Introduction: HGSOC is characterized by TP53 loss and genomic instability. Despite PARP inhibitor success, chemotherapy remains first-line for advanced BRCA mutant and HRD HGSOC. Its impact on tumor heterogeneity and response to targeted therapies remains unclear. We investigated how HGSOC evolves under treatment by examining single-cell genomic changes in PDX models and circulating tumor DNA (ctDNA) from the same HGSOC patients. We aimed to understand if the molecular changes seen in PDX’s could be assessed through ctDNA and whether ctDNA can be used for tracking clonal tumor dynamics over time.

Methods: 11 treatment naive HGSOC PDX were developed in immunodeficient mice. Two lines (one BRCA mutant) have been treated with platinum (cisplatin) or targeted PARP inhibitor (olaparib). Single-cell whole-genome sequencing (scWGS) conducted on PDX and original tumors identified copy number events, enabling cell clustering and clone identification. Hierarchical clustering was utilized to determine clonal structure pre and post-treatment, and a phylogenetic tree was computed.  Additionally plasma samples matched to PDX’s underwent WGS for ctDNA analysis.

Results: From scWGS data of PDX, we observed initial clonal heterogeneity leading to emergent clones in later passages. Evolving CN changes were found on chromosomes 19, 8, and 3, along with TP53 loss of heterozygosity on Chr17p. Despite normal ploidy, focal CN alterations are visible in all plasma samples. In patient 1, gains and amplifications appeared on chromosomes 3 and 8, with losses on 4, 15, and 16. Bulk tumor CN profiles of patient 1 and corresponding PDXs largely matched those derived from the same patient’s plasma.

Conclusion: Through genome sequencing at both single-cell tumor and plasma sample levels, we captured diversification between HGSOC tumors, particularly PDXs after drug exposures. ctDNA shows promise as an alternative to conventional tissue sampling measuring treatment associated with genomic changes.