Prognosis; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D002403:Cathepsins; D014568:Urokinase-Type Plasminogen Activator; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; D002402:Cathepsin D