Analysis of serum and urine miRNAs as biomarkers of cancer cachexia in pancreatic cancer.

773 Background: Cancer cachexia (CC), characterized by anorexia, weight loss and skeletal muscle wasting, is a common complication in patients (pts) with pancreatic cancer (PC). The association of CC with treatment-related toxicity and decreased quality of life has been reported. Although CC is believed to result from systemic inflammation and cancer-induced metabolic changes, the underlying mechanisms remain poorly understood. Early diagnosis of CC is particularly challenging, highlighting the need for reliable biomarkers. We analyzed microRNAs (miRNAs) in serum and urine as potential biomarkers for the early detection of CC in PC. Methods: Clinical information, along with serum and urine samples were collected from pts with PC treated at the National Cancer Center Hospital, Tokyo, from March 2022 to March 2024. CC diagnosis according to Fearon et al: (1) ≥5% weight loss in 6 months, (2) ≥2% weight loss in individuals with a BMI of <20 kg/m², or (3) ≥2% weight loss in pts with sarcopenia. In this study, pts were considered to have CC if they met the definition of CC at enrollment or within six months. Serum and urine extracellular vesicle (EV) miRNA profiles were sequenced by NGS and compared by means of counts per million (CPM). Differential expression of miRNAs between pts with and without CC was investigated by DEseq2. Results: Of the 84 enrolled cases, 73 had sufficient sample volume for NGS assay. After excluding 4 cases with low miRNA read counts and 10 cases with unknown CC status, 59 cases were analyzed. CC was present in 41 pts (69%). Patients’ background was as follows (CC/no CC); median age 70 [IQR:62–75]/ 67 [63–69], male 21/9 pts, cStage {I (7/0), II (1/0), III (18/5), IV (15/13)} pts, median BMI (21.7 [IQR:19.6–24.0]/21.8 [20.7–22.4]) kg/m2, respectively. There were 141 common miRNA species between serum and urine samples, 81 miRNAs unique to serum and 33 unique to urine. The correlation between the common miRNAs was moderate (R = 0.60). No significant differences in miRNA expression were observed between pts with and without CC in serum samples. In urine samples, miR-141-5p was significantly downregulated (log2FoldChange = -0.667, padj = 0.0463), while miR-146b-5p was significantly upregulated (log2FoldChange = 1.03, padj = 0.0463) in pts with CC compared to those without. Conclusions: The results of this study suggest that urine is a suitable biofluid for detecting CC in patients with PC, as differentially expressed miRNAs were not observed in serum. However, the mechanism underlying the superiority of urine over serum in detecting CC remains unclear and should be addressed in future studies.