Utility of circulating tumor DNA for detection and monitoring of endometrial cancer recurrence and progression

Despite the increasing incidence of endometrial cancer (EC) worldwide and the poor overall survival of patients who recur, no reliable biomarker exists for detecting and monitoring EC recurrence and progression during routine follow-up. Circulating tumor DNA (ctDNA), the tumor-derived fraction of cell-free DNA (cfDNA) holds promise as a sensitive method for monitoring cancer activity and stratifying patients that are likely to respond to chemotherapy. Here, we investigated the utility of ctDNA for detecting and monitoring EC recurrence and progression in 13 patients using a combination of highly-sensitive digital droplet PCR (ddPCR), targeted next-generation sequencing (tNGS) and personalized ctDNA assays. Using the OncomineTM Pan-cancer cfDNA tNGS panel, at least 1 somatic mutation at a variant allele frequency (VAF) >20% was detected in 69% (9/13) of patient tumors. The four patients with no detectable tumor mutations at >20% VAF were whole exome sequenced, with all four harbouring mutations in genes not analyzed by the OncomineTM Pan-cancer cfDNA panel. Analysis of matched and longitudinal plasma DNA revealed earlier detection of EC recurrence and progression compared to standard clinical imaging techniques and dynamic kinetics of ctDNA levels reflecting treatment response. We also detected, for the first time to our knowledge, acquired high microsatellite instability (MSI-H) in ctDNA from one patient whose primary tumor was MSI stable. Overall, our study suggests that ctDNA analysis, and in particular MSI analysis in ctDNA could become a useful biomarker for early detection and monitoring of EC recurrence and progression.