Abstract
Peritoneal metastasis (PM) poses a significant clinical challenge, yet the patient characteristics and genomic drivers underlying PM remain poorly characterized. Leveraging the MSK-MetTropism cohort (n = 25,755), our pan-cancer analysis reveals PM occurs in 29% of metastatic patients with extreme incidence variation (1% in THPA to 92% in HGSOC), and digestive/gynecologic malignancies exhibit the highest PM propensity with significant sex disparities. PM confers worse survival in 11/39 subtypes. Genomic profiling of 5,942 PM patients identifies enriched mutations in ESR1, TCF7L2, and FBXW7, pathway-level of TGF-Beta mutation, and subtype-specific drivers, including RET mutations in gastric PM. Mutational signatures implicate ROS (SBS18), HR deficiency (SBS3), and SBS8 across ≥9 cancer types. These results establish foundational insights into PM biology, though future PM tissue profiling is warranted to overcome primary tumor bias in genomic data.