Malignant ascites as a marker of peritoneal carcinomatosis burden in patients with colorectal and gastroesophageal cancer.

Abstract

455 Background: Malignant ascites occurs frequently in patients with gastric cancer (GC) and colorectal cancer (CRC) with peritoneal metastasis (PM). The presence of PM and malignant ascites have been independently reported to confer resistance to systemic therapy and poorer prognosis. However, the occurrence of malignant ascites as a function of increasing peritoneal carcinomatosis burden has been less studied and reported. Methods: We reviewed prospective cohorts of gastric cancer and colorectal cancer patients with PM. The first cohort was a prospective group of GCPM patients receiving bi-directional systemic and peritoneal-directed therapies (catheter-based intraperitoneal chemotherapy and/or pressurized intraperitoneal aerosol chemotherapy respectively) at a tertiary oncology center in Singapore. Clinico-pathological data, including Peritoneal Cancer Index (PCI) and the presence or absence of ascites based on diagnostic laparoscopy, was collected. To orthogonally validate the hypothesis of malignant ascites as a function of peritoneal carcinomatosis burden in gastrointestinal malignancies, we studied the relationship between ascites, PM and survival in an independent cohort of metastatic CRC patients eligible for first-line systemic treatment enrolled in two randomized clinical trials in different Italian cancer centers. Results: In the first cohort of 82 patients with GCPM, the median PCI was 19 (inter-quartile range (IQR) 8 – 26) in the group with ascites and 3 (IQR 1 – 12) in the group without ascites (p=0.005), suggesting ascites occurs with higher PM burden. The median overall survival (OS) was poorer in patients with ascites (13.4 vs 16.4 months, HR 1.6, 95% CI 0.9 – 2.8, p=0.082). The median OS in patients with PCI of <7 was 17.3 months (95% 12.0 – 22.7) and 13.8 months (95% CI 11.0 – 16.6) in those with PCI score >7. In the validation cohort of 900 CRC patients, presence of malignant ascites and PM resulted in poorer survival compared to patients with PM and no malignant ascites (HR for OS PM with ascites vs PM without ascites 2.01 (95% CI 1.37 - 2.96), p<0.001). Interestingly, those with PM and ascites had a poorer survival to those with stage IV disease without peritoneal involvement, while those with PM without ascites did not have a statistically significant difference (PM with malignant ascites vs. no peritoneal disease, HR for OS 2.14, 95% CI 1.57 – 3.01, p=0.007; PM without ascites vs no peritoneal disease, HR for OS 1.10, 95% CI 0.91 – 1.34). Conclusions: Our study of patients with colorectal or gastric cancer and peritoneal metastases suggest the presence of malignant ascites as a function of increased peritoneal carcinomatosis burden among patients with metastatic gastrointestinal malignancies, with correspondingly poorer survival outcomes.

Spatially resolved niche and tumor microenvironmental alterations in gastric cancer peritoneal metastases

“…h. Dot plot of CIBERSORT/xCell cell type and pathway GSEA analysis between adjacent peritoneum from the intra-peritoneal and orthotopic humanized mouse model. ARID1A [ 39] MUC6 [ 28] PIK3CA [ 24] RNF43 [ 18] CDH1 [ 16] ERBB2 [ 16] MACF1 [ 16] KRAS [ 12] APC [ 11] BCOR [ 10] BNC2 [ 10] CTNNB1 [ 9] PIGR [ 9] RHOA [ 9] SMAD4 [ 9] PLB1 [ 8] PTEN [ 7] RASA1 [ 6] ABCA10 [ 5] PTPRC [ 4] SOHLH2 [ 4] CNGA4 [ 2] SMAD2 [ 2] EYA4 [ 1] FAM46D [ 1] TP53 [105] ARID1A [ 39] MUC6 [ 28] PIK3CA [ 24] RNF43 [ 18] CDH1 [ 16] ERBB2 [ 16] MACF1 [ 16] KRAS [ 12] APC [ 11] BCOR [ 10] BNC2 [ 10] CTNNB1 [ 9] PIGR [ 9] RHOA [ 9] SMAD4 [ 9] PLB1 [ 8] PTEN…”

“…Abbreviations: GC, gastric cancer; PM, peritoneal metastasis; PCI, peritoneal carcinomatosis index; ES enrichment score; myCAF, myofibroblastic-like cancer associated fibroblasts; NES, normalized enrichment score; ECM, extracellular matrix; GSEA, gene set enrichment analysis. ARID1A [ 39] MUC6 [ 28] PIK3CA [ 24] RNF43 [ 18] CDH1 [ 16] ERBB2 [ 16] MACF1 [ 16] KRAS [ 12] APC [ 11] BCOR [ 10] BNC2 [ 10] CTNNB1 [ 9] PIGR [ 9] RHOA [ 9] SMAD4 [ 9] PLB1 [ 8] PTEN [ 7] RASA1 [ 6] ABCA10 [ 5] PTPRC [ 4] SOHLH2 [ 4] CNGA4 [ 2] SMAD2 [ 2] EYA4 [ 1] FAM46D [ 1] TP53 [105] ARID1A [ 39] MUC6 [ 28] PIK3CA [ 24] RNF43 [ 18] CDH1 [ 16] ERBB2 [ 16] MACF1 [ 16] KRAS [ 12] APC [ 11] BCOR [ 10] BNC2 [ 10] CTNNB1 [ 9] PIGR [ 9] RHOA [ 9] SMAD4 [ 9] PLB1…”

“…The development of malignant ascites is also likely a late biological event in the evolution of PM, and studies restricted to this sample source may limit insight into early dissemination mechanisms. 12 Similarities and differences between gastric PTs and the peritoneal niche thus remain poorly understood.…”