Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer
Sasha C Main1,2, David W Cescon1,3, Scott V Bratman1,2,4
1Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C1, Ontario, Canada.
Abstract:
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors combined with endocrine therapy have transformed the treatment of estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. However, some patients do not respond to this treatment, and patients inevitably develop resistance, such that novel biomarkers are needed to predict primary resistance, monitor treatment response for acquired resistance, and personalize treatment strategies. Circumventing the spatial and temporal limitations of tissue biopsy, newly developed liquid biopsy approaches have the potential to uncover biomarkers that can predict CDK4/6 inhibitor efficacy and resistance in breast cancer patients through a simple blood test. Studies on circulating tumor DNA (ctDNA)-based liquid biopsy biomarkers of CDK4/6 inhibitor resistance have focused primarily on genomic alterations and have failed thus far to identify clear and clinically validated predictive biomarkers, but emerging epigenetic ctDNA methodologies hold promise for further discovery. The present review outlines recent advances and future directions in ctDNA-based biomarkers of CDK4/6 inhibitor treatment response.
Insights
Novel liquid biopsy biomarkers using circulating tumor DNA (ctDNA) show promise for predicting cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor efficacy and resistance in metastatic breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors plus endocrine therapy are standard for ER+/HER2- metastatic breast cancer.
- Treatment failure due to primary resistance and acquired resistance necessitates new biomarkers for personalized therapy.
- Tissue biopsies have limitations; liquid biopsies offer a minimally invasive alternative.
Purpose of the Study:
- To review advances in circulating tumor DNA (ctDNA)-based biomarkers for predicting CDK4/6 inhibitor response.
- To explore the potential of liquid biopsies to overcome limitations of traditional tissue biopsies.
- To highlight future directions in ctDNA biomarker discovery for CDK4/6 inhibitor therapy.
Main Methods:
- Review of recent studies on ctDNA-based biomarkers.
- Focus on genomic and emerging epigenetic ctDNA methodologies.
- Analysis of liquid biopsy approaches for breast cancer treatment monitoring.
Main Results:
- Genomic ctDNA alterations have not yet yielded clear predictive biomarkers for CDK4/6 inhibitor resistance.
- Epigenetic ctDNA methodologies show emerging promise for biomarker discovery.
- Liquid biopsies can potentially monitor treatment response and resistance.
Conclusions:
- ctDNA-based liquid biopsies are a promising avenue for identifying biomarkers of CDK4/6 inhibitor efficacy and resistance.
- Epigenetic ctDNA analysis represents a key area for future research in this field.
- Personalized treatment strategies for metastatic breast cancer can be advanced through these novel biomarkers.
