The characteristics and clinical significance of atypical mitosis in breast cancer

Abstract

Atypical mitosis is considered a feature of malignancy, however, its significance in breast cancer (BC) remains elusive. Here, we aimed to assess the clinical value of atypical mitoses in BC and to explore their underlying molecular features. Atypical and typical mitotic figures were quantified and correlated with clinicopathological variables in a large cohort of primary BC tissue sections (n = 846) using digitalized hematoxylin and eosin whole-slide images (WSIs). In addition, atypical mitoses were assessed in The Cancer Genome Atlas (TCGA) BC dataset (n = 1032) and were linked to the genetic alterations and pathways. In this study, the median of typical mitoses was 17 per 3 mm2 (range 0–120 mitoses), while the median of atypical mitoses was 4 (range 0–103 mitoses). High atypical mitoses were significantly associated with parameters characteristic of aggressive tumor behavior. The total number of mitoses, and a high atypical-to-typical mitoses ratio (>0.27) were associated with poor BC specific survival (BCSS), (p = 0.04 and 0.01, respectively). The atypical-to-typical mitoses ratio dichotomized triple negative-BC (TNBC) patients into two distinct groups in terms of the association with the outcome, while the overall number of mitoses was not. Moreover, TNBC patients with high atypical-to-typical mitoses ratio treated with adjuvant chemotherapy were associated with shorter survival (p = 0.003). Transcriptomic analysis of the TCGA-BRCA cohort dichotomized based on atypical mitoses identified 2494 differentially expressed genes. These included genes linked to pathways involved in chromosomal localization and segregation, centrosome assembly, spindle and microtubule formation, regulation of cell cycle and DNA repair. To conclude, the atypical-to-typical mitoses ratio has prognostic value independent of the overall mitotic count in BC patients and could predict the response to chemotherapy in TNBC.

Characteristics and prognostic significance of polo‐like kinase‐1 (PLK1) expression in breast cancer

“…In this study, a significant association was found between high PLK1 expression and high mitotic score, supporting a previous study findings 26 . This confirms the role of PLK1 in regulation of mitosis process and its function to ensure the correct execution by phosphorylating centromere protein A (CENPA) to promote its assembly during the metaphase‐anaphase transition in mitosis 5,49,50 …”

“…However, others found that knockdown of PLK1 inhibited ER expression and the PLK1 mRNA overexpression correlates with poor prognosis in luminal BC 24,25 . In a recent study, we found that PLK1 was significantly associated with atypical mitosis in BC 26 …”

“…PLK1 is a promising prognostic surrogate in BC, which is a key regulator of mitotic cell division 44 . Also, PLK1 was one of the associated genes with atypical mitosis in a previous study 26 . It has been proposed that overexpression of PLK1 is associated with poor prognosis in BC, hence PLK1 was considered an oncogene 45 .…”

“…BC is the leading cause of cancer‐related deaths in women worldwide and the therapeutic decision of BC patients currently depends on histopathological data and molecular biomarkers 26,39–41 . However, many patients show resistance to treatment due to the clinical heterogeneity of BC 42 .…”

Expression, assessment and significance of Ki67 expression in breast cancer: an update

“…Ki67 and mitotic index (MI) are indicators of tumour proliferation rate and both are significantly correlated 6. Analogous to Ki67, the advancing edge of the tumour, probably in the areas of highest mitotic counts, is likely to be representative of tumour clones that drive the biological potential of the tumour 26 69. Mitotic count, which can easily be assessed in a defined area on H&E-stained slides, represents the dividing cells, while Ki67 IHC represents the cells in the cell cycle.…”