Prognostic value of tissue vascular endothelial growth factor (VEGF) in breast cancer compared with other common prognostic indicators

A Nicolini MD^a, D Campani MD^b, P Ferrari MD^a, M Menicagli PhD^b, L Anselmi MD^a, M Conte MD^c, C Spinelli MD^c

^aDepartment of Internal Medicine, ^bDepartment of Oncology, ^cDepartment of Surgery; University of Pisa, Pisa, Italy

AIM: In cancer patients prognostic value of tissue VEGF is still controversial. In breast cancer some reported that tissue VEGF expression positively correlates with axillary lymph-node involvement and poor prognosis and some others did not. In this study VEGF, estrogen (ER) and progesterone (PgR) receptors, c-erbB2, p53, MIB-1 and Cyclin D-1 were determined by immunohistochemistry (IHC) in the primary tumour tissue of 129 breast cancer patients besides tumour size (T) and axillary lymph-node (N) involvement. METHODS: All biological prognostic factors were semiquantitatively assessed. VEGF staining was scored by intensity (negative (Neg) or weak (W), moderate (M), strong (S)) and by the proportion of positive cells (% of staining). A final score < 3 or > 3 was attributed taking into account both intensity and the proportion of positive cells. Intensity was scored 0 (negative), 1 (weak), 2 (moderate), 3 (strong) and the proportion of positive cells was scored 0 (0%), 1 (1% to 25%), 2 (26% to 50%), 3 (> 50%). Cut off values of ER, PgR, MIB-1, Cyclin D-1, p53 and c-erbB2 were > 10%, > 10%, > 10%, > 10%, > 0% and > 0% respectively. Seventy-four of the 129 studied breast cancer patients developed distant metastases and the remaining 55 were disease-free 194 ± 37 months after mastectomy. RESULTS: No significant difference between these two populations occurred with regard to tumours with M and S or W and Neg VEGF IS, tumours with VEGF scored > 3 or < 3, T1-T2 or T3-T4 tumours. N+, ER–, PgR–, c-erbB2+, p53+, MIB-1+ and Cyclin-D1+ tumours were significantly less (p ranging from <0.01 to <0.0001, chi square test) in the 55 disease-free than in the 74 metastatic breast cancer patients. PgR and MIB-1 showed the highest negative and positive predictive value (69% and 93.5% respectively). When N– and N+ tumours were considered in combination with the studied biological prognostic factors, 7 categories of decreasing sensitivity and specificity were respectively obtained. N+ and/or M-S VEGF IS and N– and/or MIB-1– showed the highest sensitivity and specificity respectively. The number of patients with W or Neg VEGF IS was compared to the number of subjects with M or S VEGF IS in the 67 N+ and in the 62 N– metastatic or disease-free breast cancer patients. No significant difference was found in the subgroup of the 67 N+ patients, while a slightly significant difference (p < 0.05, chi square test) occurred in the subgroup of the 62 N– subjects. CONCLUSION: a) Tissue VEGF IS has no prognostic value unlike N, ER, PgR, c-erbB2, p53, MIB-1 and Cyclin D-1. b) In N– subgroup, tumours with W or Neg VEGF IS are significant less than tumours with M or S VEGF IS in metastatic compared to disease-free parients. c) N+ and/or M-S VEGF IS category has the highest sensitivity to define patients with distant metastases.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 798 (Growth factors & signalling).