Ki-67 as a Prognostic Biomarker in Invasive Breast Cancer

Abstract

The advent of molecular medicine has transformed breast cancer management. Breast cancer is now recognised as a heterogenous disease with varied morphology, molecular features, tumour behaviour, and response to therapeutic strategies. These parameters are underpinned by a combination of genomic and immunohistochemical tumour factors, with estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor-2 (HER2) status, Ki-67 proliferation indices, and multigene panels all playing a contributive role in the substratification, prognostication and personalization of treatment modalities for each case. The expression of Ki-67 is strongly linked to tumour cell proliferation and growth and is routinely evaluated as a proliferation marker. This review will discuss the clinical utility, current pitfalls, and promising strategies to augment Ki-67 proliferation indices in future breast oncology.

Keywords: Ki-67; MIB-1; biomarker; breast cancer; personalised medicine.

Figure 1

List of all genes assessed through the polymerase chain reaction in the OncotypeDX© 21-gene Recurrence Score signature (Genomic Health inc., Redwood City, CA, USA); proliferation contributes the largest proportion of included genes to the score with Ki-67 a key component of Ki-67 expression to the Recurrence Score through a number of techniques, including traditional immunohistochemistry [127] and novel machine learning techniques [114].

Figure 2

Figure demonstrating Ki-67 staining in lymphoid tissue illustrating the challenge required for digital image analysis in relation to assigning where the threshold for detection lies as evidenced by the differences in staining between cells from intense (black arrow) to intermediate (white arrow) to faint (thin arrow) (40× Magnification).

Figure 3

This figure depicts the systematic stages required to augment therapeutic decision making in relation to neoadjuvant chemotherapy in conjunction with Ki-67 evaluation using radiogenomic tumour appraisal. These stages begin at (A) initial presentation and are conducted through to combined analysis of clinicopathological, radiomic, and genomic data in order to personalise oncological care: (B) represents diagnostic preoperative imaging which is (C) segmented before quantitative data are retrieved from the acquired preoperative imaging (D). Histopathological data obtained from core tissue biopsy remain the ‘gold standard’ method of diagnosing malignancy (E); however, (F) molecular profiling of tumour tissue through RNA sequencing may be included in genomic data. Radiogenomics looks to collate clinical, radiomic, and genomic parameters through association analysis in order to better inform treatment selection, predict responses to therapies, and substratify disease subtypes and their associated prognoses (G). This schema illustrates the value of radiogenomics as an adjunct to enhance predicting the response to neoadjuvant chemotherapy (H) in the setting of breast carcinoma, with a focus upon utilising Ki-67 expression to aid this process.