Multi-Omics Evaluation of Peritoneal Fluid in Gastroesophageal Cancer: Results From Interim Analysis

Background Gastroesophageal cancers commonly spread to the peritoneum. Peritoneal disease significantly alters patient prognosis and treatment-intent. Despite the pervasive use of peritoneal lavage cytology (PLC), it has a variable sensitivity of 10%—80% in detecting peritoneal micro-metastasis in gastroesophageal cancers. Peritoneal tumour DNA (ptDNA) is tumour-derived DNA detectable in peritoneal lavage fluid. ptDNA-positivity may indicate peritoneal micro-metastasis and may be more sensitive than PLC in staging the peritoneum. We aimed to develop and test multi-omic ptDNA detection platforms, validate their sensitivity and specificity against PLC, and evaluate their role in predicting survival outcomes. Methods A prospective observational trial is set up to recruit 200 eligible patients with gastroesophageal adenocarcinoma who have undergone curative-intent treatment. For this interim analysis, peritoneal lavage fluid was collected at staging laparoscopy from 41 patients with gastroesophageal cancer. Cytology and peritoneal metastases (where clinically detectable) were confirmed by histopathology. A tumour-informed ptDNA testing was performed via whole-genome sequencing of tumour tissue and buffy coat to identify somatic variants for each patient, followed by tracking up to 96 variants in each patient’s peritoneal fluid. DFS, and peritoneal-specific event-free survival (PSS) were recorded during follow-up. Results 9 out of 41 patients were cytology-positive or had macroscopic peritoneal disease, and all tested positive for ptDNA. The remaining 32 cytology-negative patients without macroscopic peritoneal disease underwent curative-intent treatment, of which 15 were ptDNA-positive and 17 were ptDNA-negative. The median follow-up was 16 (4–24) months. DFS was 60% in the ptDNA-positive group and 82.4% in the ptDNA-negative group (HR = 2.69, 95% CI 0.71–10.12, P = 0.14). PSS was 66.7% in the ptDNA-positive group and 100% in the ptDNA-negative group (HR = 9.7, 95% CI 1.66–56.82, P = 0.01). Conclusion Interim analysis of this study demonstrates that a tumor-informed ptDNA detection platform is feasible and highly sensitive in gastroesophageal cancer. Early survival outcomes suggest that ptDNA predicts peritoneal-specific survival and the use of ptDNA is potentially more sensitive and specific than PLC in detecting peritoneal micrometastasis.