Possible Roles of Ki67 and other Biomarkers for Treatment Decision Making in Breast Cancer

Abstract

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have revolutionized the treatment landscape for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). However, response rates and overall survival vary significantly among patients. This abstract summarizes the impact of Ki-67 proliferation index and progesterone receptor (PR) status as predictive biomarkers for clinical benefit from CDK4/6 inhibitor therapy in MBC. Ki-67, a marker of cellular proliferation, reflects tumor growth rate and is inversely correlated with PR expression in HR+ breast cancer. Higher Ki-67 levels generally indicate a more aggressive tumor phenotype and poorer prognosis. Preclinical and clinical data suggest that patients with high Ki-67 expression may derive less benefit from CDK4/6 inhibitors. This is potentially due to the dependence of CDK4/6 inhibition on effectively suppressing cell cycle progression, which is less impactful in tumors with intrinsically high proliferative rates. Studies analyzing the impact of Ki-67 on progression-free survival (PFS) and overall survival (OS) in MBC patients receiving CDK4/6 inhibitors show variable results, with some demonstrating a significant association between high Ki-67 and reduced benefit, while others report less conclusive findings. The heterogeneity of study populations, including varying CDK4/6 inhibitor regimens and inclusion criteria, likely contributes to this inconsistency. PR status, a key component of HR status, also influences the response to CDK4/6 inhibitors. While CDK4/6 inhibitors primarily target the estrogen receptor (ER) pathway, PR expression is often correlated with ER status and may modulate the sensitivity to endocrine therapy, impacting the effectiveness of combined CDK4/6 inhibitor and endocrine therapy regimens. Patients with PR-negative tumors may exhibit different responses compared to their PR-positive counterparts, potentially owing to divergent downstream signaling pathways involved in cell cycle regulation and tumor growth. Evidence suggests a potential interaction between Ki-67 and PR status, with the impact of Ki-67 on treatment response potentially being more pronounced in PR-positive patients. Further research is crucial to clarify the interplay between Ki-67 and PR status in predicting the efficacy of CDK4/6 inhibitors. Standardized methodologies for Ki-67 assessment and larger, well-designed clinical trials are needed to definitively establish the clinical utility of these biomarkers in guiding treatment decisions and personalizing therapy for MBC patients. Ultimately, incorporating these biomarkers into clinical practice could optimize the selection of patients who are most likely to benefit from CDK4/6 inhibitors, improving treatment outcomes and reducing unnecessary exposure to potential toxicities.