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Background: Circulating tumor DNA (ctDNA) of patients with colorectal peritoneal metastases (PM) was obtained to identify prognostic factors associated for ctDNA detection and with overall survival (OS). Prior studies have identified a correlation between ctDNA detection and OS in colorectal liver metastases (CRLM) and after resection of primary tumors. However, detection rates for PM may be lower than other metastatic sites. Methods: Peripheral blood was drawn from 152 patients after diagnosis with PM with or without other synchronous sites of disease. Patients who underwent cytoreduction were excluded. Next-generation sequencing of a panel of 70 genes commonly mutated in colorectal cancer was performed on all samples. Mutations were identified and variant allele frequencies (VAFs) calculated. Clinical data including OS from time of CRCC diagnosis, tumor grade, tumor histology, synchronous non-peritoneal metastases and patient demographics were obtained from medical records .Chi-squared tests were performed to compare differences in ctDNA detection based on clinical factors, and Cox regression analyses were performed to identify associations with ctDNA characteristics and OS. Results: The overall detection rate of any mutation in ctDNA was 74.3% (110/145 patients). The most frequently detected mutations were TP53 (55%), APC (47%), KRAS (32%), and PIK3CA (14%). Sensitivity for detecting individual mutations ranged from 50%-63%. Mucinous and signet-ring cell histology were more common in patients with PM alone (Mucinous: 37% vs 24%, p=0.0003, Signet Ring Cell: 10% vs. 2.2%, p=0.0001) and associated with lower sensitivity (mucinous: 59%, signet-ring cell: 57% and adenocarcinoma 85%, p=0.002). Synchronous CRLM were associated with increased detection compared to PM alone (88% vs. 68%, p=0.011). After adjustment for differences in histology, synchronous CRLM (OR 3.32, 95CI: 1.52-8.02, p=0.016) was associated with higher detection rates. Grade was not associated with detection (moderately differentiated: 79%, poorly differentiated: 74%, p=0.81). Detection of any ctDNA was associated with a trend towards worse OS (HR 2.18, 95% CI: 0.98-4.95, p=0.06). KRAS (HR 2.02, 95% CI: 1.14-3.60, p=0.017) and PIK3CA (HR 2.26, 95% CI: 1.07-4.78, p=0.033) ctDNA detection was associated worse OS. Detection of multiple mutations (HR: 0.85, 95% CI 0.50-1.42, p=0.52) and maximum VAF (HR 0.99, 95% CI: 0.97- 1.01, p=0.17) were not associated with OS. Conclusion: ctDNA detection is lower in patients with PM alone compared to those with PM and CRLM. Mucinous tumors had lower rates of ctDNA detection after accounting for extra-PM metastases. Presence of ctDNA is associated with a trend towards worse OS, especially for patients with detectable mutations in KRAS or PIK3CA. Quantification of ctDNA by number of mutations or VAF was not associated with OS. Interpretation of ctDNA results for PM patients should take into consideration the lower sensitivity in the absence of other metastatic sites, but may have prognostic utility. Citation Format: Abhineet Uppal, Michael G. White, George J. Chang, Scott Kopetz, John Paul Y. C. Shen. Circulating tumor DNA in colorectal carcinomatosis: Detection and prognostic value [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B027.