Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with eitheradjuvant chemotherapy or hormone therapy

PURPOSE To determine the role of the two angiogenic peptides, vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) (the latter also bein g a target enzyme for cytotoxicity of 5-fluorouracil and methotrexate), and conventional prognostic factors in predicting relapse-free survival (RFS) and overall survival (OS) probabilities in two cohorts of patients with nod e-positive breast cancer (NPBC) treated with either adjuvant chemotherapy ( CMF [cyclophosphamide, methotrexate, 5-fluorouracil] schedule) or hormone t herapy (tamoxifen). PATIENTS AND METHODS We studied two groups of 137 and 164 patients with NPBC, median follow-up o f 72 months for both, treated with adjuvant chemotherapy or hormone therapy , respectively. The cytosolic levels of VEGF and TP were determined in the primary tumor by original immunometric methods. The association between VEGF and TP and of these angiogenic peptides with other prognostic indicators were tested by u sing the Spearman correlation coefficient (for continuous variables) or the Kolmogorov-Smirnov test (for dichotomous variables). Results of the clinic al outcome were analyzed by both univariate and multivariate (for RFS only) Cor regression models in which VEGF and TP were treated as continuous vari ables. RESULTS In the CMF group, the concentrations of VEGF and TP ranged from 5.8 to 7798 pg/mg of protein (median, 87.5 pg/mg) and from 1.2 to 904 U/mg (median, 13 8.2 U/mg), respectively. There was no significant association between the t wo angiogenic peptides. VEGF was not associated with any other variable, wh ereas TP showed a positive association with age and an inverse association with the number of involved nodes. In the tamoxifen group, the concentratio ns of VEGF (5.9-2482; median, 79.3 pg/mg protein) and TP (6.1-1542; median, 146.5 U/mg) were similar to those of the CMF group, and the two angiogenic peptides were not correlated. VEGF was positively associated with age and was inversely associated with estrogen receptor and progesterone receptor, whereas TP was not associated with any other variable. Univariate analysis in the CMF group showed that VEGF and TP were significantly predictive of b oth RFS and OS. Likewise, the number of involved axillary nodes was signifi cantly associated with both RFS and OS. Univariate analysis in the tamoxife n group showed that TP did not significantly influence either RFS or OS. On the contrary, VEGF levels were significantly predictive of both RFS and OS , as were the number of involved nodes, estrogen receptor concentrations, a nd progesterone receptor concentration. In the multivariate analysis on RFS in the CMF group, VEGF, TP, their first-order interaction term, and age we re significant and independent predictive factors. In the tamoxifen group, only VEGF and the number of involved, nodes were significant and independen t predictive factors. DISCUSSION The results of our study suggest that high levels of TP and low levels of V EGF characterize the patients with NPBC treated with adjuvant CMF who have the highest likelihood of favorable outcome. Low levels of VEGF and the pre sence of less than three involved axillary nodes characterize the patients with NPBC treated with adjuvant tamoxifen who have the highest likelihood o f favorable outcome. This information may be useful to plan future studies to better select the patients with NPBC for conventional adjuvant treatment s as well as to monitor the efficacy of novel therapeutic strategies of adj uvant therapy based on inhibition of angiogenesis.