A Ki67/BCL2 index based on immunohistochemistry is highly prognostic in ER-positive breast cancer

• Published in: The Journal of pathology Vol. 226; no. 1; pp. 97 - 107
• Main Authors: Ali, H Raza, Dawson, Sarah-Jane, Blows, Fiona M, Provenzano, Elena, Leung, Samuel, Nielsen, Torsten, Pharoah, Paul D, Caldas, Carlos
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2012; Wiley
• Subjects: Adult; Aged; BCL2; Biological and medical sciences; Biomarkers, Tumor - analysis; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; ER positive; Female; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Kaplan-Meier Estimate; Ki-67 Antigen - analysis; Ki67; Mammary gland diseases; Medical sciences; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins c-bcl-2 - analysis; Receptors, Estrogen - biosynthesis; Receptors, Estrogen - genetics; Tissue Array Analysis; TMA; Tumors; Young Adult; Immunohistochemistry; Breast disease; Prognosis; ER positive; Biological marker; TMA; Breast cancer; Index; Malignant tumor; Mammary gland diseases; Anatomic pathology; Tissue microarrays; C-Onc gene; Ki67 antigen; BCL2; Ki67; Protooncogene; Cancer
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2976

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.