Prognostic significance of Ki‐67 and topoisomerase IIα expression in infiltrating ductal carcinoma of the breast

Abstract

To evaluate the prognostic relevance of Ki-67 and topoisomerase IIalpha expression in relation to tumor stage, grade, and hormone receptor content, 942 ductal infiltrating carcinomas of the breast were examined by means of the monoclonal antibodies Ki-S11 (Ki-67) and Ki-S4 (topoisomerase IIalpha). pS2, c-erbB2, and p53 were additionally considered as prognostic variables. The median follow-up time was 149 months. Eight-hundred-and-sixty-three tumors reacted with Ki-S11 and Ki-S4; the labeling indices of the two antigens were closely associated (r = 0.93). Both correlated positively with the tumor size, c-erbB2, and p53 expression, and negatively with patient age, hormone receptor content, and pS2 immunostaining. In the univariate analysis, Ki-S11 and Ki-S4 scores, nodal status, tumor size, tumor grade, and progesterone 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 regression analysis selected a Ki-S4 score >25% (p < 0.00001) next to the nodal status, 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, in that order. The Ki-S11 score was of independent prognostic significance only if examined as a continuous variable. We conclude that topoisomerase IIalpha 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 tumor cells.

DNA topoisomerase IIα expression and the response to primary chemotherapy in breast cancer

“…Contrary to previous results from our group (Rudolph et al, 1999a) and others (Jarvinen et al, 1996(Jarvinen et al, , 1998Rudolph et al, 1999b), we failed to observe a significant positive correlation between Topo IIa expression and Her-2/neu-overexpression in this series. Approximately 50% of the Her-2/neu overexpressing tumours in our series contained high levels of Topo IIa, whereas in the remaining 50%, Topo IIa was low (Table 1).…”

“…In line with the proliferation-specific expression of Topo IIa (Kellner et al, 1997(Kellner et al, , 2002, we observed a highly significant correlation between Ki-S7 and Ki-67, which was also reported by others (Depowski et al, 2000;Rudolph et al, 1999a;Tuccari et al, 1993), in addition to a strong link between the number of Topo IIa-expressing cells and the S-phase fraction of the cell cycle (Jarvinen et al, 1996;Sandri et al, 1996a). Given the known association between high tumour cell proliferation and chemosensitivity (Tannock, 1978;Belembaogo et al, 1992;O'Reilly et al, 1992), one might suspect the observed therapy response to be related to the proliferative activity of the tumours.…”

“…In the same study, Järvinen et al (2000) observed an increased sensitivity to doxorubicin in a breast cancer cell line (UACC-812) with TOP2a gene amplification and consequent protein overexpression and conversely, a decreased sensitivity to doxorubicin in a breast cancer cell line with TOP2a deletion and concomitantly reduced protein content (MDA-361). In a previous study on 863 primary operable invasive ductal carcinomas with long-term follow-up (Rudolph et al, 1999a), of which only a minor proportion had been treated with Topo IIa inhibitors, high Topo IIa expression consequently emerged as an important independent predictor of adverse outcome next to nodal metastasis and before other classical or immunohistochemical factors, including Ki-67. However, no such correlation between Topo IIa and survival was found in the present series.…”

Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients

“…Different antibodies were used through all trials: anti-Ki-67 was used in 24 studies (52.1%), anti-MIB-1 in 24 studies (52.1%), both antibodies were performed in five studies (Keshgegian and Cnaan, 1995;Veronese et al, 1995;Bevilacqua et al, 1996;Querzoli et al, 1996;Billgren et al, 2002), anti-Ki-S5 in two studies (Rudolph et al, 1999a;Esteva et al, 2004) and anti-Ki-S11 in one study (Rudolph et al, 1999b). The different cut-off values used were those of the authors (range: 3.5 -34%).…”

Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications

“…The proliferation fraction of the invasive component (i.e. not including ductal carcinoma in situ) of the tumour cells outside lymph vessels (PF-T), was scored using a method similar to that described by Potemski et al and by Rudolph et al [37,38]. First the tumour fields with highest reactivity for MIB-1 were selected and then the number of MIB-1 positive tumour nuclei was counted in 500 tumour cells and this gave the percent of the proliferating tumour cells (500 tumour cells were present in 2-3 high magnification fields, 9400 according to amount of tumoural stroma).…”