Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients.

We have performed a systematic review and meta-analysis of proliferation markers (Ki-67, mitotic index (MI), proliferating cell nuclear antigen (PCNA) and thymidine or bromodeoxyuridine labelling index (LI)) with respect to survival in early breast cancer. Eighty-five studies involving 32,825 patients were analysed. Ki-67 (43 studies, 15,790 patients), MI (20 studies, 7021 patients), and LI (11 studies, 7337 patients) were associated with significantly shorter overall and disease free survival, using results from univariate and multivariate analyses from the individual studies. PCNA (11 studies, 2677 patients) was associated with shorter overall survival by multivariate analysis only, because of lack of data. There was some evidence for publication bias, but all markers remained significant after allowing for this. Ki-67, MI, PCNA and LI are associated with worse survival outcomes in early breast cancer. However, whether these proliferation markers provide additional prognostic information to commonly used prognostic indices remains unclear.