Monitoring response to camizestrant next-generation oral SERD in ER+ advanced breast cancer patient-derived xenografts via circulating tumor DNA profiling

Background: While circulating tumor DNA (ctDNA) is widely used clinically for disease monitoring, its preclinical application has been limited by perceived constraints of small blood volumes in animal models. Patient-derived xenograft (PDX) models offer unique advantages for ctDNA analysis, as human tumor DNA can be distinguished from murine background DNA, enabling clearer assessment of treatment-induced changes compared to clinical samples where tumor and normal DNA separation is more complex. Methods: We developed a preclinical ctDNA monitoring platform using ER-positive advanced breast cancer PDX models, including both wild-type and ESR1-mutant tumors. Digital Droplet PCR (ddPCR) informs whether sufficient human ctDNA levels are present (human repeat elements) to perform next generation sequencing (NGS). This feature allows the ability to monitor ctDNA levels over time, in response to various therapies. Mice received camizestrant, a next-generation oral selective estrogen receptor degrader (SERD), as monotherapy and in combination with CDK4/6 inhibition. Human-specific LINE-1 DNA levels and variant allele frequency (VAF) of tumor-specific somatic mutations were quantified in mouse plasma samples and correlated with tumor volume measurements. Results: Treatment with camizestrant, either as monotherapy or in combination with CDK4/6 inhibition, resulted in significant reductions in tumor volume and growth rate in both wild-type and ESR1-mutant PDX models which correlated with marked decreases in human-specific LINE-1 in mouse plasma, as measured by ddPCR. Variant allele frequency in ctDNA decreased significantly, correlating with anti-tumor efficacy following treatment with camizestrant monotherapy or in combination with CDK4/6 inhibition. Conclusions: This study establishes a robust, minimally invasive preclinical platform for evaluating ctDNA-based biomarkers and treatment efficacy in oncology research. The approach enables investigation of ctDNA release biology and treatment response in preclinical models that are difficult to address using human samples alone. These findings demonstrate the translational potential of preclinical ctDNA monitoring to inform clinical biomarker strategies and optimize therapeutic development in ER+ breast cancer.