Early Detection of Pancreatic Cancer: Are We Ready for Prime Time?

See “An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: a multicenter cohort study,” by Nakamura K, Zhu Z, Roy S, et al, on page 1252. See “An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: a multicenter cohort study,” by Nakamura K, Zhu Z, Roy S, et al, on page 1252. The annual incidence of pancreatic cancer has been gradually increasing worldwide.1Gaddam S. Abboud Y. Oh J. et al.Incidence of Pancreatic cancer by age and sex in the US, 2000–2018.JAMA. 2021; 326: 2075-2077Crossref PubMed Scopus (29) Google Scholar,2Huang J. Lok V. Ngai C.H. et al.Worldwide burden of, risk factors for, and trends in pancreatic cancer.Gastroenterology. 2021; 160: 744-754Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Despite multidisciplinary research regarding the pathophysiology, genomics, epigenetics, and single-cell transcriptomics of pancreatic cancer,3Waddell N. Pajic M. Patch A.M. et al.Whole genomes redefine the mutational landscape of pancreatic cancer.Nature. 2015; 518: 495-501Crossref PubMed Scopus (1711) Google Scholar,4Peng J. Sun B.F. Chen C.Y. et al.Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma.Cell Res. 2019; 29: 725-738Crossref PubMed Scopus (365) Google Scholar which led to rapid advances in screening and diagnostic techniques, surgery, and comprehensive treatments, the 5-year survival rate is currently a mere 11%.5Siegel R.L. Miller K.D. Fuchs H.E. et al.Cancer statistics, 2022.CA Cancer J Clin. 2022; 72: 7-33Crossref PubMed Scopus (2937) Google Scholar Treatment modalities, such as surgery, are much more effective for early stage pancreatic cancer than later stages of disease. However, several obstacles still stand in the way of early detection and diagnosis. Pancreatic cancer typically presents with minimal symptoms until the disease is advanced. The retroperitoneal position of the pancreas makes detection challenging by conventional ultrasound examination. Endoscopic ultrasound examination, although more precise and effective, lacks convenience and applicability. Computed tomography scans and magnetic resonance imaging are inefficient for population-based screening and unable to detect small lesions under the detection threshold.6Del Chiaro M. Verbeke C.S. Kartalis N. et al.Short-term results of a magnetic resonance imaging-based swedish screening program for individuals at risk for pancreatic cancer.JAMA Surg. 2015; 150: 512-518Crossref PubMed Scopus (65) Google Scholar,7Overbeek K.A. Goggins M.G. Dbouk M. et al.Timeline of development of pancreatic cancer and implications for successful early detection in high-risk individuals.Gastroenterology. 2022; 162: 772-785.e4Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar With the advances in multi-omics techniques, liquid biopsies are garnering increasing attention owing to their convenient, affordable, and reliable nature, and the search for effective biomarkers for early diagnosis is becoming a new research hotspot. Amongst the various noninvasive biomarkers, plasma/serum microRNA (miRNA) has drawn considerable attention. miRNAs are involved in the epigenetic regulation of pancreatic cancer carcinogenesis through unique signaling pathways.8Cao L. Huang C. Cui Zhou D. et al.Proteogenomic characterization of pancreatic ductal adenocarcinoma.Cell. 2021; 184: 5031-5052.e26Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar A previous study used such a strategy to distinguish between pancreatic cancer, pancreatitis, and healthy individuals, and identified several significant miRNA biomarkers, including miR-486-5p and miR-938.9Xu J. Cao Z. Liu W. et al.Plasma miRNAs effectively distinguish patients with pancreatic cancer from controls: a multicenter study.Ann Surg. 2016; 263: 1173-1179Crossref PubMed Scopus (59) Google Scholar Another multicenter study used a miRNA biomarker combination to differentiate those with pancreatic cancer, intraductal papillary mucinous neoplasm, and pancreatitis.10Vila-Navarro E. Duran-Sanchon S. Vila-Casadesús M. et al.Novel circulating miRNA signatures for early detection of pancreatic neoplasia.Clin Transl Gastroenterol. 2019; 10e00029Crossref Scopus (34) Google Scholar Blood miRNA biomarker combinations can be used to differentiate pancreatic cancer from other pancreatic diseases and healthy individuals. Although multilevel studies of miRNA in pancreatic cancer have been conducted, the exact role of miRNA in early screening for pancreatic cancer requires further investigation. Cell-free miRNA (cf-miRNA) and exosomal miRNA (exo-miRNA) are useful biomarkers for cancer detection. cf-miRNA are fragments of miRNA released into circulation by cells (such as tumor cells) and stay in body fluids,11Nakamura K. Sawada K. Yoshimura A. et al.Clinical relevance of circulating cell-free microRNAs in ovarian cancer.Mol Cancer. 2016; 15: 48Crossref PubMed Scopus (124) Google Scholar and exo-miRNA are encapsulated in extracellular vesicles and released from cells,12Tomasetti M. Lee W. Santarelli L. et al.Exosome-derived microRNAs in cancer metabolism: possible implications in cancer diagnostics and therapy.Exp Mol Med. 2017; 49: e285Crossref PubMed Scopus (142) Google Scholar which may be particularly valuable because exosomes are enriched with selected sets of miRNAs before they are released into the circulation. Both types of miRNAs may be dysregulated in cancer cells and have been explored in malignancies, such as ovarian cancer.11Nakamura K. Sawada K. Yoshimura A. et al.Clinical relevance of circulating cell-free microRNAs in ovarian cancer.Mol Cancer. 2016; 15: 48Crossref PubMed Scopus (124) Google Scholar Nakamura et al13Nakamura K. Zhu Z. Roy S. et al.An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: a multicenter cohort study.Gastroenterology. 2022; 163: 1252-1266Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar performed a genome-wide profiling of blood specimens to develop an exosome-based transcriptomic signature for noninvasive and early detection of pancreatic cancer (Figure 1). They examined cf-miRNA and exo-miRNA from peripheral serum or plasma in a discovery cohort and identified a panel of 13 cf-miRNAs and 17 exo-miRNAs that were significantly up-regulated in patients with relatively early-stage (stage I/II) pancreatic cancer, both with excellent predictive probabilities. Additionally, the 30-miRNA biomarker combination provided impressive sensitivity and specificity in diagnosing early-stage pancreatic cancer. Nakamura et al subsequently established a clinically feasible panel using a reduced number of biomarkers (5 cf-miRNAs and 8 exo-miRNAs) in a training cohort and evaluated its performance in both training and validation cohorts. Nakamura’s study used independent multicenter cohorts established from multiple countries, yielding a pool of research subjects who were more heterogenous and representative of the population, improving generalizability and reliability. The study also considered the inclusion of CA19-9 in the biomarker combination and discovered strong sensitivity and specificity of the miRNA biomarker combination in early-stage pancreatic cancer. These results shed light on the earlier detection of pancreatic cancer; however, using these diagnostic biomarkers to detect and alert ones with dynamic progression of pancreatic malignancy remains challenging. First, the disease evinces limited tumor burden at early stages and theoretically minimal disturbances to blood biomarkers. Whether the miRNA combination correlates with cancer stage and can be used as predictors of disease progression remains a challenge. In addition, cohorts with true early pancreatic cancer (stage 0, TisN0M0, carcinoma in situ)14Kakar S. Pawlik T.M. Allen P.J. et al.Exocrine pancreas.in: Amin M.B. AJCC cancer staging manual. 8th ed. AJCC, Chicago2017: 337Crossref Google Scholar are difficult to establish, making it nearly impossible to test the diagnostic accuracy directly in stage 0 pancreatic cancer. In addition, whether such sets of miRNA can distinguish pancreatic cancer from pancreatic benign neoplasms and pancreatitis requires further exploration. Owing to the low incidence of pancreatic cancer in the general population, the currently accepted screening strategy focuses on screening and follow-up of high-risk individuals. The high-risk population usually include ones with history of pancreatitis,15Saluja A. Maitra A. Pancreatitis and pancreatic cancer.Gastroenterology. 2019; 156: 1937-1940Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar cystic pancreatic lesions (ie, intraductal papillary mucinous neoplasm: IPMN, mucinous cystic neoplasm: MCN),16European Study Group on Cystic Tumours of the PancreasEuropean evidence-based guidelines on pancreatic cystic neoplasms.Gut. 2018; 67: 789-804Crossref PubMed Scopus (594) Google Scholar new-onset diabetes,17Sharma S. Tapper W.J. Collins A. et al.Predicting pancreatic cancer in the UK Biobank cohort using polygenic risk scores and diabetes mellitus.Gastroenterology. 2022; 162: 1665-1674.e2Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,18Sharma A. Kandlakunta H. Nagpal S.J.S. et al.Model to determine risk of pancreatic cancer in patients with new-onset diabetes.Gastroenterology. 2018; 155: 730-739.e3Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar a family history of pancreatic cancer, and pancreatic cancer-related germline mutations.19Goggins M. Overbeek K.A. Brand R. et al.Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.Gut. 2020; 69: 7-17Crossref PubMed Scopus (233) Google Scholar The incidence of pancreatic cancer during the follow-up of high-risk cohorts is almost certain, yet risk stratifications for pancreatic cancer occurrence will rely on biomarker panels. An ideal biomarker panel will alert clinicians before disease occurrence in high-risk individuals, and therefore prompt a more proactive follow-up regime and imaging evaluations. Nakamura et al highlighted the fact that combinations of biomarkers would allow clinicians to detect early stages of pancreatic cancer. Combinations of diagnostic biomarkers may be used to enhance sensitivity, to capture changes in peripheral blood biomarkers associated with pancreatic malignancies more acutely. In contrast, the high-risk cohort is an important benchmark with which to measure the detection ability of biomarker panels. In conclusion, although there has been no effective biomarker panel for early screening of pancreatic cancer applied in a clinical setting, with continuous investigation of disease behavior and advancements in detection techniques, a solution to the early detection of pancreatic cancer is feasible and will have a high impact on the prognosis and overall survival for patients with pancreatic cancer. An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort StudyGastroenterologyVol. 163Issue 5PreviewOur exosome-based transcriptomic signature that combines cell-free and exosomal microRNAs has the potential to identify patients with pancreatic ductal adenocarcinoma with high diagnostic accuracy, and offers an important noninvasive assay for early detection of this fatal malignancy. Full-Text PDF