1: Breast Cancer Res Treat. 1999 Mar;54(2):147-57. 

Invasion marker PAI-1 remains a strong prognostic factor after long-term
follow-up both for primary breast cancer and following first relapse.

Harbeck N, Thomssen C, Berger U, Ulm K, Kates RE, Hofler H, Janicke F, Graeff H,
Schmitt M.

Frauenklinik, Technische Universitat Munchen, Munich, Germany.
nadia.harbeck@lrz.tu-muenchen.de

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.

PMID: 10424405 [PubMed - indexed for MEDLINE]


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2: Anticancer Res. 1998 May-Jun;18(3C):2173-80. 

Identification of low-risk node-negative breast cancer patients by tumor
biological factors PAI-1 and cathepsin L.

Thomssen C, Oppelt P, Janicke F, Ulm K, Harbeck N, Hofler H, Kuhn W, Graeff H,
Schmitt M.

Universitatsfrauenklinik Eppendorf, Hamburg, Germany.

In node-negative breast cancer, 70% of patients are cured by surgery alone and
thus should be spared the necessity of systemic adjuvant treatment.
Histomorphological and tumor biological prognostic factors may be employed to
assess the patient's risk profile with regard to disease recurrence and death.
To evaluate the relationship between tumor biological factors and the metastatic
potential of primary breast cancer, proteolytic factors uPA, PAI-1, and
cathepsin L, which are associated with tumor invasion and metastasis, were
determined in breast cancer tissue extracts by ELISA and the values assessed by
uni- and multivariate analysis as well as CART (classification and regression
trees) in comparison with traditional prognostic factors. Cysteine protease
cathepsin L, serine protease uPA, and the protease inhibitor PAI-1 were
determined by ELISA in extracts of primary tumors of 103 node-negative breast
cancer patients and values assessed by univariate and multivariate analysis in
comparison with traditional prognostic factors (tumor size, steroid hormone
receptor status, grading, vessel invasion, menopausal status). Median follow-up
of patients still alive at time of follow-up was 56.5 months (range 34-88).
PAI-1, cathepsin L, tumor size, grading, and steroid hormone receptor status but
not uPA, vessel invasion, and menopausal status were of prognostic relevance for
disease-free survival (univariate analysis). Multivariate analysis of
disease-free survival (Cox proportional hazards model) disclosed PAI-1 (relative
risk of 8.6, p = 0.0001) to be the only strong and statistically independent
prognostic factor. By CART-analysis, however, the combination of PAI-1 (< or =
14 ng/mg protein) and cathepsin L (< or = 1,100 ng/mg protein) allowed the
identification of a subgroup comprising 68% of the node-negative breast cancer
patients having a very low risk of disease recurrence (2/70; incidence of 0.8%
per year) versus the high-risk group with PAI-1 (> 14 ng/mg protein) and
cathepsin L (> 1,100 ng/mg protein) showing an increased recurrence rate (14/33;
incidence of 8.6% per year). We conclude that by the combined determination of
PAI-1 and cathepsin L tumor levels low-risk node-negative breast cancer patients
may be identified. These patients most probably will not benefit from systemic
adjuvant therapy.

PMID: 9703780 [PubMed - indexed for MEDLINE]


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