Identification of low-risk node-negative breast cancer patients by tumor biological factors PAI-1 and cathepsin L.
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.
Thomssen
C
C
Universitätsfrauenklinik Eppendorf, Hamburg, Germany.
Oppelt
P
P
Jänicke
F
F
Ulm
K
K
Harbeck
N
N
Höfler
H
H
Kuhn
W
W
Graeff
H
H
Schmitt
M
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011379:Prognosis; D011987:Receptors, Steroid / Q000378:metabolism; D012307:Risk Factors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D011987:Receptors, Steroid; D002403:Cathepsins; D010450:Endopeptidases; D014568:Urokinase-Type Plasminogen Activator; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L