Abstract 2581: Identification and establishment of a novel, circulating miRNA signature, for pre-operative diagnosis of occult distant metastasis in patients with pancreatic ductal adenocarcinoma

Abstract

Abstract Purpose: In spite of recent advances in radiographic imaging technologies, not all patients with resectable pancreatic ductal adenocarcinoma (PDAC) with occult distant metastasis (ODM; including peritoneal or liver metastasis) can be robustly diagnosed with such approaches. A more accurate pre-operative diagnosis for ODM is of clinical significance, as it could facilitate selection of patients that are most appropriate candidates for such complex surgeries. Currently there is lack of availability of biomarkers, which can help diagnose presence of ODM in PDAC patients. Herein, using a systematic and comprehensive biomarker discovery and validation approaches, we aimed to develop a blood-based miRNA signature for the diagnosis of ODM in PDAC patients. Methods: During a biomarker discovery step, we analyzed serum miRNA expression profiles in stage I-III vs. stage IV PDAC patients (GSE59856: n=100) to identify a circulating miRNA-signature for ODM. This miRNA signature was subsequently validated in sera from a clinical training cohort (n=129), which included 44 stage-IV and 85 stage I-III PDAC patients. Using a multivariate logistic regression model, this circulating miRNA signature was further refined, and its performance was evaluated in an independent patient cohort of PDAC patients who were clinically diagnosed stage I to III by radiographic imaging, for the detection of ODM pre-operatively. Results: The expression profiling of 2556 miRNAs during the biomarker step led to the identification of a panel of 10 differentially expressed miRNAs in stage-IV PDAC patients (miR-99b,1304-3p, 3609, 4728-5p, 4788, 6802-5p, 6820-3p, 6823-5p, 6858-5p, 6867-5p); and a combination signature of these 10-miRNAs yielded an impressive diagnostic accuracy for distinguishing stage-IV vs. stage I-III PADC patients (AUC=0.85, 95% Confidence interval (CI) 0.76 - 0.91). We next examined the expression of this 10-miRNA panel by qRT-PCR assays in a serum training cohort, which resulted in a reduced and optimized 4-miRNA signature, with a demonstrated robust diagnostic accuracy (AUC=0.84, 95% CI, 0.76 - 0.90) in distinguishing stage-IV PDAC patients. We subsequently validated the diagnostic performance of this 4-miRNA signature for the presence of ODM in an independent patient cohort (AUC=0.82, 95% CI, 0.72 - 0.90). Finally, using a multivariate logistic regression analysis for ODM, we developed a diagnostic risk-assessment model by combining the 4-miRNA signature, tumor location and tumor size, which exhibited an even superior diagnostic performance vis-à-vis individual factors (AUC= 0.94, 95% CI, 0.86 - 0.98). Conclusions: We for the first time have identified and established a novel, noninvasive, serum-based miRNA signature that can pre-operatively diagnose PDAC patients with high risk occult distant metastasis. Citation Format: Kensuke Yamamura, Susan Tsai, Jasjit K. Banwait, Fuminori Sonohara, Douglas B. Evans, Yasuhiro Kodera, Hideo Baba, Ajay Goel. Identification and establishment of a novel, circulating miRNA signature, for pre-operative diagnosis of occult distant metastasis in patients with pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2581.