Genomic instability and proliferative activity as risk factors for distant metastases in breast cancer

Abstract

The role of genomic instability and proliferative activity for development of distant metastases in breast cancer was analysed, and the relative contribution of these two risk factors was quantified. A detailed quantitative comparison was performed between Ki67 and cyclin A as proliferative markers. The frequency of Ki67 and cyclin A-positive cells was scored in the same microscopic areas in 428 breast tumours. The frequency of Ki67-positive cells was found to be highly correlated with the frequency of cyclin A-positive cells, and both proliferation markers were equally good to predict risk of distant metastases. The relative contribution of degree of aneuploidy and proliferative activity as risk markers for developing distant metastases was studied independently. Although increased proliferative activity in general was associated with an increased risk of developing distant metastases, ploidy level was found to be an independent and even stronger marker when considering the group of small (T1) node negative tumours. By combining proliferative activity and ploidy level, a large group of low risk breast tumours (39%) could be identified in which only a few percentage of the tumours (5%) developed distant metastases during the 9-year follow-up time period.

Figure 1

Ki67 (A and B) and cyclin A (C and D) immunostaining of the very same tumor areas of a slowly proliferating D-tumour (A and C) and a rapidly proliferating A-tumour (B and D).

Figure 2

Quantitative relationship between Ki67- and cyclin A-positive cells counted in the same 5–14 randomly selected microscopic fields in four different tumours exhibiting low, intermediate and high proliferative activity (A), in a total of 428 tumours analysed in the same way (B) as well as in D-tumours (C) and A-tumours (D) performed on 375 of the 428 tumours.

Figure 3

Relative risk of developing distant metastases independently of node status and tumour size when Ki67 (A) or cyclin A (B) was used as proliferative marker.

Figure 4

Relative risk of developing distant metastases in N0 (A, C and E) and N+ patients (B, D and F) when Ki67 (A and B), cyclin A (C and D) or ploidy type (E and F) was used as marker in T1 and T2 tumours.

Figure 5

Relative risk of developing distant metastases in patients with T1N0 T2N0, T1N+ and T2N+ tumours of D- and A-tumour type showing low and high proliferative activity using 15% Ki67 positive cells as cut off value (A). By combining ploidy type, proliferative activity, node status and tumour size two breast cancer risk groups could be identified with respect to developing distant metastasis (B).