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Background: PREDICT (http://www.predict.nhs.uk) is a prognostication and treatment benefit tool for early breast cancer (EBC). The aim of this study was to incorporate the prognostic effect of KI67 status in a new version (v3), and compare performance with the Predict model that includes HER2 status (v2)., Methods: The validation study was based on 1,726 patients with EBC treated in Nottingham between 1989 and 1998. KI67 positivity for PREDICT is defined as >10% of tumour cells staining positive. ROC curves were constructed for Predict models with (v3) and without (v2) KI67 input. Comparison was made using the method of DeLong., Results: In 1274 ER+ patients the predicted number of events at 10 years increased from 196 for v2 to 204 for v3 compared to 221 observed. The area under the ROC curve (AUC) improved from 0.7611 to 0.7676 (p=0.005) in ER+ patients and from 0.7546 to 0.7595 (p=0.0008) in all 1726 patients (ER+ and ER-)., Conclusion: Addition of KI67 to PREDICT has led to a statistically significant improvement in the model performance for ER+ patients and will aid clinical decision making in these patients. Further studies should determine whether other markers including gene expression profiling provide additional prognostic information to that provided by PREDICT.

Background: Proliferation has emerged as a major prognostic factor in luminal breast cancer. The immunohistochemical (IHC) proliferation marker Ki67 has been most extensively investigated but has not gained widespread clinical acceptance., Methods: We have conducted a head-to-head comparison of a panel of proliferation markers, including Ki67. Our aim was to establish the marker of the greatest prognostic utility. Tumour samples from 3093 women with breast cancer were constructed as tissue microarrays. We used IHC to detect expression of mini-chromosome maintenance protein 2, Ki67, aurora kinase A (AURKA), polo-like kinase 1, geminin and phospho-histone H3. We used a Cox proportional-hazards model to investigate the association with 10-year breast cancer-specific survival (BCSS). Missing values were resolved using multiple imputation., Results: The prognostic significance of proliferation was limited to oestrogen receptor (ER)-positive breast cancer. Aurora kinase A emerged as the marker of the greatest prognostic significance in a multivariate model adjusted for the standard clinical and molecular covariates (hazard ratio 1.3; 95% confidence interval 1.1-1.5; P=0.005), outperforming all other markers including Ki67., Conclusion: Aurora kinase A outperforms other proliferation markers as an independent predictor of BCSS in ER-positive breast cancer. It has the potential for use in routine clinical practice., (© 2012 Cancer Research UK)

There is an urgent need to improve prognostic classifiers in breast cancer. Ki67 and B-cell lymphoma 2 protein (BCL2) are established prognostic markers which have traditionally been assessed separately, in a dichotomous manner. This study was conducted to test the hypothesis that combinatorial assessment of these markers would provide superior prognostic information and improve their clinical utility. Tissue microarrays were used to assess the expression of Ki67 and BCL2 in 2749 cases of invasive breast cancer. We devised a Ki67/BCL2 index representing the relative expression of each protein and assessed its association with breast cancer-specific survival (BCSS) using a Cox proportional-hazards model. Based on our findings, an independent cohort of 3992 cases was used to validate the prognostic significance of the Ki67/BCL2 index. All survival analyses were conducted on complete data as well as data where missing values were resolved using multiple imputation. This study complied with reporting recommendations for tumour marker prognostic studies (REMARK) criteria. The Ki67/BCL2 index showed a significant association with BCSS at 10 years in estrogen receptor (ER)-positive disease. In multivariate analysis, adjusting for major clinical and molecular markers, the Ki67/BCL2 index retained prognostic significance, robustly classifying cases into three risk groups [intermediate- versus low-risk hazard ratio (HR), 1.5; 95% confidence interval (95% CI), 1.0-2.0; p = 0.031; high- versus low-risk HR, 2.6; 95% CI, 1.3-5.0; p = 0.005]. This finding was validated in an independent cohort of 3992 tumours containing 2761 ER-positive tumours (intermediate- versus low-risk HR, 1.7; 95% CI, 1.3-2.1; p < 0.001; high- versus low-risk HR, 2.0; 95% CI, 1.4-2.9; p < 0.001). Ki67 and BCL2 can be effectively combined to produce an index which is an independent predictor of BCSS in ER-positive breast cancer, enhancing their potential prognostic utility., (Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)