Mechanisms of Resistance to CDK4/6 Inhibitors and Predictive Biomarkers of Response in HR+/HER2-Metastatic Breast Cancer—A Review of the Literature

Abstract

The latest and newest discoveries for advanced and metastatic hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer are the three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) in association with endocrine therapy (ET). However, even if this treatment revolutionized the world and continued to be the first-line treatment choice for these patients, it also has its limitations, caused by de novo or acquired drug resistance which leads to inevitable progression after some time. Thus, an understanding of the overview of the targeted therapy which represents the gold therapy for this subtype of cancer is essential. The full potential of CDK4/6i is yet to be known, with many trials ongoing to expand their utility to other breast cancer subtypes, such as early breast cancer, and even to other cancers. Our research establishes the important idea that resistance to combined therapy (CDK4/6i + ET) can be due to resistance to endocrine therapy, to treatment with CDK4/6i, or to both. Individuals’ responses to treatment are based mostly on genetic features and molecular markers, as well as the tumor’s hallmarks; therefore, a future perspective is represented by personalized treatment based on the development of new biomarkers, and strategies to overcome drug resistance to combinations of ET and CDK4/6 inhibitors. The aim of our study was to centralize the mechanisms of resistance, and we believe that our work will have utility for everyone in the medical field who wants to deepen their knowledge about ET + CDK4/6 inhibitors resistance.

Real-World Outcomes of CDK4/6 Inhibitors Treatment in Metastatic Breast Cancer in Romania

“…An updated search in PubMed of other daily practice analyses of inhibitor CDK4/6 treatment for metastatic breast cancer in Romania revealed just one case report, and no other published data are displayed in databases or registries [28]. Our real-world retrospective study is the first to show efficacy data on this research topic in Romania.…”

“…In line I of treatment, the PALOMA trials paired Palbociclib with Letrozole, the MONALEESA trials paired Ribociclib with Letrozole and the MONARCH trials paired Abemaciclib with Letrozole. In line II, these studies replaced Letrozole with Fulvestrant [28]. In our study, most patients were treated as per line I, adding as hormone therapy Letrozole (54.2%) + Anastrozole (11%); while line II treatment with Fulvestrant included 34.6% of patients.…”

Comparative overall survival of CDK4/6 inhibitors in combination with endocrine therapy in advanced breast cancer

“…It can be difficult to distinguish treatment-related from disease-related causes of death especially among patients with breast cancer who do not have disease which is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria 26 . However, with data suggesting that mechanisms of resistance to CDK4/6 inhibitors seem uniform between the different agents, the higher odds of non-cancer deaths with abemaciclib relative to placebo compared to other CDK4/6 inhibitors is an important observation 27 .…”

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer—A Systematic Review of Randomized Phase II and III Clinical Trials

“…However, approximately 10% of patients will have primary resistance to CDK4/6 inhibitors [ 22 ]. The possible mechanisms of resistance to CDK4/6 inhibitors and predictive biomarkers of response were assessed in a review of the literature performed from January 2013 to January 2023 [ 23 ]. For instance, patients with evidence of functional pRB loss at baseline or with increased cyclin E1/E2 expression are not likely to benefit from CDK4/6 inhibition [ 23 ].…”