title: Invasion marker PAI-1 remains a strong prognostic factor after long-term follow-up both for primary breast cancer and following first relapse.
abstract: In 1991, our group was the first to report the prognostic strength of plasminogen activator inhibitor type 1 (PAI-1) in primary breast cancer. The prognostic impact of invasion markers PAI-1 and urokinase-type plasminogen activator (uPA) on disease-free survival (DFS) and overall survival (OS) in breast cancer has since been independently confirmed. We now report on the prognostic impact of PAI-1 and uPA after long-term median follow-up of 77 months for our cohort (n = 316). Levels of uPA, PAI-1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. S-phase fraction (SPF) was measured flowcytometrically in paraffin sections. Using log-rank statistics, optimized cutoffs were found for PAI-1 (14 ng/mg), uPA (3 ng/mg), cathepsin D (41 pmol/mg), and SPF (6%). In all patients, various factors (PAI-1, uPA, nodal status, SPF, cathepsin D, grading, tumor size, hormone receptor status) showed significant univariate impact on DFS. In Cox analysis, only nodal status (p < 0.001, RR: 3.1) and PAI-1 (p < 0.001, RR: 2.7) remained significant. In node-negative patients (n = 147), PAI-1, uPA, and SPF had significant univariate impact on DFS, whereas in Cox analysis, only PAI-1 was significant. PAI-1 was also significant for DFS within subgroups defined by established factors. In CART analysis, uPA enhanced the prognostic value of PAT-1 and nodal status for determination of a very-low-risk subgroup. For OS, only lymph node status and PAI-1 were significant in multivariate analysis. PAI-1 levels in the primary tumor were also a significant prognostic marker for survival after first relapse in both univariate and multivariate analysis.
authors.affiliation: Frauenklinik, Technische Universität München, Munich, Germany. nadia.harbeck@lrz.tu-muenchen.de
authors.forename: N
authors.initials: N
authors.lastname: Harbeck
authors.forename: C
authors.initials: C
authors.lastname: Thomssen
authors.forename: U
authors.initials: U
authors.lastname: Berger
authors.forename: K
authors.initials: K
authors.lastname: Ulm
authors.forename: R E
authors.initials: RE
authors.lastname: Kates
authors.forename: H
authors.initials: H
authors.lastname: Höfler
authors.forename: F
authors.initials: F
authors.lastname: Jänicke
authors.forename: H
authors.initials: H
authors.lastname: Graeff
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery; D002402:Cathepsin D / Q000032:analysis; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis*; D011003:Ploidies; D011379:Prognosis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016196:S Phase; D016019:Survival Analysis; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014568:Urokinase-Type Plasminogen Activator; D002402:Cathepsin D