Association Between Ki-67 Proliferative Index and Oncotype-Dx Recurrence Score in Hormone Receptor-Positive, HER2-Negative Early Breast Cancers. A Systematic Review of the Literature

Abstract

Background: Oncotype-Dx (ODx) is a 21-gene assay used as a prognostic and predictive tool for hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative, node-negative, or 1 to 3 lymph node-positive early breast cancers (EBCs). The cost of the test, which is not available in low-middle income countries (LMICs), is not within the means of most individuals. The Ki-67 index is a marker of tumor proliferation that is cost-effective and easily performed and has been substituted in many cases to obtain prognostic information.

Objective: We aimed to identify the correlation between the ODx recurrence score (RS) and the Ki-67 index in HR-positive EBCs and to determine whether Ki-67, like the ODx, can help facilitate clinical decision-making.

Design: Systematic review correlating Ki-67 index and ODx in HR-positive and HER2-negative EBCs as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Data sources and methods: We searched different databases between January 2010 and May 2023 and included retrospective/prospective cohorts, clinical trials, case-control, and cross-sectional studies involving HR-positive and HER2-negative EBCs correlating the Ki-67 index and ODx RS categories.

Results: Of the 18 studies included, 16 indicated a positive or weakly positive correlation between ODx and the Ki-67 index. The combined P value of the included studies is <0.05 (P = .000), which shows a statistical significance between the 2. Our review also discusses the potential of machine learning and artificial intelligence (AI) in Ki-67 assessment, offering a cost-effective and reproducible alternative.

Conclusion: Even although there are limitations, studies indicate a favorable association between ODx and the Ki-67 index in specific situations. This implies that Ki-67 can offer important predictive details, especially regarding the likelihood of relapse in HR-positive EBC. This is particularly significant in LMICs where financial constraints often hinder the availability of costly diagnostic tests.

Keywords: Ki-67 Antigen; breast cancer; clinical decision-making; genotype; immunohistochemistry.

Figure 1.

PRISMA flow diagram for studies correlating Oncotype-Dx Recurrence Score and Ki-67 Index. Figure 1. From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372: n71. doi:10.1136/bmj.n71.

Figure 2.

Genes whose mRNA expression profiles are assessed by the ODx assay. All these genes are overexpressed in BCs. However, overexpression of certain genes may also be expressed in stromal cells (fibroblasts, lymphocytes, macrophages) present within the tumor microenvironment. The ODx assay uses whole-tissue mRNA; hence, tumors with an inflammatory stroma may have higher expression profiles for certain genes, for example, Ki-67.

Figure 3.

The procedure for obtaining a sample and subsequent testing is described for both the Oncotype-Dx and Ki-67 index. FFPE—formalin-fixed paraffin-embedded. The IKWG has determined that the Ki-67 index be categorized as low at 5% or less and high for values 30% or more.