A prediction model for breast cancer recurrence after adjuvant hormone therapy.

Hormone therapy with tamoxifen has long been the established adjuvant treatment for node-positive, estrogen-receptor-positive breast cancer in postmenopausal women. Since 30-40% of these patients fail to respond, reliableoutcome prediction is necessary for successful treatment allocation. Using pathobiological variables (available in mostclinical records: tumor size, nodal involvement, estrogen and progesterone receptor content) from 596 patients recruitedat a comprehensive cancer center, we developed a prediction model which we validated in an independent cohort of 175patients recruited at a general hospital. Calculated at 3 and 4 years of follow-up, the discrimination indices were 0.716[confidence limits (CL) 0.641, 0.752] and 0.714 (CL 0.650, 0.750) for the training data, and 0.726 (CL 0.591, 0.769) and0.677 (CL 0.580, 0.745) for the testing data. Waiting for more effective approaches from genomic and proteomic studies, amodel based on consolidated pathobiological variables routinely assessed at relatively low costs may be considered as thereference for assessing the gain of new markers over traditional ones, thus substantially improving the conventional use ofprognostic criteria.

Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant 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 being 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 node-positive breast cancer (NPBC) treated with either adjuvant chemotherapy (CMF [cyclophosphamide, methotrexate, 5-fluorouracil] schedule) or hormone therapy (tamoxifen). PATIENTS AND METHODS: We studied two groups of 137 and 164 patients with NPBC, median follow-up of 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 using the Spearman correlation coefficient (for continuous variables) or the Kolmogorov-Smirnov test (for dichotomous variables). Results of the clinical outcome were analyzed by both univariate and multivariate (for RFS only) Cox regression models in which VEGF and TP were treated as continuous variables. 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, 138.2 U/mg), respectively. There was no significant association between the two angiogenic peptides. VEGF was not associated with any other variable, whereas TP showed a positive association with age and an inverse association with the number of involved nodes. In the tamoxifen group, the concentrations 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 both RFS and OS. Likewise, the number of involved axillary nodes was significantly associated with both RFS and OS. Univariate analysis in the tamoxifen 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, and progesterone receptor concentration. In the multivariate analysis on RFS in the CMF group, VEGF, TP, their first-order interaction term, and age were significant and independent predictive factors. In the tamoxifen group, only VEGF and the number of involved nodes were significant and independent predictive factors. DISCUSSION: The results of our study suggest that high levels of TP and low levels of VEGF characterize the patients with NPBC treated with adjuvant CMF who have the highest likelihood of favorable outcome. Low levels of VEGF and the presence of less than three involved axillary nodes characterize the patients with NPBC treated with adjuvant tamoxifen who have the highest likelihood of favorable outcome. This information may be useful to plan future studies to better select the patients with NPBC for conventional adjuvant treatments as well as to monitor the efficacy of novel therapeutic strategies of adjuvant therapy based on inhibition of angiogenesis.

PS2 in breast cancer--alternative or complementary tool to steroid receptor status? Evaluation of 446 cases.

The oestrogen induced pS2 protein was measured in the cytosol of 446 breast cancer samples by an immunoradiometric assay. The relationships between pS2 and several clinical and biological parameters were evaluated. pS2 was not correlated to age, pT and nodal status, while it was higher in pre- than in peri- and post-menopausal women. A statistically significant positive association was found between pS2 and ER, PgR and cathepsin D. However, the frequency of pS2 negative values in ER+ (25.6%), PgR+ (21.7%) and cathepsin D-(19.0%) cases suggests that pS2 provides information independent of the above parameters in a fairly high percentage of patients. The prognostic role of pS2 was evaluated in 267 cases (follow up time 24-102 months). pS2+ showed longer RFS (P = 0.016) and OS (P = 0.004) than pS2-. pS2+ cases were significantly associated with a better prognosis in N+ but not in N- cases. Multivariate analysis showed that pS2 is an independent prognostic factor being the second most effective indicator for OS after nodal status and the third for RFS after nodal status and cathepsin D. From the present findings, we conclude that pS2 probably provides additional biological information to steroid receptor status and cathepsin D in patients with primary breast cancer.