Diagnostic and predictive utility of peritoneal tumor DNA in gastroesophageal cancer: A prospective multicenter study.

4101 Background: Gastric and gastroesophageal cancers (G/GEC) commonly spread to the peritoneum. Accurate peritoneal staging is critical for guiding intent and therapy, however staging PET, CT and peritoneal cytology have low sensitivity for peritoneal micro-metastases. Whilst circulating tumor DNA (ctDNA) poorly correlates with peritoneal disease, tumor DNA from the peritoneum (ptDNA) may identify early peritoneal metastases missed by conventional staging. We developed a tumor-informed whole-genome sequencing (WGS) platform to detect ptDNA and evaluated its accuracy in diagnosing peritoneal metastases and predicting survival in curative-intent G/GEC. Methods: This Australian multicenter prospective cohort study enrolled patients receiving curative-intent treatment for G/GEC (upfront surgery, perioperative FLOT or neoadjuvant CROSS/nivolumab). Tumor biopsies, blood, and peritoneal lavage fluid were collected at staging laparoscopy, and at surgery for those receiving neoadjuvant therapy. Tumor-informed WGS was used to identify ctDNA and ptDNA, which were correlated with disease free survival (DFS), peritoneal recurrence free survival (pRFS), non-peritoneal recurrence free survival (npRFS), and overall survival (OS) using multivariate Cox regression. The diagnostic utility of ptDNA for peritoneal metastases was evaluated by comparing true-negative patients ( > 2 years disease-free post-surgery alone) with an independently enrolled cohort of true-positive patients (macroscopic/cytology-positive peritoneal disease). Results: ptDNA was detected in 28 (30.4%) of 92 consecutive non-metastatic patients (59 with and 33 without neoadjuvant therapy). ptDNA-positivity significantly correlated with advanced cT and (y)pT stage. At a median follow-up of 17 months, there were 12 (13.0%) peritoneal and 10 (10.9%) non-peritoneal recurrences. ptDNA-positivity independently predicted poorer pRFS (HR 26.74, 95%CI 3.94-181.66), DFS (HR 4.51, 95%CI 1.77-11.47) and OS (HR 6.65, 95%CI 1.72-25.76), but not npRFS (HR 0.87, 95%CI 0.16-4.78). Importantly, 9 (60%) patients converted from ptDNA-positive to ptDNA-negative post-neoadjuvant treatment. Patients who remained ptDNA-positive had significantly worse pRFS (3/6 recurrences, HR 45.4, 95%CI 3.5-595.2) than those who were ptDNA-negative (0/25 recurrences). The diagnostic accuracy of ptDNA was validated in 10 true negative and 12 true positive patients. In this cohort, ptDNA achieved 100% sensitivity, specificity, positive and negative predictive values (95%CI 75.8-100%) for detecting peritoneal metastases. ctDNA data will be presented at the meeting. Conclusions: Tumor-informed WGS-based ptDNA accurately diagnoses peritoneal disease and predicts peritoneal recurrence post curative-intent treatment, informing its potential to personalize clinical management using intraperitoneal therapies.