The use of automated Ki67 analysis to predict Oncotype DX risk-of-recurrence categories in early-stage breast cancer

Abstract

Ki67 is a commonly used marker of cancer cell proliferation, and has significant prognostic value in breast cancer. In spite of its clinical importance, assessment of Ki67 remains a challenge, as current manual scoring methods have high inter- and intra-user variability. A major reason for this variability is selection bias, in that different observers will score different regions of the same tumor. Here, we developed an automated Ki67 scoring method that eliminates selection bias, by using whole-slide analysis to identify and score the tumor regions with the highest proliferative rates. The Ki67 indices calculated using this method were highly concordant with manual scoring by a pathologist (Pearson’s r = 0.909) and between users (Pearson’s r = 0.984). We assessed the clinical validity of this method by scoring Ki67 from 328 whole-slide sections of resected early-stage, hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. All patients had Oncotype DX testing performed (Genomic Health) and available Recurrence Scores. High Ki67 indices correlated significantly with several clinico-pathological correlates, including higher tumor grade (1 versus 3, P<0.001), higher mitotic score (1 versus 3, P<0.001), and lower Allred scores for estrogen and progesterone receptors (P = 0.002, 0.008). High Ki67 indices were also significantly correlated with higher Oncotype DX risk-of-recurrence group (low versus high, P<0.001). Ki67 index was the major contributor to a machine learning model which, when trained solely on clinico-pathological data and Ki67 scores, identified Oncotype DX high- and low-risk patients with 97% accuracy, 98% sensitivity and 80% specificity. Automated scoring of Ki67 can thus successfully address issues of consistency, reproducibility and accuracy, in a manner that integrates readily into the workflow of a pathology laboratory. Furthermore, automated Ki67 scores contribute significantly to models that predict risk of recurrence in breast cancer.

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

“…For example, presurgical Ki67 has been shown to be a marker for recurrence‐free survival and, in the neoadjuvant setting, a marker for endocrine‐resistant tumour that may require more aggressive treatment . Excellent intra ‐ observer reproducibility under controlled pre‐analytical and staining conditions has contributed to the body of evidence showing the potential of Ki67 immunohistochemistry assay to be implemented in hospital laboratories as a cost‐effective part of clinical management . However, poor interobserver reproducibility and variability due to technical aspects of the assay has limited its adoption in clinical practice …”

“…20 Excellent intra-observer reproducibility under controlled pre-analytical and staining conditions 21 has contributed to the body of evidence showing the potential of Ki67 immunohistochemistry assay to be implemented in hospital laboratories as a cost-effective part of clinical management. [22][23][24] However, poor interobserver reproducibility and variability due to technical aspects of the assay has limited its adoption in clinical practice. 4,9,[25][26][27][28] The International Ki67 Working Group (IKWG) has undertaken a systematic multiphase programme to determine whether Ki67 scoring can be standardised and analytically validated throughout laboratories.…”

Ki-67 Expression is a Significant Prognostic Factor Only When Progesterone Receptor Expression is Low in Estrogen Receptor-Positive and HER2-Negative Early Breast Cancer

“…Allison et al reported a strong correlation between high Oncotype DX Recurrence Scores with grade 3 and low-to-absent PR expression and Ki-67 > 10% [24]. In addition, akur et al demonstrated that high Ki-67 status was significantly correlated with the higher Oncotype DX risk-of-recurrence group (low versus high, p < 0.001) [25]. If a genomic analysis is not available, the patient of low PgR and high Ki-67 expression in active treatment can be considered in the ER-positive and HER2negative breast cancer.…”

Integration of Ki-67 index into AJCC 2018 staging provides additional prognostic information in breast tumours candidate for genomic profiling

“…Actually, Oncotype DX® is based, among others, on the expression of 5 genes related to proliferation (namely MKI67, STK15, Survivin, CCNB1 and MYBL2), and the association between both RS and single gene expression with the Ki67 IHC levels has previously been addressed. [20][21][22][23] Since use of Oncotype DX® in routine practice requires important financial resources and its cost-effectiveness has been questioned in the literature, 24,25 especially for low-risk BC patients, Ki67-PS can possibly provide additional information with an inferior burden on National Health System budget.…”