Thrombospondin-l and-2 in node-negative breast cancer: Correlation with angiogenic factors, p53, cathepsin D, hormone receptors and prognosis

Objective: Thrombospondins (TSPs) are a multigene family of five secreted g lycoproteins involved in the regulation of cell proliferation, adhesion and migration. Two members of the TSP family, namely TSP-1 and TSP-2, are also naturally occurring inhibitors of angiogenesis. The aim of the present stu dy was to determine the prognostic significance of the determination of TSP -1 and -2 and their correlation with the angiogenic peptides vascular endot helial growth factor (VEGF) and thymidine phosphorylase (TP), as well as wi th other biological and clinicopathological features investigated. Methods: We evaluated a series of 168 women with node-negative breast cancer with a median follow-up period of 66 months, not treated with adjuvant therapy. T he cytosolic levels of TSP-1 and -2 were determined in the primary tumour b y a commercially available immunometric assay. Results: We found that 166 t ested tumours had measurable levels of TSP-1 and -2 protein (median value 5 .978, range 0.579-31.410 ng/mg of protein). On the basis of Spearman's rank correlation coefficient, a weak inverse association of TSP-1 and -2 with t umour size and cathepsin D was found. Moreover, principal component analysi s on ranks evidenced a poor association between TSP-1 and -2, VEGF and TP. The results of the clinical outcome were ana lysed by both univariate and m ultivarlate [for relapse-free survival (RFS) only]) Cox regression models. TSP-1 and -2 were not significant prognostic factors in univariate analysis for either RFS (p = 0.427) or overall survival (p = 0.069). To investigate the 'angiogenic balance hypothesis', bivariate analyses were performed to investigate the interactions of TSP-1 and -2 with VEGF, TP or p53, but none were included in the selected models. Finally, in multivariate analysis fo r RFS a baseline model, previously defined in a larger case series and incl usive of VEGF, TP and their interaction was adopted. It was highly signific ant (p = 0.002, Harrell c statistic value of 0.703); but when TSP-1 and -2 were added, their contribution was negligible (p = 0.731, Harrell c statist ic value of 0.705). Conclusions: The results of this study suggest that TSP -1 and -2 do not provide additional prognostic contribution to the joint ef fects of VEGF and TP. In the series of node-negative breast cancer patients investigated, determination of the angiogenic peptides VEGF and TP gave si gnificant prognostic information. On the contrary, TSP-1 and -2, potential naturally occurring negative regulators of angiogenesis, lacked of prognost ic value. Copyright (C) 2001 S. Karger AG, Basel.