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Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
Cyclin-Dependent Kinase 4/6 Inhibitors Beyond Progression in Metastatic Breast Cancer: A Retrospective Real-World
Lorenzo Gerratana1, Andrew A Davis2, Marko Velimirovic3,4
1Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy.
Purpose:
As the continuation beyond progression (BP) of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is becoming increasingly attractive for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), the definition of resistance factors is crucial. The aim of the study was to investigate the impact of CDK 4/6i BP and to explore potential genomic stratification factors.
Materials And Methods:
We retrospectively analyzed a multi-institutional cohort of patients with HR-positive HER2-negative MBC characterized for circulating tumor DNA through next-generation sequencing before treatment start. Differences across subgroups were analyzed by chi-square test, and survival was tested by univariable and multivariable Cox regression. Further correction was applied by propensity score matching.
Results:
Among the 214 patients previously exposed to CDK4/6i, 172 were treated with non-CDK4/6i-based treatment (non-CDK) and 42 with CDK4/6i BP. Multivariable analysis showed a significant impact of CDK4/6i BP, TP53 single-nucleotide variants, liver involvement, and treatment line on both progression-free survival (PFS) and overall survival (OS). Propensity score matching confirmed the prognostic role of CDK4/6i BP both for PFS and OS. The favorable impact of CDK4/6i BP was consistent across all subgroups, and a differential benefit was suggested for ESR1-mutated patients. ESR1 and RB1 mutations were more represented in the CDK4/6i BP subgroup with respect to CDK4/6i upfront.
Conclusion:
The study highlighted a significant prognostic impact of the CDK4/6i BP strategy with a potential added benefit in patients with ESR1 mutations suggesting the need for an extensive biomarker characterization.
Insights
Continuing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) beyond progression improves outcomes for metastatic breast cancer patients. This strategy shows a significant prognostic impact, especially for patients with ESR1 mutations.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are a standard treatment for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC).
- Continuation of CDK4/6i beyond progression (BP) is an emerging strategy, necessitating the identification of resistance factors and predictive biomarkers.
- Understanding the impact of CDK4/6i BP is crucial for optimizing treatment sequencing and patient selection.
Purpose of the Study:
- To investigate the clinical impact of continuing CDK4/6i beyond progression in HR-positive, HER2-negative MBC.
- To explore potential genomic alterations that stratify patients for CDK4/6i BP efficacy.
- To identify factors influencing progression-free survival (PFS) and overall survival (OS) in patients treated with or without CDK4/6i BP.
Main Methods:
- Retrospective analysis of a multi-institutional cohort of HR-positive, HER2-negative MBC patients.
- Circulating tumor DNA (ctDNA) analysis using next-generation sequencing at baseline.
- Statistical analysis including chi-square tests, univariable/multivariable Cox regression, and propensity score matching.
Main Results:
- Among 214 patients, 42 received CDK4/6i BP and 172 received non-CDK4/6i treatment.
- CDK4/6i BP, TP53 variants, liver involvement, and treatment line significantly impacted PFS and OS.
- Propensity score matching confirmed the prognostic role of CDK4/6i BP. ESR1 and RB1 mutations were more frequent in the CDK4/6i BP group.
Conclusions:
- The CDK4/6i BP strategy demonstrates a significant positive prognostic impact in HR-positive, HER2-negative MBC.
- A potential differential benefit of CDK4/6i BP was observed in patients with ESR1 mutations.
- Extensive biomarker characterization, particularly for ESR1, is warranted to guide CDK4/6i BP treatment decisions.
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