Ratios of miRNAs in Peritoneal Exosomes are Useful Biomarkers to Predict Tumor Response to Intraperitoneal Chemotherapy in Patients with Peritoneal Metastases from Gastric Cancer.

BACKGROUND Repeat intraperitoneal (IP) chemotherapy has been successfully used for treatment of peritoneal metastases (PM) from gastric cancer (GC). Exosomes play important roles not only in tumor progression but also in chemoresistance via transfer of microRNAs (miRNAs). However, there is little evidence of an effect of miRNAs in peritoneal exosomes on chemosensitivity of peritoneal lesions. METHODS In 74 patients with advanced GC who underwent staging laparoscopy, exosomes were isolated from peritoneal fluid and expression levels of miR-21-5p, miR-223-3p, and miR-29b-3p determined using TaqMan Advanced miRNA assays. In 43 patients with PM treated with combination chemotherapy, S-1 plus Oxaliplatin together with IP Paclitaxel, the relationship between their relative expression levels and outcomes was examined. RESULTS The ratios of miR-21-5p/miR-29b-3p and miR-223-3p/miR-29b-3p were significantly upregulated in patients with PM, especially in patients with high serum CA125 levels. They showed a mild association with Peritoneal Cancer Index (PCI) score and ascites. More impressively, the ratios were significantly higher in 16 patients with progression of PM within 1 year compared with 27 patients with an excellent tumor response (miR-21-5p/miR-29b-3p: median 17.49, range 1.83-50.90 vs. median 4.64, range 0.40-38.96, p = 0.0015, miR-223-3p/miR-29b-3p: median 1.02, range 0.23-25.85 vs. median 0.21, range 0.01-50.07, p = 0.0006). Overall survival of patients with high miR-21/miR-29b or miR-223/miR-29b ratios was significantly worse than in patients with low ratios (p = 0.0117, p = 0.0021). CONCLUSIONS The ratios of miRNAs in peritoneal exosome correlate with survival of the patients with PM from GC and suggest the possibility that they modify the chemosensitivity against IP chemotherapy.