Abstract
BACKGROUND: Next-generation sequencing (NGS) is a useful tool for detecting genomic alterations in circulating tumor DNA (ctDNA). To date, most ctDNA tests have been performed on patients with widely metastatic disease. Patients with peritoneal carcinomatosis (metastases) present unique prognostic and therapeutic challenges. We therefore explored preoperative ctDNA in patients with peritoneal metastases undergoing surgery. METHODS: Patients referred for surgical resection of peritoneal metastases underwent preoperative blood-derived ctDNA analysis (clinical-grade NGS [68-73 genes]). ctDNA was quantified as the percentage of altered circulating cell-free DNA (% cfDNA). RESULTS: Eighty patients had ctDNA testing: 46 (57.5%) women; median age 55.5 years. The following diagnoses were included: 59 patients (73.8%), appendix cancer; 11 (13.8%), colorectal; five (6.3%), peritoneal mesothelioma; two (2.5%), small bowel; one (1.3%) each of cholangiocarcinoma, ovarian, and testicular cancer. Thirty-one patients (38.8%) had detectable preoperative ctDNA alterations, most frequently in the following genes: TP53 (25.8% of all alterations detected) and KRAS (11.3%). Among 15 patients with tissue DNA NGS, 33.3% also had ctDNA alterations (overall concordance = 96.7%). Patients with high ctDNA quantities (≥ 0.25% cfDNA, n = 25) had a shorter progression-free survival (PFS) than those with lower ctDNA quantities (n = 55; 7.8 vs. 15.0 months; hazard ratio 3.23, 95% confidence interval 1.43-7.28, p = 0.005 univariate, p = 0.044 multivariate). CONCLUSIONS: A significant proportion of patients with peritoneal metastases referred for surgical intervention have detectable ctDNA alterations preoperatively. Patients with high levels of ctDNA have a worse prognosis independent of histologic grade.