Tumor cell proliferation by mitotic count and Ki67 in prognostication and subclassification of hormone receptor-positive breast cancer

Abstract Purpose Mitotic count (MC) and Ki67 expression are well-known prognostic factors in breast cancer. Whereas MC is part of histologic grade but not always reported separately, Ki67 is hampered by lack of methodological standardization. Our aim was to assess how proliferation markers MC, Ki67, and PHH3 perform in prognostication based on different tissue categories (WS, whole sections; CNB, core needle biopsies; TMA, tissue microarrays), and how these markers can stratify hormone receptor positive/HER2 negative breast cancer. Methods We examined a prospective population-based breast cancer series including 534 women (50–69 years) diagnosed during 1996–2003, with a median follow-up time of 13 years. MC, Ki67, and mitotic count by PHH3 were assessed in paired samples of WS ( N = 534), CNB ( N = 154) and TMA ( N = 101). The level of MC in four additional and independent cohorts are presented for comparison (1598 cases). Results By univariate survival analysis, all proliferation markers showed significant prognostic impact. By multivariate models, MC and Ki67 demonstrated independent prognostic significance. In the luminal/HER2 negative subgroup, which is currently the primary target group for proliferation assessment, MC retained prognostic significance in multivariate analysis, whereas Ki67 and PHH3 did not. In whole sections, a mitotic count of 2.5 per mm 2 corresponded to Ki67 of 20% as cutoff value for separating luminal B from luminal A tumors (HER2 negative cases). Conclusion Manual proliferation markers should preferably be assessed on WS for prognostication. Our findings indicate that mitotic count might support or replace Ki67 as a marker for stratification of luminal breast cancer, being particularly useful as an accessible biomarker in settings with limited resources.