Letter to the Editor Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 7, 2021; 27(45): 7862-7865
Published online Dec 7, 2021. doi: 10.3748/wjg.v27.i45.7862
Diagnostic biomarkers for pancreatic cancer: An update
Ming Yang, Chun-Ye Zhang
Ming Yang, Department of Surgery, University of Missouri, Columbia, MO 65212, United States
Chun-Ye Zhang, Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, United States
ORCID number: Ming Yang (0000-0002-4895-5864); Chun-Ye Zhang (0000-0003-2567-029X).
Author contributions: Yang M and Zhang CY collected data, wrote, finalized the letter, and contributed equally.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ming Yang, DVM, PhD, Postdoctoral Fellow, Department of Surgery, University of Missouri, One Hospital Dr., Medical Science Building, Room M272, Columbia, MO 65212, United States. yangmin@health.missouri.edu
Received: July 20, 2021
Peer-review started: July 20, 2021
First decision: August 6, 2021
Revised: August 10, 2021
Accepted: November 24, 2021
Article in press: November 24, 2021
Published online: December 7, 2021

Abstract

Pancreatic ductal adenocarcinoma accounts for the primary type of pancreatic cancer (PC) with a 5-year survival rate of only about 10% in the United States. Early diagnosis will improve chances for curative treatment. To date, a broadly used serum marker for PC diagnosis is carbohydrate antigen 19-9, which is the only approved biomarker currently by the United States Food and Drug Administration. However, it has low specificity; therefore, development of novel biomarkers is urgently needed. Clinical trials are ongoing to evaluate candidate biomarkers for PC diagnosis, and the use of a multi-biomarker panel with current PC diagnostic biomarkers appears promising.

Key Words: Pancreatic ductal adenocarcinoma, Diagnosis, Biomarkers, Panel, Clinical trials

Core Tip: The development of ideal diagnostic biomarkers for pancreatic cancer (PC) is critically important for early diagnosis, large-scale screening, monitoring of therapeutic response, prediction of risk, and prognosis. So far, the only approved serum marker for PC diagnosis is carbohydrate antigen 19-9 (CA 19-9) in the United States; although, many potential biomarkers have been investigated. However, CA 19-9 has low sensitivity; hence, new solutions are needed. Herein, we summarize some of the ongoing clinical trials that aim to investigate the application of biomarkers in PC diagnosis.



TO THE EDITOR

We read with great interest a review paper recently published by O'Neill and Stoita[1], reviewing diagnostic biomarkers currently applied in pancreatic cancer (PC). The biomarkers are from serum, urinary, pancreatic, salivary, biliary, and fecal sources and comprise many different types of molecules. For example, serum biomarkers include proteins of glycolipids, growth factors, cytokines, chemokines, adhesion molecules, non-coding RNAs (long non-coding RNAs and microRNAs), and liquid biopsy (exosomes, circulating tumor DNA or ctDNA, and circulating tumor cells or CTCs)[1].

Moreover, we agree with the authors' suggestion that early diagnosis of PC improves chances for curative treatment. PC comprises two main subtypes, including the more common exocrine cancers and less common endocrine cancers. Pancreatic ductal adenocarcinoma (PDAC) accounts for the primary type of PC, consisting of around 95% in exocrine cancers and about 90% in all PCs. The 5-year survival rate of PC is relatively low and was only 10% for all patients with PC in the United States from 2010 to 2016[2]. To date, the only approved serum marker for PC diagnosis is carbohydrate antigen 19-9 (CA 19-9) in the United States, even though it has low specificity[3]. However, CA 19-9 is a non-PC-specific marker, shown to increase in colorectal, liver, lung, and ovarian cancers, as well as desmoplastic fibroblastoma[4,5]. Because of the low specificity of CA 19-9, a multi-marker panel that combines some of the currently investigated biomarkers (with CA 19-9) can be used to improve the specificity and sensitivity of PC diagnosis. For example, a multi-biomarker panel with enzyme-linked immunosorbent assay using three potential biomarkers, leucine-rich alpha-2-glycoprotein 1, transthyretin, and CA 19-9, improved the diagnosis of PDAC in normal pancreas and benign pancreatic disease and other tumors[6]. Although a multi-biomarker panel provides a better approach for early PC diagnosis, some limitations, including cost, the requirement for large sample volumes, good technique and analytical performance, and practical feasibility, may impact their broad application[3,7,8].

In addition, many of the biomarkers discussed in the abovementioned paper, including extracellular matrix-associated proteins such as matrix metalloproteinase and tissue inhibitor of metalloproteinase 1, profibrotic factors such as transforming growth factor-beta, growth factors such as vascular endothelial growth factor, cell-cell interacting protein such as intercellular adhesion molecule 1, and microRNAs such as mi-R21, are not specific markers implicated in many other cancers and diseases[9-12]. Furthermore, germline mutations in genes such as cyclin-dependent kinase inhibitor 2A, tumor protein p53, serine/threonine kinase ATM, MutL homolog 1, and breast cancer 1 and 2 have been significantly associated with PC[13]. The authors also mentioned genetic factors associated with PC, such as KRAS in ctDNA and KRAS mutation in CTCs. Therefore, genetic mutation or inherited factors may be a predisposing factor for PC and should be considered during the diagnosis.

Finally, this letter summarizes the actively recruiting and completed clinical trials to evaluate diagnostic methods or biomarkers for PC (Table 1). The data were collected from the website https://clinicaltrials.gov (accessed on July 18, 2021) using the keywords biomarkers and PC. Overall, the specificity and sensitivity of PC diagnosis can be increased by using multiple marker panels in combination with CA 19-9 or with novel screened biomarkers. In addition, accuracy, cost-effectiveness, and ease of application together will ensure the broad application of any new diagnostic method.

Table 1 Clinical trials for pancreatic cancer with representative diagnostic biomarkers.
Trial number
Biomarkers
Status
Year to complete
Results/Trial titles
NCT03311776HA and PRO-C3Completed2035Serum HA and PRO-C3 were prognostic for overall survival in patients with PC[14]
NCT04241367ctDNARecruiting2025Verification of predictive biomarkers for pancreatic cancer treatment using multicenter liquid biopsy
NCT04143152sTRA and CA 19-9Recruiting2023Two biomarker panels with sTRA and CA 19-9 improved sensitivity and accuracy, compared to using only CA19-9[15]
NCT03404661Methylated DNA markers Recruiting2023Optical and biochemical biomarkers in early pancreatic cancer significance: a prospective study
NCT04584996CircRNAsRecruiting2023Circular and non-coding RNAs as clinically useful biomarkers in pancreaticobiliary cancers
NCT04636788Circulating exosomal small RNAsRecruiting2022Diagnostic and prognostic values of EUS-FNA specimens and circulating exosomal small RNA in patients with pancreatic cancer
NCT03536793Urinary tissue factor and Endo180Recruiting2022Study of uTF and Endo180 as markers of early malignancy in cystic pancreatic lesions
NCT04549064AREGRecruiting2021Identification of AREG for the detection of pancreatic cancer by the biosensor
NCT03817866Chromogranin A Recruiting2021To validate the performance of Brahms Chromogranin A II Kryptor assay to monitor the course of disease in patients with well-defined gastroentero-pancreatic neuroendocrine tumors
NCT03214991DNAUnknown2021Circulating tumor DNA as a prognostic marker in patients with pancreatic cancer
NCT01664169VEGF-A and VEGF-R2Completed2018Validation of circulating biomarkers using the immunological multiparameter chip technology (IMPACT) platform on plasma specimens collected on CALGB 80303
NCT02974764Circulating tumor cells Completed2018Alterations in circulating tumor cells predicted the progression of pancreatic ductal adenocarcinoma, treatment response, and clinical outcomes[16]
NCT00674973AREG, EGF, sHER2, TGF-α Completed2015Exploratory analyses suggested that high AREG might predict progression-free survival in patients with pancreatic cancer treated with erlotinib[17]
NCT01675258Four messenger RNA biomarkers (KRAS, MBD3L2, ACRV1, and DPM1) in salivary samplesCompleted2013The logistic regression model using four biomarkers yielded an area under the curve value of 0.971 (cutoff 0.433) to detect resectable pancreatic cancer with 90.0% sensitivity and 95.0% specificity[18]
NCT00899158Caspase-3 and pAkt in muscle, and urinary 3-MHCompleted2008Role of caspase-3, phosphatidylinositol-3 kinase, and 3-methylhistidine in the pathophysiology of skeletal muscle loss in weight-losing pancreas cancer patients
Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

Grade A (Excellent): A

Grade B (Very good): B

Grade C (Good): C

Grade D (Fair): 0

Grade E (Poor): E

P-Reviewer: Imai Y, Jin ZD, Ling Q, Yu F S-Editor: Fan JR L-Editor: A P-Editor: Fan JR

References
1.  O'Neill RS, Stoita A. Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol. 2021;27:4045-4087.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
2.  Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 809]  [Cited by in F6Publishing: 980]  [Article Influence: 809.0]  [Reference Citation Analysis (1)]
3.  Choi YJ, Yoon W, Lee A, Han Y, Byun Y, Kang JS, Kim H, Kwon W, Suh YA, Kim Y, Lee S, Namkung J, Han S, Choi Y, Heo JS, Park JO, Park JK, Kim SC, Kang CM, Lee WJ, Park T, Jang JY. Diagnostic model for pancreatic cancer using a multi-biomarker panel. Ann Surg Treat Res. 2021;100:144-153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
4.  Rasappan K, Shaw LKRM, Chan LWM, Chuah KL, Cheng MHW. A case of raised CA 19-9 in a patient with desmoplastic fibroblastoma of the upper limb. Int Cancer Conf J. 2021;10:222-227.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
5.  Kim SY, Lee HS, Bang SM, Han DH, Hwang HK, Choi GH, Chung MJ, Kim SU. Serum Dickkopf-1 in Combined with CA 19-9 as a Biomarker of Intrahepatic Cholangiocarcinoma. Cancers (Basel). 2021;13.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
6.  Lee DH, Yoon W, Lee A, Han Y, Byun Y, Kang JS, Kim H, Kwon W, Suh YA, Choi Y, Namkung J, Han S, Yi SG, Heo JS, Han IW, Park JO, Park JK, Kim SC, Jun E, Kang CM, Lee WJ, Lee HK, Lee H, Lee S, Jeong SY, Lee KE, Han W, Park T, Jang JY. Multi-biomarker panel prediction model for diagnosis of pancreatic cancer. J Hepatobiliary Pancreat Sci. 2021;.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
7.  Mellby LD, Nyberg AP, Johansen JS, Wingren C, Nordestgaard BG, Bojesen SE, Mitchell BL, Sheppard BC, Sears RC, Borrebaeck CAK. Serum Biomarker Signature-Based Liquid Biopsy for Diagnosis of Early-Stage Pancreatic Cancer. J Clin Oncol. 2018;36:2887-2894.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 33]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
8.  Park J, Choi Y, Namkung J, Yi SG, Kim H, Yu J, Kim Y, Kwon MS, Kwon W, Oh DY, Kim SW, Jeong SY, Han W, Lee KE, Heo JS, Park JO, Park JK, Kim SC, Kang CM, Lee WJ, Lee S, Han S, Park T, Jang JY. Diagnostic performance enhancement of pancreatic cancer using proteomic multimarker panel. Oncotarget. 2017;8:93117-93130.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 13]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
9.  Barabás L, Hritz I, István G, Tulassay Z, Herszényi L. The Behavior of MMP-2, MMP-7, MMP-9, and Their Inhibitors TIMP-1 and TIMP-2 in Adenoma-Colorectal Cancer Sequence. Dig Dis. 2021;39:217-224.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 1]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
10.  Bar-Shai A, Shenhar-Tsarfaty S, Ahimor A, Ophir N, Rotem M, Alcalay Y, Fireman E. A novel combined score of biomarkers in sputum may be an indicator for lung cancer: A pilot study. Clin Chim Acta. 2018;487:139-144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 2]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
11.  Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut. 2021;70:784-795.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 33]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
12.  Yang M, Zhang C. The role of liver sinusoidal endothelial cells in cancer liver metastasis. Am J Cancer Res. 2021;11:1845-1860.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, Lilyquist J, Na J, Moore R, Antwi SO, Bamlet WR, Chaffee KG, DiCarlo J, Wu Z, Samara R, Kasi PM, McWilliams RR, Petersen GM, Couch FJ. Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA. 2018;319:2401-2409.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 171]  [Cited by in F6Publishing: 154]  [Article Influence: 42.8]  [Reference Citation Analysis (0)]
14.  Chen IM, Willumsen N, Dehlendorff C, Johansen AZ, Jensen BV, Hansen CP, Hasselby JP, Bojesen SE, Pfeiffer P, Nielsen SE, Holländer NH, Yilmaz MK, Karsdal M, Johansen JS. Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer. Int J Cancer. 2020;146:2913-2922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 10]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
15.  Staal B, Liu Y, Barnett D, Hsueh P, He Z, Gao C, Partyka K, Hurd MW, Singhi AD, Drake RR, Huang Y, Maitra A, Brand RE, Haab BB. The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis. Clin Cancer Res. 2019;25:2745-2754.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 9]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
16.  Gemenetzis G, Groot VP, Yu J, Ding D, Teinor JA, Javed AA, Wood LD, Burkhart RA, Cameron JL, Makary MA, Weiss MJ, He J, Wolfgang CL. Circulating Tumor Cells Dynamics in Pancreatic Adenocarcinoma Correlate With Disease Status: Results of the Prospective CLUSTER Study. Ann Surg. 2018;268:408-420.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 55]  [Cited by in F6Publishing: 27]  [Article Influence: 13.8]  [Reference Citation Analysis (0)]
17.  Propper D, Davidenko I, Bridgewater J, Kupcinskas L, Fittipaldo A, Hillenbach C, Klughammer B, Ducreux M. Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma. Ann Oncol. 2014;25:1384-1390.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 20]  [Article Influence: 2.6]  [Reference Citation Analysis (0)]
18.  Zhang L, Farrell JJ, Zhou H, Elashoff D, Akin D, Park NH, Chia D, Wong DT. Salivary transcriptomic biomarkers for detection of resectable pancreatic cancer. Gastroenterology. 2010;138:949-57.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 188]  [Cited by in F6Publishing: 173]  [Article Influence: 14.5]  [Reference Citation Analysis (0)]