The prognosis of
cancer is primarily dependent on its potential to invade and metastasize. Data from both preclinical and clinical studies strongly suggest that
serine proteases, as well as their inhibitors and receptor, play a central role in the processes leading to
metastasis. We therefore investigated the prognostic value of
plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2) and the combination of both inhibitors in 332 patients with operable
breast cancer.
PAI-1 and
PAI-2 content was measured in the primary
tumor cytosols using an
enzyme-linked
immunosorbent assay. For
PAI-1 the median value (3.9 ng/mg
protein) was used as cutoff, while the optimized cutoff for
PAI-2 (6.5 ng/mg
protein) was obtained using the log-rank statistic. After a median follow-up of 46 months 96 (29%) patients relapsed. In univariate analysis patients with a high
PAI-1 or a low
PAI-2 content had an increased risk of relapse. The difference was statistically significant for
PAI-1 (p<0.0001) and almost statistically significant for
PAI-2 (p=0.057). Stage,
tumor size, differentiation grade, lymph node status and
hormone receptor status also showed significant univariate impact on disease-free survival (DFS). In multivariate analysis (Cox model)
PAI-1 (p<0.0001, RR=2.78),
PAI-2 (p=0.0075, RR=2.17), UICC stage (p=0.0014, RR=2.2), differentiation grade (p=0.0097, RR=1.91) and nodal status (p<0.0001, RR=2.9) retained their significance. When both inhibitors were combined the worst prognosis was observed in patients with simultaneous high
PAI-1 and low
PAI-2 levels, whereas low
PAI-1 in combination with high
PAI-2 values indicated a very favorable prognosis. In conclusion, our study showed that both
PAI-1 and
PAI-2 had independent prognostic value in
breast cancer. Combination of both inhibitors further improved the differentiation of patients with respect to prognosis.