The Evolution of Ki-67 and Breast Carcinoma: Past Observations, Present Directions, and Future Considerations

SIMPLE SUMMARY: Cellular proliferation is a central determinant of breast cancer recurrence risk and response to chemotherapy. The discovery of the Ki-67 antibody by Dr. Johannes Gerdes in 1983, with the observation that Ki-67 immunohistochemical expression was only present in proliferating cells, opened the door for considerations about using Ki-67 immunohistochemical expression for the evaluation of breast cancer recurrence risk, as well as for the evaluation of how well patients with breast cancer might respond to chemotherapy. Unfortunately, the lack of consistently reproducible Ki-67 results between pathologists has limited the use of Ki-67 for these prognostic and predictive evaluations in routine clinical practice. We review how the use of Ki-67 in breast cancer has evolved over the past 40 years, with a summary of the present literature on Ki-67 in breast cancer, and a discussion on the future of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice. ABSTRACT: The 1983 discovery of a mouse monoclonal antibody—the Ki-67 antibody—that recognized a nuclear antigen present only in proliferating cells represented a seminal discovery for the pathologic assessment of cellular proliferation in breast cancer and other solid tumors. Cellular proliferation is a central determinant of prognosis and response to cytotoxic chemotherapy in patients with breast cancer, and since the discovery of the Ki-67 antibody, Ki-67 has evolved as an important biomarker with both prognostic and predictive potential in breast cancer. Although there is universal recognition among the international guideline recommendations of the value of Ki-67 in breast cancer, recommendations for the actual use of Ki-67 assays in the prognostic and predictive evaluation of breast cancer remain mixed, primarily due to the lack of assay standardization and inconsistent inter-observer and inter-laboratory reproducibility. The treatment of high-risk ER-positive/human epidermal growth factor receptor-2 (HER2) negative breast cancer with the recently FDA-approved drug abemaciclib relies on a quantitative assessment of Ki-67 expression in the treatment decision algorithm. This further reinforces the urgent need for standardization of Ki-67 antibody selection and staining interpretation, which will hopefully lead to multidisciplinary consensus on the use of Ki-67 as a prognostic and predictive marker in breast cancer. The goals of this review are to highlight the historical evolution of Ki-67 in breast cancer, summarize the present literature on Ki-67 in breast cancer, and discuss the evolving literature on the use of Ki-67 as a companion diagnostic biomarker in breast cancer, with consideration for the necessary changes required across pathology practices to help increase the reliability and widespread adoption of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice.