Prognostic significance of Ki-67 and topoisomerase II alpha expression in infiltrating ductal carcinoma of the breast - A multivariate analysis of 863 cases

To evaluate the prognostic relevance of Ki-67 and topoisomerase II alpha ex pression in relation to tumor stage, grade, and hormone receptor content, 9 42 ductal infiltrating carcinomas of the breast were examined by means of t he monoclonal antibodies Ki-S11 (Ki-67) and Ki-S4 (topoisomerase II alpha). pS2, c-erbB2, and p53 were additionally considered as prognostic variables . The median follow-up time was 149 months. Eight-hundred-and-sixty-three t umors reacted with Ki-S11 and Ki-S4; the labeling indices of the two antige ns were closely associated (r=0.93). Both correlated positively with the tu mor size, c-erbB2, and p53 expression, and negatively with patient age, hor mone receptor content, and pS2 immunostaining. In the univariate analysis, Ki-S11 and Ki-S4 scores, nodal status, tumor size, tumor grade, and progest erone receptor content strongly predicted both overall and metastasis-free survival (p < 0.00001). Estrogen receptor status, p53, and c-erbB2 were of minor significance. Concerning overall survival, multivariate Cox regressio n analysis selected a Ki-S4 score > 25% (p < 0.00001) next to the nodal sta tus, and before tumor size, progesterone receptor content, and patient age. Independent predictors of the occurrence of distant metastases were nodal status, Ki-S4, tumor size, grade 1, and progesterone receptor negativity, i n that order. The Ki-S11 score was of independent prognostic significance o nly if examined as a continuous variable. We conclude that topoisomerase II alpha expression as assessed by monoclonal antibody Ki-S4 may add valuable information to current prognostic models for breast cancer. Its predictive value appears to be essentially related to the proliferative activity of t umor cells.