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Minichromosome Maintenance Protein 2 Is a Strong Independent Prognostic Marker in Breast Cancer

Michael A. Gonzalez, Sarah E. Pinder, Grace Callagy, Sarah L. Vowler, Lesley S. Morris, Kate Bird, Jane A. Bell, Ronald A. Laskey, Nicholas Coleman

From the Medical Research Council Cancer Cell Unit, Hutchison/Medical Research Council Research Centre; Department of Histopathology, Addenbrooke’s Hospital; and Centre for Applied Medical Statistics, University of Cambridge, Cambridge; and Department of Histopathology, Nottingham City Hospital, Nottingham, United Kingdom.

Address reprint requests to Nicholas Coleman, MD, Medical Research Council Cancer Cell Unit, Hutchison/Medical Research Council Research Centre, Hills Rd, Cambridge CB2 2XZ, United Kingdom; e-mail: nc109{at}cam.ac.uk.

Purpose: To test the hypothesis that prognostic information in breast cancer may be derived from an accurate assessment of epithelial cell cycle entry, as indicated by expression of minichromosome maintenance (MCM) proteins.

Materials and Methods: We used immunohistochemistry to examine the distribution of Mcm-2 in breast tissue. Power calculations based on a pilot study of 67 whole tissue sections led to selection of an independent 347-core breast carcinoma tissue microarray validation set. We tested for associations between Mcm-2 (and Ki-67) labeling index (LI) and various clinicopathologic parameters.

Results: Mcm-2 was expressed more frequently than the standard proliferation marker Ki-67 in whole tissue sections of normal breast (P = .0003) and breast carcinoma (P < .0001). In 221 assessable cores of invasive carcinoma, the Mcm-2 LI showed a positive association with tumor size (P = .002), mitotic index (P < .0001), histologic grade (P < .0001), and the Nottingham Prognostic Index (NPI) score (P < .0001). Using a cutoff value of 50%, Mcm-2 LI was associated with overall survival (P = .0007), disease-free interval (P = .0002), and with the development of regional recurrence (P = .011) and distant metastases (P = .0016). Cox regression analysis suggested that the Mcm-2 LI is a strong prognostic factor in breast cancer that is independent and superior to histologic grade, lymph node stage, and Ki-67 LI, but not the NPI score.

Conclusion: Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.

Supported by the Medical Research Council and Cancer Research United Kingdom.

M.A.G. is a Medical Research Council Clinical Research Training Fellow.

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