Integrating ctDNA Dynamics and Sequential Organoid Drug Screening Enhances Breast Cancer Treatment Efficacy

Abstract Dynamic changes in ctDNA variant allele frequency reflect real-time therapeutic efficacy. Timely treatment modification guided by ctDNA variant allele frequency may enable precision selection of optimized regimens to counteract evolving resistance in breast cancer. In this study, we developed a therapeutic approach integrating ctDNA dynamics with sequential organoid drug screening to optimize breast cancer treatment. Targeted deep sequencing on plasma samples from 71 patients with breast cancer revealed that ctDNA clearance correlates with improved disease-free survival. Additionally, analysis of 40 breast cancer organoid models demonstrated the potential of organoid culture supernatants for comprehensive mutation profiling and drug sensitivity testing. Together, these findings suggest that combining ctDNA monitoring with organoid-based drug screening can guide adjustments to treatment strategies, offering a promising solution to optimize patient outcomes. Significance: Monitoring circulating tumor DNA in combination with drug screening of organoids enables dynamic, personalized breast cancer therapy adjustments to overcome resistance and improve treatment efficacy.