title: Current breast cancer proliferative markers correlate variably based on decoupled duration of cell cycle phases.
abstract: Mitotic count, PhH3, and MIB-1 are used as measures of the proportion of proliferating malignant cells in surgical pathology. They highlight different stages of the cell cycle, but little is known about how this affects their counts. This study assesses the strength of their correlations and attempts to determine the relationship between them. Proliferation counts for forty-nine consecutive cases of invasive breast carcinomas were analyzed, with the same tumor area on each stain counted using digital image analysis. The integrated optical density (IOD) of nuclei was measured as an approximation of nuclear DNA content. PhH3 strongly correlated with mitotic count (r = 0.94). Weaker correlations were found between MIB-1 versus PhH3 (r = 0.79) and mitotic count (r = 0.83). Nuclear IOD showed stronger correlation with MIB-1 (r = 0.37) than to mitotic count (r = 0.23) and PhH3 (r = 0.34). With evidence from a literature review, it is suggested that the weaker correlations with MIB-1 are not explained by count imprecision or error, but relies on temporal decorrelation between cell cycle phases. Consequences on correlation between these proliferative markers are illustrated by mathematical models.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Calgary, AB, Canada.
authors.forename: Lik Hang
authors.initials: LH
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Calgary, AB, Canada.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, AB, Canada.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Bigras
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002452:Cell Count / Q000379:methods; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013223:Statistics as Topic
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; D019394:Ki-67 Antigen