Measures of proliferation in breast cancer: practicality and utility

Abstract

The precision of any clinical test biochemically, mathematically, or genetically is less important than is its proven relevance and practical reliability relative to a clinical problem.’ Recent developments in breast cancer prognostication have established the importance of adding proliferation parameters to the measures of stage encompassed by tumour size and nodal status.Im5 It seems that of all the currently available measures of the complex regulators of cell cycle kinetics, MIBl immunostaining and mitotic counts provide the most practical and clinically useful information on cellular proliferation. The presentation by Conner et al6 follows a rule of the history of scientific medicine that recognizes that the rate of advances is limited by technical developments. This important study by the group from Nottingham further confirms a method of measuring proliferation that may be as good as other methods currently being validated clinically, i.e. flow cytometric analysis and mitosis counting. The MIB 1 antibody against the Ki67 antigen7 may be potentially better because it assumes the best features of these methods. Similar to quantitating mitoses, MIB 1 immunostaining allows the ‘proliferation signal’ to be assessed in the context of histopathology.‘.” As with flow cytometric analysis, a measure of cells progressing through the cell cycle is obtained, not just the short mitotic phase; and although clear-cut guidelines are in place for recognizing mitotic features,“’ distinguishing positive MIB1 immunostaining is likely to be easier for the majority of pathologists. In any case, there will have to be an acceptance of guidelines and rules that foster reproducibility and interobserver agreement.“-‘3 Because interpretation of MIB1 immnunostaining is done on microscope slides, important observations (such as the importance of preferential proliferation at the periphery) can be made. Proponents of mitotic figure counting have long since known this.” Conner et al6 have underscored this with their comparison of MIBl immunostainning centrally and peripherally in individual breast carcinomas. The centre of some tumours may be non-viable, ranging from an acellular scar to a cystic cavity. What has not been widely recognized or formally discussed is that some tumours, having a good prognosis, have low cellularity centrally. Undoubtedly in these cancers with regional variability in cellularity as well as proliferation, measurement of the proliferative rate at the edge of the tumour should be more important. Recognition that some growth features, such as a single cell pattern of infiltration, are associated with even distribution of proliferative activity also emphasizes the importance of tumour type and growth pattern. There has not been sufficient recognition of the importance of cellular density in some of these considerations.‘” All of this serves to accentuate the importance of recognizing the heterogeneity of breast cancer, and the difficulty of assigning reproducible measures of prognostic utility whether they apply to all breast cancers or to special subtypes. This continuing challenge to students of breast disease will encourage the acceptance of repeatedly validated measures of prognostication.