Using prognostic signatures and machine learning to identify core features associated with response to CDK4/6
Agnieszka K Witkiewicz1,2, Jianxin Wang3, Emily Schultz3
1Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Street, Buffalo, NY, 14263, USA. agnieszka.witkiewicz@roswellpark.org.
Abstract:
CDK4/6 inhibitors in combination with endocrine therapy are widely used to treat HR+/HER2- metastatic breast cancer leading to improved progression-free survival (PFS) compared to single agent endocrine therapy. Over 300 patients receiving standard-of-care CDK4/6 inhibitor combination therapy for metastatic disease were enrolled at a single institution. Clinical, pathological, and gene expression data were employed to define determinants for PFS duration. Visceral disease (HR 1.55, p = 0.0013), prior endocrine therapy (HR 2.34, p < 0.001), and the type of endocrine therapy (HR 2.16, p < 0.001) were highly associated with PFS duration. Multiple pre-defined gene expression signatures were employed to determine association with response to CDK4/6 inhibitor-based therapy. Random survival forest was applied to define key gene expression and clinical features associated with PFS and develop a predictive model. The time to progression predicted by this model was related to the median PFS observed in PALOMA-2/3 and PEARL studies. Interrogating genes identified as highly significant across all studies indicated common enrichment of gene networks associated with cell cycle and estrogen receptor signaling. These findings indicate that there are common features from real-world use of CDK4/6 inhibitors that could be used to infer time to progression and better inform treatment.
Insights
Standard-of-care CDK4/6 inhibitors plus endocrine therapy improve progression-free survival (PFS) in metastatic breast cancer. Real-world data identified clinical and gene expression factors predicting PFS, aiding treatment decisions.
Area of Science:
- Oncology
- Genomics
- Clinical Research
Background:
- CDK4/6 inhibitors combined with endocrine therapy are standard for HR+/HER2- metastatic breast cancer.
- This combination improves progression-free survival (PFS) over endocrine therapy alone.
Purpose of the Study:
- To identify clinical and gene expression determinants of PFS in patients receiving CDK4/6 inhibitor combination therapy.
- To develop a predictive model for time to progression using real-world data.
Main Methods:
- Analysis of clinical, pathological, and gene expression data from over 300 patients.
- Utilized random survival forest to identify key predictive features and build a model.
- Examined gene expression signatures associated with treatment response.
Main Results:
- Visceral disease, prior endocrine therapy, and endocrine therapy type were significantly associated with PFS.
- A predictive model for time to progression showed correlation with established clinical trial data.
- Key gene networks involved in cell cycle and estrogen receptor signaling were identified.
Conclusions:
- Real-world data reveals clinical and genomic factors influencing PFS with CDK4/6 inhibitor therapy.
- These findings can inform the development of predictive models to better estimate time to progression.
- Understanding these determinants may optimize treatment strategies for metastatic breast cancer.
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