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.

Intratumoral heterogeneity of Ki67 expression in early breast cancers exceeds variability between individual tumours

“…However, while Ki67‐labelling captures all cells within the cell cycle that may or may not undergo division, mitoses are recognizable only when cells actually divide. Although a correlation of both markers has been shown, the duration of cell cycles may vary among tumours and decouple from effective cell division . Thus, the extent of heterogeneity in Ki67 expression demonstrated in our study may be comparable but not identical to intratumoral heterogeneity of mitotic activity due to differences in assessment method and biological context.…”

Predicting breast tumor proliferation from whole-slide images: The TUPAC16 challenge

“…The lack of standardized procedures, debates about clinical utility, issues with Ki67 assay interpretation, and the complex molecular workflow to obtain gene expression has impeded the translation of Ki67 and PAM50 proliferation score for clinical use (Penault-Llorca and Radosevic-Robin, 2017). Ki67 and PAM50 proliferation score are significantly associated with mitotic counts (Heng et al, 2017;Lee et al, 2014), but their agreement is not perfect. There are limited studies investigating the relationship between molecular and morphological data, specifically, none has explored the potential of predicting PAM50 proliferation scores from H&E WSIs.…”

Biological rationale for a patient-specific approach in the treatment of breast cancer. Clinical value of novel biomarkers of breast cancer

“…Белок экспрессируется клетками в митотической фазе. Фосфорилирование PHH3 серина-10 и -38 -процесс, задействованный в конденсации хроматина и прохождении по клеточному циклу во время митоза или мейоза [39]. Фосфорилирование происходит с поздней фазы G2 до ранней профазы, дефосфорилирование -медленно с поздней анафазы до ранней телофазы.…”

“…Таким образом, во время метафазы гистон H3 всегда фосфорилирован и положителен по PHH3, в то время как в интерфазу экспрессии PHH3 не наблюдается. За счет этого свойства PHH3 позволяет выделять только митотически активные клетки, что делает PHH3 маркером пролиферации [39].…”