Biomarkers reflecting real-time response to therapy and recurrence are lacking. We assessed the clinical value of detecting cell-free circulating tumor DNA (ctDNA) mutations in endometrial cancer (EC) and ovarian cancer (OC) patients.OBJECTIVEBiomarkers reflecting real-time response to therapy and recurrence are lacking. We assessed the clinical value of detecting cell-free circulating tumor DNA (ctDNA) mutations in endometrial cancer (EC) and ovarian cancer (OC) patients.EC/OC patients undergoing primary surgery were consented for tissue banking and 2-year serial blood draws. Tumor tissue DNA and plasma ctDNA underwent next generation sequencing using a targeted gene panel to identify somatic mutations.METHODSEC/OC patients undergoing primary surgery were consented for tissue banking and 2-year serial blood draws. Tumor tissue DNA and plasma ctDNA underwent next generation sequencing using a targeted gene panel to identify somatic mutations.Of 44 patients (24 EC, 17 OC, 2 synchronous endometrial and ovarian carcinomas SEOC and 1 endocervical adenocarcinoma EA) at least one somatic mutation was identified in tumor tissue in 40 (91%, 20/24 EC, all OC/SEOC/EA), and in preoperative plasma ctDNA in 12 (27%) patients (6/24 25% EC and 6/17 35% OC). Detection of preoperative ctDNA mutations was associated with advanced stage, higher preoperative CA125, and disease recurrence. In 5/12 (42%) patients with preoperative ctDNA mutations, examination/imaging suggested clinical stage I however final pathology revealed stage II/III. In 11 patients where serial timepoints were assessed during treatment for ctDNA and CA125, ctDNA clearance preceded normalization of CA125. Thirteen patients developed recurrent disease (4 EC, 8 OC, 1 EA); 8 in whom ctDNA mutations were detected postoperatively, and 4 followed through time of recurrence with ctDNA mutations identified 2-5 months prior to clinical/radiologic/biomarker progression in 3.RESULTSOf 44 patients (24 EC, 17 OC, 2 synchronous endometrial and ovarian carcinomas SEOC and 1 endocervical adenocarcinoma EA) at least one somatic mutation was identified in tumor tissue in 40 (91%, 20/24 EC, all OC/SEOC/EA), and in preoperative plasma ctDNA in 12 (27%) patients (6/24 25% EC and 6/17 35% OC). Detection of preoperative ctDNA mutations was associated with advanced stage, higher preoperative CA125, and disease recurrence. In 5/12 (42%) patients with preoperative ctDNA mutations, examination/imaging suggested clinical stage I however final pathology revealed stage II/III. In 11 patients where serial timepoints were assessed during treatment for ctDNA and CA125, ctDNA clearance preceded normalization of CA125. Thirteen patients developed recurrent disease (4 EC, 8 OC, 1 EA); 8 in whom ctDNA mutations were detected postoperatively, and 4 followed through time of recurrence with ctDNA mutations identified 2-5 months prior to clinical/radiologic/biomarker progression in 3.ctDNA can reflect larger tumor volume/metastases, treatment response and recurrence in EC and OC. Careful patient selection is critical to direct resources to patients most likely to benefit, considering disease burden and risk group.CONCLUSIONctDNA can reflect larger tumor volume/metastases, treatment response and recurrence in EC and OC. Careful patient selection is critical to direct resources to patients most likely to benefit, considering disease burden and risk group.