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The role of biomarkers in the early detection of pancreatic cancer

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Abstract

Pancreatic surveillance can detect early-stage pancreatic cancer and achieve long-term survival, but currently involves annual endoscopic ultrasound and MRI/MRCP, and is recommended only for individuals who meet familial/genetic risk criteria. To improve upon current approaches to pancreatic cancer early detection and to expand access, more accurate, inexpensive, and safe biomarkers are needed, but finding them has remained elusive. Newer approaches to early detection, such as using gene tests to personalize biomarker interpretation, and the increasing application of artificial intelligence approaches to integrate complex biomarker data, offer promise that clinically useful biomarkers for early pancreatic cancer detection are on the horizon.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

EUS:

Endoscopic ultrasonography

CT:

Computed tomography

MRI:

Magnetic resonance imaging

MRCP:

Magnetic resonance cholangiopancreatography

PanIN:

Pancreatic intraepithelial neoplasia

IPMN:

Intraductal papillary mucinous neoplasm

AUC:

Area under the receiver operator characteristics curve

AI:

Artificial intelligence

MCED:

Multi-cancer early detection

NOD:

New-onset diabetes

References

  1. Dbouk M, Katona BW, Brand RE, Chak A, Syngal S, Farrell JJ, Kastrinos F, Stoffel EM, Blackford AL, Rustgi AK, Dudley B, Lee LS, Chhoda A, Kwon R, Ginsberg GG, Klein AP, Kamel I, Hruban RH, He J, Shin EJ, Lennon AM, Canto MI, Goggins M (2022) The multicenter cancer of pancreas screening study: impact on stage and survival. J Clin Oncol 40:3257–66. https://doi.org/10.1200/JCO.22.00298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Klatte DCF, Boekestijn B, Wasser M, Feshtali Shahbazi S, Ibrahim IS, Mieog JSD, Luelmo SAC, Morreau H, Potjer TP, Inderson A, Boonstra JJ, Dekker FW, Vasen HFA, van Hooft JE, Bonsing BA, van Leerdam ME (2022) Pancreatic cancer surveillance in carriers of a germline CDKN2A pathogenic variant: yield and outcomes of a 20-year prospective follow-up. J Clin Oncol 40:3267–77. https://doi.org/10.1200/JCO.22.00194

    Article  CAS  PubMed  Google Scholar 

  3. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, Bassi C, Carrato A, Farrell J, Fishman EK, Fockens P, Gress TM, van Hooft JE, Hruban RH, Kastrinos F, Klein A, Lennon AM, Lucas A, Park W, Rustgi A, Simeone D, Stoffel E, Vasen HFA, Cahen DL, Canto MI, Bruno M (2020) Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 69:7–17

    Article  CAS  PubMed  Google Scholar 

  4. Canto MI, Harinck F, Hruban RH, Offerhaus GJ, Poley JW, Fockens P, Kamel I, Nio Y, Schulick R, Bassi C, Kluijt I, Goggins M, Bruno M (2013) International consensus recommendations on the management of patients with increased risk for familial pancreatic cancer (The Cancer of the Pancreas Screening (CAPS) Consortium Summit). Gut 62:339–47

    Article  PubMed  Google Scholar 

  5. Blackford AL, Canto MI, Klein AP, Hruban RH, Goggins M (2020) Recent trends in the incidence and survival of stage 1A pancreatic cancer: a surveillance, epidemiology, and end results analysis. J Natl Cancer Inst 112:1162–9

    Article  PubMed  PubMed Central  Google Scholar 

  6. safety: WIpoc (1993) Biomarkers and risk assessment: concepts and principles. https://www.inchem.org/documents/ehc/ehc/ehc155.htm

  7. Sullivan Pepe M, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, Winget M, Yasui Y (2001) Phases of biomarker development for early detection of cancer. J Natl Cancer Inst 93:1054–61

    Article  Google Scholar 

  8. Canto MI, Almario JA, Schulick RD, Yeo CJ, Klein A, Blackford A, Shin EJ, Sanyal A, Yenokyan G, Lennon AM, Kamel IR, Fishman EK, Wolfgang C, Weiss M, Hruban RH, Goggins M (2018) Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 155:740–51.e2

    Article  PubMed  Google Scholar 

  9. Van Calster B, McLernon DJ, van Smeden M, Wynants L, Steyerberg EW (2019) Calibration: the Achilles heel of predictive analytics. BMC Med 17:230. https://doi.org/10.1186/s12916-019-1466-7

    Article  PubMed  PubMed Central  Google Scholar 

  10. Board on Mathematical Sciences and Their Applications; Division on Engineering and Physical Sciences; National Academies of Sciences E, and Medicine (2016) Conceptualizing, measuring, and studying reproducibility. National Academies Press, Washington

    Google Scholar 

  11. Davis JGM (2006) The relationship between precision-recall and ROC curves. In: Proceedings of the 23rd international conference on machine learning. ACM, New York. pp 233–240

  12. Ozenne B, Subtil F, Maucort-Boulch D (2015) The precision–recall curve overcame the optimism of the receiver operating characteristic curve in rare diseases. J Clin Epidemiol 68:855–9. https://doi.org/10.1016/j.jclinepi.2015.02.010

    Article  PubMed  Google Scholar 

  13. O’Neill RS, Stoita A (2021) Biomarkers in the diagnosis of pancreatic cancer: are we closer to finding the golden ticket? World J Gastroenterol 27:4045–87. https://doi.org/10.3748/wjg.v27.i26.4045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Toshima F, Watanabe R, Inoue D, Yoneda N, Yamamoto T, Sasahira N, Sasaki T, Matsuyama M, Minehiro K, Tateishi U, Gabata T (2021) CT Abnormalities of the pancreas associated with the subsequent diagnosis of clinical stage I pancreatic ductal adenocarcinoma more than 1 year later: a case–control study. AJR Am J Roentgenol 217:1353–64. https://doi.org/10.2214/AJR.21.26014

    Article  PubMed  Google Scholar 

  15. Singh DP, Sheedy S, Goenka AH, Wells M, Lee NJ, Barlow J, Sharma A, Kandlakunta H, Chandra S, Garg SK, Majumder S, Levy MJ, Takahashi N, Chari ST (2020) Computerized tomography scan in pre-diagnostic pancreatic ductal adenocarcinoma: stages of progression and potential benefits of early intervention: a retrospective study. Pancreatology 20:1495–501

    Article  PubMed  Google Scholar 

  16. Hoogenboom SA, Engels MML, Chuprin AV, van Hooft JE, LeGout JD, Wallace MB, Bolan CW (2022) Prevalence, features, and explanations of missed and misinterpreted pancreatic cancer on imaging: a matched case-control study. Abdom Radiol (NY) 47:4160–72. https://doi.org/10.1007/s00261-022-3671-6

    Article  PubMed  Google Scholar 

  17. Vasen HFA, Boekestijn B, Ibrahim IS, Inderson A, Bonsing BA (2019) Dilatation of the main pancreatic duct as first manifestation of small pancreatic ductal adenocarcinomas detected in a hereditary pancreatic cancer surveillance program. HPB (Oxford) 21:1371–5

    Article  PubMed  Google Scholar 

  18. Sato T, Ito K, Tamada T, Sone T, Noda Y, Higaki A, Kanki A, Tanimoto D, Higashi H (2012) Age-related changes in normal adult pancreas: MR imaging evaluation. Eur J Radiol 81:2093–8. https://doi.org/10.1016/j.ejrad.2011.07.014

    Article  PubMed  Google Scholar 

  19. Miura S, Takikawa T, Kikuta K, Hamada S, Kume K, Yoshida N, Tanaka Y, Matsumoto R, Ikeda M, Kataoka F, Sasaki A, Hatta W, Inoue J, Masamune A (2021) Focal parenchymal atrophy of the pancreas is frequently observed on pre-diagnostic computed tomography in patients with pancreatic cancer: a case–control study. Diagnostics (Basel) 11:1693. https://doi.org/10.3390/diagnostics11091693

    Article  PubMed  Google Scholar 

  20. Crippa S, Bassi C, Salvia R, Malleo G, Marchegiani G, Rebours V, Levy P, Partelli S, Suleiman SL, Banks PA, Ahmed N, Chari ST, Fernandez-Del Castillo C, Falconi M (2017) Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis. Gut 66:495–506

    Article  PubMed  Google Scholar 

  21. Ohtsuka T, Fernandez-Del Castillo C, Furukawa T, Hijioka S, Jang JY, Lennon AM, Miyasaka Y, Ohno E, Salvia R, Wolfgang CL, Wood LD (2023) International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas. Pancreatology 28:01883–5

    Google Scholar 

  22. Hirono S, Kawai M, Okada KI, Miyazawa M, Shimizu A, Kitahata Y, Ueno M, Yanagisawa A, Yamaue H (2017) Factors associated with invasive intraductal papillary mucinous carcinoma of the pancreas. JAMA Surg 152:e165054. https://doi.org/10.1001/jamasurg.2016.5054

    Article  PubMed  Google Scholar 

  23. Khoury RE, Kabir C, Maker VK, Banulescu M, Wasserman M, Maker AV (2018) What is the incidence of malignancy in resected intraductal papillary mucinous neoplasms? An analysis of over 100 US institutions in a single year. Ann Surg Oncol 25:1746–51

    Article  PubMed  Google Scholar 

  24. Hoogenboom SA, Bolan CW, Chuprin A, Raimondo MT, van Hooft JE, Wallace MB, Raimondo M (2021) Pancreatic steatosis on computed tomography is an early imaging feature of pre-diagnostic pancreatic cancer: a preliminary study in overweight patients. Pancreatology 21:428–33. https://doi.org/10.1016/j.pan.2021.01.003

    Article  PubMed  Google Scholar 

  25. Wong VW, Wong GL, Yeung DK, Abrigo JM, Kong AP, Chan RS, Chim AM, Shen J, Ho CS, Woo J, Chu WC, Chan HL (2014) Fatty pancreas, insulin resistance, and β-cell function: a population study using fat-water magnetic resonance imaging. Am J Gastroenterol 109:589–97. https://doi.org/10.1038/ajg.2014.1

    Article  CAS  PubMed  Google Scholar 

  26. Aliyari Ghasabeh M, Shaghaghi M, Khoshpouri P, Pan L, Pandy A, Pandy P, Zhong X, Kannengiesser S, Kamel IR (2020) Correlation between incidental fat deposition in the liver and pancreas in asymptomatic individuals. Abdom Radiol (NY) 45:203–10

    Article  PubMed  Google Scholar 

  27. Brune K, Abe T, Canto M, O’Malley L, Klein AP, Maitra A, Volkan Adsay N, Fishman EK, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH (2006) Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer. Am J Surg Pathol 30:1067–76

    PubMed  PubMed Central  Google Scholar 

  28. Kiemen AL, Dbouk M, Diwan EA, Forjaz A, Dequiedt L, Baghdadi A, Madani SP, Grahn MP, Jones C, Vedula S, Wu P, Wirtz D, Kern S, Goggins M, Hruban RH, Kamel IR, Canto MI (2024) Magnetic resonance imaging-based assessment of pancreatic fat strongly correlates with histology-based assessment of pancreas composition. Pancreas 4:180

    Article  Google Scholar 

  29. Chu LC, Park S, Kawamoto S, Fouladi DF, Shayesteh S, Zinreich ES, Graves JS, Horton KM, Hruban RH, Yuille AL, Kinzler KW, Vogelstein B, Fishman EK (2019) Utility of CT radiomics features in differentiation of pancreatic ductal adenocarcinoma from normal pancreatic tissue. AJR Am J Roentgenol 213:349–57

    Article  PubMed  Google Scholar 

  30. Mukherjee S, Patra A, Khasawneh H, Korfiatis P, Rajamohan N, Suman G, Majumder S, Panda A, Johnson MP, Larson NB, Wright DE, Kline TL, Fletcher JG, Chari ST, Goenka AH (2022) Radiomics-based machine-learning models can detect pancreatic cancer on prediagnostic computed tomography scans at a substantial lead time before clinical diagnosis. Gastroenterology 163:1435–46.e3

    Article  PubMed  Google Scholar 

  31. Sah RP, Sharma A, Nagpal S, Patlolla SH, Sharma A, Kandlakunta H, Anani V, Angom RS, Kamboj A, Ahmed N, Mohapatra S, Vivekanandan S, Philbrick KA, Weston A, Takahashi N, Kirkland J, Javeed N, Matveyenko A, Levy MJ, Mukhopadhyay D, Chari ST (2019) Phases of metabolic and soft tissue changes in months preceding a diagnosis of pancreatic ductal adenocarcinoma. Gastroenterology 156(6):1742–52

    Article  PubMed  Google Scholar 

  32. Danai LV, Babic A, Rosenthal MH, Dennstedt EA, Muir A, Lien EC, Mayers JR, Tai K, Lau AN, Jones-Sali P, Prado CM, Petersen GM, Takahashi N, Sugimoto M, Yeh JJ, Lopez N, Bardeesy N, Fernandez-Del Castillo C, Liss AS, Koong AC, Bui J, Yuan C, Welch MW, Brais LK, Kulke MH, Dennis C, Clish CB, Wolpin BM, Vander Heiden MG (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600–4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Babic A, Rosenthal MH, Sundaresan TK, Khalaf N, Lee V, Brais LK, Loftus M, Caplan L, Denning S, Gurung A, Harrod J, Schawkat K, Yuan C, Wang QL, Lee AA, Biller LH, Yurgelun MB, Ng K, Nowak JA, Aguirre AJ, Bhatia SN, Vander Heiden MG, Van Den Eeden SK, Caan BJ, Wolpin BM (2023) Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer. Nat Commun 14:4317. https://doi.org/10.1038/s41467-023-0024-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cao K, Xia Y, Yao J, Han X, Lambert L, Zhang T, Tang W, Jin G, Jiang H, Fang X, Nogues I, Li X, Guo W, Wang Y, Fang W, Qiu M, Hou Y, Kovarnik T, Vocka M, Lu Y, Chen Y, Chen X, Liu Z, Zhou J, Xie C, Zhang R, Lu H, Hager GD, Yuille AL, Lu L, Shao C, Shi Y, Zhang Q, Liang T, Zhang L, Lu J (2023) Large-scale pancreatic cancer detection via non-contrast CT and deep learning. Nat Med 29:3033–43. https://doi.org/10.1038/s41591-023-02640-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Korfiatis P, Suman G, Patnam NG, Trivedi KH, Karbhari A, Mukherjee S, Cook C, Klug JR, Patra A, Khasawneh H, Rajamohan N, Fletcher JG, Truty MJ, Majumder S, Bolan CW, Sandrasegaran K, Chari ST, Goenka AH (2023) Automated artificial intelligence model trained on a large data set can detect pancreas cancer on diagnostic computed tomography scans as well as visually occult preinvasive cancer on prediagnostic computed tomography scans. Gastroenterology 165:1533–46.e4

    Article  PubMed  Google Scholar 

  36. Kawamoto S, Zhu Z, Chu LC, Javed AA, Kinny-Köster B, Wolfgang CL, Hruban RH, Kinzler KW, Fouladi DF, Blanco A, Shayesteh S, Fishman EK (2024) Deep neural network-based segmentation of normal and abnormal pancreas on abdominal CT: evaluation of global and local accuracies. Abdom Radiol (NY) 49:501–11. https://doi.org/10.1007/s00261-023-4122-6

    Article  PubMed  Google Scholar 

  37. Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello F, Hruban R (2004) Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol 2:606–21

    Article  PubMed  Google Scholar 

  38. Canto MI, Goggins M, Hruban RH, Petersen GM, Giardiello FM, Yeo C, Fishman EK, Brune K, Axilbund J, Griffin C, Ali S, Richman J, Jagannath S, Kantsevoy SV, Kalloo AN (2006) Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 4:766–81

    Article  PubMed  Google Scholar 

  39. Stevens T, Lopez R, Adler DG, Al-Haddad MA, Conway J, Dewitt JM, Forsmark CE, Kahaleh M, Lee LS, Levy MJ, Mishra G, Piraka CR, Papachristou GI, Shah RJ, Topazian MD, Vargo JJ, Vela SA (2010) Multicenter comparison of the interobserver agreement of standard EUS scoring and Rosemont classification scoring for diagnosis of chronic pancreatitis. Gastrointest Endosc 71:519–26

    Article  PubMed  Google Scholar 

  40. Shi C, Klein AP, Goggins M, Maitra A, Canto M, Ali S, Schulick R, Palmisano E, Hruban RH (2009) Increased prevalence of precursor lesions in familial pancreatic cancer patients. Clin Cancer Res 15:7737–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Topazian M, Enders F, Kimmey M, Brand R, Chak A, Clain J, Cunningham J, Eloubeidi M, Gerdes H, Gress F, Jagannath S, Kantsevoy S, LeBlanc JK, Levy M, Lightdale C, Romagnuolo J, Saltzman JR, Savides T, Wiersema M, Woodward T, Petersen G, Canto M (2007) Interobserver agreement for EUS findings in familial pancreatic-cancer kindreds. Gastrointest Endosc 66:62–7

    Article  PubMed  Google Scholar 

  42. Hausner SH, Bold RJ, Cheuy LY, Chew HK, Daly ME, Davis RA, Foster CC, Kim EJ, Sutcliffe JL (2019) Preclinical development and first-in-human imaging of the integrin α(v)β(6) with [(18)F]α(v)β(6)-binding peptide in metastatic carcinoma. Clin Cancer Res 25:1206–15

    Article  CAS  PubMed  Google Scholar 

  43. Ganguly T, Bauer N, Davis RA, Foster CC, Harris RE, Hausner SH, Roncali E, Tang SY, Sutcliffe JL (2023) Preclinical evaluation of (68)Ga- and (177)Lu-labeled integrin α(v)β(6)-targeting radiotheranostic peptides. J Nucl Med 64:639–44. https://doi.org/10.2967/jnumed.122.264749

    Article  CAS  PubMed  Google Scholar 

  44. Galli C, Basso D, Plebani M (2013) CA 19–9: handle with care. Clin Chem Lab Med 51:1369–83

    Article  CAS  PubMed  Google Scholar 

  45. Abe T, Koi C, Kohi S, Song KB, Tamura K, Macgregor-Das A, Kitaoka N, Chuidian M, Ford M, Dbouk M, Borges M, He J, Burkhart R, Wolfgang CL, Klein AP, Eshleman JR, Hruban RH, Canto MI, Goggins M (2020) Gene variants that affect levels of circulating tumor markers increase identification of patients with pancreatic cancer. Clin Gastroenterol Hepatol 18:1161–9.e5

    Article  CAS  PubMed  Google Scholar 

  46. Dbouk M, Abe T, Koi C, Ando Y, Saba H, Abou Diwan E, Macgregor-Das A, Blackford AL, Mocci E, Beierl K, Dbouk A, He J, Burkhart R, Lennon AM, Sokoll L, Canto MI, Eshleman JR, Goggins M (2023) Diagnostic performance of a tumor marker gene test to personalize serum CA19-9 reference ranges. Clin Cancer Res 11:23–0655

    Google Scholar 

  47. Metzgar RS, Gaillard MT, Levine SJ, Tuck FL, Bossen EH, Borowitz MJ (1982) Antigens of human pancreatic adenocarcinoma cells defined by murine monoclonal antibodies. Cancer Res 42:601–8

    CAS  PubMed  Google Scholar 

  48. Luo G, Jin K, Deng S, Cheng H, Fan Z, Gong Y, Qian Y, Huang Q, Ni Q, Liu C, Yu X (2021) Roles of CA19-9 in pancreatic cancer: biomarker, predictor and promoter. Biochim Biophys Acta Rev Cancer 1875:188409. https://doi.org/10.1016/j.bbcan.2020

    Article  CAS  PubMed  Google Scholar 

  49. Hansson GC, Zopf D (1985) Biosynthesis of the cancer-associated sialyl-Lea antigen. J Biol Chem 260:9388–92

    Article  CAS  PubMed  Google Scholar 

  50. Metzgar RS, Rodriguez N, Finn OJ, Lan MS, Daasch VN, Fernsten PD, Meyers WC, Sindelar WF, Sandler RS, Seigler HF (1984) Detection of a pancreatic cancer-associated antigen (DU-PAN-2 antigen) in serum and ascites of patients with adenocarcinoma. Proc Natl Acad Sci USA 81:5242–6. https://doi.org/10.1073/pnas.81.16.5242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Takasaki H, Uchida E, Tempero MA, Burnett DA, Metzgar RS, Pour PM (1988) Correlative study on expression of CA 19–9 and DU-PAN-2 in tumor tissue and in serum of pancreatic cancer patients. Cancer Res 48:1435–8

    CAS  PubMed  Google Scholar 

  52. Kawa S, Oguchi H, Kobayashi T, Tokoo M, Furuta S, Kanai M, Homma T (1991) Elevated serum levels of Dupan-2 in pancreatic cancer patients negative for Lewis blood group phenotype. Br J Cancer 64:899–902. https://doi.org/10.1038/bjc.991.422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Omiya K, Oba A, Inoue Y, Kobayashi K, Wu YHA, Ono Y, Sato T, Sasaki T, Ozaka M, Sasahira N, Ito H, Saiura A, Takahashi Y (2022) Serum DUPAN-2 could be an alternative biological marker for CA19-9 non-secretors with pancreatic cancer. Ann Surg 25:0000000000005395

    Google Scholar 

  54. Sasaki A, Sakata K, Nakano K, Tsutsumi S, Fujishima H, Futsukaichi T, Terashi T, Ikebe M, Bandoh T, Utsunomiya T (2023) DUPAN-2 as a risk factor of early recurrence after curative pancreatectomy for patients with pancreatic ductal adenocarcinoma. Pancreas 52:e110–e4. https://doi.org/10.1097/MPA.0000000000002209

    Article  CAS  PubMed  Google Scholar 

  55. Ando Y, Dbouk M, Yoshida T, Saba H, Abou Diwan E, Yoshida K, Dbouk A, Blackford AL, Lin MT, Lennon AM, Burkhart RA, He J, Sokoll L, Eshleman JR, Canto MI, Goggins M (2024) Using tumor marker gene variants to improve the diagnostic accuracy of DUPAN-2 and carbohydrate antigen 19–9 for pancreatic cancer. J Clin Oncol. https://doi.org/10.1200/JCO.23.01573

    Article  PubMed  Google Scholar 

  56. Klein EA, Richards D, Cohn A, Tummala M, Lapham R, Cosgrove D, Chung G, Clement J, Gao J, Hunkapiller N, Jamshidi A, Kurtzman KN, Seiden MV, Swanton C, Liu MC (2021) Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol 32:1167–77

    Article  CAS  PubMed  Google Scholar 

  57. Guler GD, Ning Y, Ku CJ, Phillips T, McCarthy E, Ellison CK, Bergamaschi A, Collin F, Lloyd P, Scott A, Antoine M, Wang W, Chau K, Ashworth A, Quake SR, Levy S (2020) Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA. Nat Commun 11:5270. https://doi.org/10.1038/s41467-020-18965-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cristiano S, Leal A, Phallen J, Fiksel J, Adleff V, Bruhm DC, Jensen S, Medina JE, Hruban C, White JR, Palsgrove DN, Niknafs N, Anagnostou V, Forde P, Naidoo J, Marrone K, Brahmer J, Woodward BD, Husain H, van Rooijen KL, Ørntoft MW, Madsen AH, van de Velde CJH, Verheij M, Cats A, Punt CJA, Vink GR, van Grieken NCT, Koopman M, Fijneman RJA, Johansen JS, Nielsen HJ, Meijer GA, Andersen CL, Scharpf RB, Velculescu VE (2019) Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 570:385–9. https://doi.org/10.1038/s41586-019-1272-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Douville C, Lahouel K, Kuo A, Grant H, Avigdor BE, Curtis SD, Summers M, Cohen JD, Wang Y, Mattox A, Dudley J, Dobbyn L, Popoli M, Ptak J, Nehme N, Silliman N, Blair C, Romans K, Thoburn C, Gizzi J, Schoen RE, Tie J, Gibbs P, Ho-Pham LT, Tran BNH, Tran TS, Nguyen TV, Goggins M, Wolfgang CL, Wang TL, Shih IM, Lennon AM, Hruban RH, Bettegowda C, Kinzler KW, Papadopoulos N, Vogelstein B, Tomasetti C (2024) Machine learning to detect the SINEs of cancer. Sci Transl Med 16:eadi3883. https://doi.org/10.1126/scitranslmed.adi3883

    Article  CAS  PubMed  Google Scholar 

  60. Lennon AM, Buchanan AH, Kinde I, Warren A, Honushefsky A, Cohain AT, Ledbetter DH, Sanfilippo F, Sheridan K, Rosica D, Adonizio CS, Hwang HJ, Lahouel K, Cohen JD, Douville C, Patel AA, Hagmann LN, Rolston DD, Malani N, Zhou S, Bettegowda C, Diehl DL, Urban B, Still CD, Kann L, Woods JI, Salvati ZM, Vadakara J, Leeming R, Bhattacharya P, Walter C, Parker A, Lengauer C, Klein A, Tomasetti C, Fishman EK, Hruban RH, Kinzler KW, Vogelstein B, Papadopoulos N (2020) Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science 369:eabb9601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schrag D, Beer TM, McDonnell CH 3rd, Nadauld L, Dilaveri CA, Reid R, Marinac CR, Chung KC, Lopatin M, Fung ET, Klein EA (2023) Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Lancet 402:1251–60

    Article  PubMed  Google Scholar 

  62. Majumder S, Taylor WR, Foote PH, Berger CK, Wu CW, Mahoney DW, Bamlet WR, Burger KN, Postier N, de la Fuente J, Doering KA, Lidgard GP, Allawi HT, Petersen GM, Chari ST, Ahlquist DA, Kisiel JB (2021) High detection rates of pancreatic cancer across stages by plasma assay of novel methylated DNA markers and CA19-9. Clin Cancer Res 27:2523–32. https://doi.org/10.1158/078-0432.CCR-20-235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ben-Ami R, Wang QL, Zhang J, Supplee JG, Fahrmann JF, Lehmann-Werman R, Brais LK, Nowak J, Yuan C, Loftus M, Babic A, Irajizad E, Davidi T, Zick A, Hubert A, Neiman D, Piyanzin S, Gal-Rosenberg O, Horn A, Shemer R, Glaser B, Boos N, Jajoo K, Lee L, Clancy TE, Rubinson DA, Ng K, Chabot JA, Kastrinos F, Kluger M, Aguirre AJ, Jänne PA, Bardeesy N, Stanger B, O’Hara MH, Till J, Maitra A, Carpenter EL, Bullock AJ, Genkinger J, Hanash SM, Paweletz CP, Dor Y, Wolpin BM (2023) Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer. Gut 13:2023–331074

    Google Scholar 

  64. Mattox AK, Douville C, Wang Y, Popoli M, Ptak J, Silliman N, Dobbyn L, Schaefer J, Lu S, Pearlman AH, Cohen JD, Tie J, Gibbs P, Lahouel K, Bettegowda C, Hruban RH, Tomasetti C, Jiang P, Chan KCA, Lo YMD, Papadopoulos N, Kinzler KW, Vogelstein B (2023) The origin of highly elevated cell-free DNA in healthy individuals and patients with pancreatic, colorectal, lung, or ovarian cancer. Cancer Discov 13:2166–79. https://doi.org/10.1158/2159-8290.CD-21-1252

    Article  PubMed  PubMed Central  Google Scholar 

  65. Chan HT, Chin YM, Nakamura Y, Low SK (2020) Clonal hematopoiesis in liquid biopsy: from biological noise to valuable clinical implications. Cancers (Basel) 12:2277. https://doi.org/10.3390/cancers12082277

    Article  CAS  PubMed  Google Scholar 

  66. Martin-Alonso C, Tabrizi S, Xiong K, Blewett T, Sridhar S, Crnjac A, Patel S, An Z, Bekdemir A, Shea D, Wang ST, Rodriguez-Aponte S, Naranjo CA, Rhoades J, Kirkpatrick JD, Fleming HE, Amini AP, Golub TR, Love JC, Bhatia SN, Adalsteinsson VA (2024) Priming agents transiently reduce the clearance of cell-free DNA to improve liquid biopsies. Science 383:eadf2341. https://doi.org/10.1126/science.adf2341

    Article  CAS  PubMed  Google Scholar 

  67. Koopmann J, Rosenweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo CJ, Chan DW, Breit SN, Goggins M (2006) Serum markers in patients with resectable pancreatic adenocarcinoma: MIC-1 vs. CA19-9. Clin Cancer Res 15:442–6

    Article  Google Scholar 

  68. Kim J, Bamlet WR, Oberg AL, Chaffee KG, Donahue G, Cao XJ, Chari S, Garcia BA, Petersen GM, Zaret KS (2017) Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med 9:eaah5583

    Article  PubMed  PubMed Central  Google Scholar 

  69. Honda K, Katzke VA, Hüsing A, Okaya S, Shoji H, Onidani K, Olsen A, Tjønneland A, Overvad K, Weiderpass E, Vineis P, Muller D, Tsilidis K, Palli D, Pala V, Tumino R, Naccarati A, Panico S, Aleksandrova K, Boeing H, Bueno-de-Mesquita HB, Peeters PH, Trichopoulou A, Lagiou P, Khaw KT, Wareham N, Travis RC, Merino S, Duell EJ, Rodríguez-Barranco M, Chirlaque MD, Barricarte A, Rebours V, Boutron-Ruault MC, Romana Mancini F, Brennan P, Scelo G, Manjer J, Sund M, Öhlund D, Canzian F, Kaaks R (2019) CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation. Int J Cancer 144:1877–87

    Article  CAS  PubMed  Google Scholar 

  70. Sato Y, Kobayashi T, Nishiumi S, Okada A, Fujita T, Sanuki T, Kobayashi M, Asahara M, Adachi M, Sakai A, Shiomi H, Masuda A, Yoshida M, Takeuchi K, Kodama Y, Kutsumi H, Nagashima K, Honda K (2020) Prospective study using plasma apolipoprotein A2-isoforms to screen for high-risk status of pancreatic cancer. Cancers (Basel) 12:2625. https://doi.org/10.3390/cancers12092625

    Article  CAS  PubMed  Google Scholar 

  71. Stewart JD, Gilvarg C (1999) Determination of the activity of carboxypeptidase A in the blood of healthy human adults. Clin Chim Acta 281:19–28

    Article  CAS  PubMed  Google Scholar 

  72. Tanaka H, Tamura K, Abe T, Yoshida T, Macgregor-Das A, Dbouk M, Blackford AL, Borges M, Lennon AM, He J, Burkhart R, Canto MI, Goggins M (2021) Serum carboxypeptidase activity and genotype-stratified CA19-9 to detect early-stage pancreatic cancer. Clin Gastroenterol Hepatol 12:01094–6

    Google Scholar 

  73. Balasenthil S, Huang Y, Liu S, Marsh T, Chen J, Stass SA, KuKuruga D, Brand R, Chen NFM, Lee JJ, Srivastava S, Sen S, Killary AM (2017) A plasma biomarker panel to identify surgically resectable early stage pancreatic cancer. J Natl Cancer Inst 109:341

    Article  Google Scholar 

  74. Yu J, Ploner A, Kordes M, Löhr M, Nilsson M, de Maturana MEL, Estudillo L, Renz H, Carrato A, Molero X, Real FX, Malats N, Ye W (2021) Plasma protein biomarkers for early detection of pancreatic ductal adenocarcinoma. Int J Cancer 148:2048–58. https://doi.org/10.1002/ijc.33464

    Article  CAS  PubMed  Google Scholar 

  75. Katona BW, Worthington C, Clay D, Cincotta H, Ahmad NA, Ginsberg GG, Kochman ML, Brand RE (2023) Outcomes of the IMMray PanCan-d test in high-risk individuals undergoing pancreatic surveillance: pragmatic data and lessons learned. JCO Precis Oncol 7:e2300445. https://doi.org/10.1200/PO.23.00445

    Article  PubMed  Google Scholar 

  76. Boyd LNC, Ali M, Leeflang MMG, Treglia G, de Vries R, LeLarge TYS, Besselink MG, Giovannetti E, vanLaarhoven HWM, Kazemier G (2023) Diagnostic accuracy and added value of blood-based protein biomarkers for pancreatic cancer: A meta-analysis of aggregate and individual participant data. EClinicalMedicine 55:101747. https://doi.org/10.1016/j.eclinm.2022.101747

    Article  PubMed  Google Scholar 

  77. Fahrmann JF, Schmidt CM, Mao X, Irajizad E, Loftus M, Zhang J, Patel N, Vykoukal J, Dennison JB, Long JP, Do KA, Zhang J, Chabot JA, Kluger MD, Kastrinos F, Brais L, Babic A, Jajoo K, Lee LS, Clancy TE, Ng K, Bullock A, Genkinger J, Yip-Schneider MT, Maitra A, Wolpin BM, Hanash S (2021) Lead-time trajectory of CA19-9 as an anchor marker for pancreatic cancer early detection. Gastroenterology 160:1373–83.e6

    Article  CAS  PubMed  Google Scholar 

  78. Nené NR, Ney A, Nazarenko T, Blyuss O, Johnston HE, Whitwell HJ, Sedlak E, Gentry-Maharaj A, Apostolidou S, Costello E, Greenhalf W, Jacobs I, Menon U, Hsuan J, Pereira SP, Zaikin A, Timms JF (2023) Serum biomarker-based early detection of pancreatic ductal adenocarcinomas with ensemble learning. Commun Med (Lond) 3:10

    Article  PubMed  Google Scholar 

  79. Nakamura K, Zhu Z, Roy S, Jun E, Han H, Munoz RM, Nishiwada S, Sharma G, Cridebring D, Zenhausern F, Kim S, Roe DJ, Darabi S, Han IW, Evans DB, Yamada S, Demeure MJ, Becerra C, Celinski SA, Borazanci E, Tsai S, Kodera Y, Park JO, Bolton JS, Wang X, Kim SC, Von Hoff D, Goel A (2022) An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: a multicenter cohort study. Gastroenterology 163:1252–66.e2

    Article  CAS  PubMed  Google Scholar 

  80. Xu C, Jun E, Okugawa Y, Toiyama Y, Borazanci E, Bolton J, Taketomi A, Kim SC, Shang D, Von Hoff D, Zhang G, Goel A (2024) A circulating panel of circRNA biomarkers for the noninvasive and early detection of pancreatic ductal adenocarcinoma. Gastroenterology 166:178–90.e16. https://doi.org/10.1053/j.gastro.2023.09.050

    Article  CAS  PubMed  Google Scholar 

  81. Hinestrosa JP, Kurzrock R, Lewis JM, Schork NJ, Schroeder G, Kamat AM, Lowy AM, Eskander RN, Perrera O, Searson D, Rastegar K, Hughes JR, Ortiz V, Clark I, Balcer HI, Arakelyan L, Turner R, Billings PR, Adler MJ, Lippman SM, Krishnan R (2022) Early-stage multi-cancer detection using an extracellular vesicle protein-based blood test. Commun Med (Lond) 2:29. https://doi.org/10.1038/s43856-022-00088-6

    Article  CAS  PubMed  Google Scholar 

  82. Yang KS, Im H, Hong S, Pergolini I, Del Castillo AF, Wang R, Clardy S, Huang CH, Pille C, Ferrone S, Yang R, Castro CM, Lee H, Del Castillo CF, Weissleder R (2017) Multiparametric plasma EV profiling facilitates diagnosis of pancreatic malignancy. Sci Transl Med 9:3226

    Article  Google Scholar 

  83. Yang KS, Ciprani D, O’Shea A, Liss AS, Yang R, Fletcher-Mercaldo S, Mino-Kenudson M, Fernández-Del Castillo C, Weissleder R (2021) Extracellular vesicle analysis allows for identification of invasive IPMN. Gastroenterology 160:1345–58.e11

    Article  CAS  PubMed  Google Scholar 

  84. Kohi S, Macgregor-Das A, Dbouk M, Yoshida T, Chuidian M, Abe T, Borges M, Lennon AM, Shin EJ, Canto MI, Goggins M (2022) Alterations in the duodenal fluid microbiome of patients with pancreatic cancer. Clin Gastroenterol Hepatol 20:e196–e227. https://doi.org/10.1016/j.cgh.2020.11.006

    Article  CAS  PubMed  Google Scholar 

  85. Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G, Gigi E, Meltser A, Douglas GM, Kamer I, Gopalakrishnan V, Dadosh T, Levin-Zaidman S, Avnet S, Atlan T, Cooper ZA, Arora R, Cogdill AP, Khan MAW, Ologun G, Bussi Y, Weinberger A, Lotan-Pompan M, Golani O, Perry G, Rokah M, Bahar-Shany K, Rozeman EA, Blank CU, Ronai A, Shaoul R, Amit A, Dorfman T, Kremer R, Cohen ZR, Harnof S, Siegal T, Yehuda-Shnaidman E, Gal-Yam EN, Shapira H, Baldini N, Langille MGI, Ben-Nun A, Kaufman B, Nissan A, Golan T, Dadiani M, Levanon K, Bar J, Yust-Katz S, Barshack I, Peeper DS, Raz DJ, Segal E, Wargo JA, Sandbank J, Shental N, Straussman R (2020) The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368:973–80. https://doi.org/10.1126/science.aay9189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Narunsky-Haziza L, Sepich-Poore GD, Livyatan I, Asraf O, Martino C, Nejman D, Gavert N, Stajich JE, Amit G, González A, Wandro S, Perry G, Ariel R, Meltser A, Shaffer JP, Zhu Q, Balint-Lahat N, Barshack I, Dadiani M, Gal-Yam EN, Patel SP, Bashan A, Swafford AD, Pilpel Y, Knight R, Straussman R (2022) Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell 185:3789–806.e17. https://doi.org/10.1016/j.cell.2022.09.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Poore GD, Kopylova E, Zhu Q, Carpenter C, Fraraccio S, Wandro S, Kosciolek T, Janssen S, Metcalf J, Song SJ, Kanbar J, Miller-Montgomery S, Heaton R, McKay R, Patel SP, Swafford AD, Knight R (2020) Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 579:567–74. https://doi.org/10.1038/s41586-020-2095-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Gihawi A, Ge Y, Lu J, Puiu D, Xu A, Cooper CS, Brewer DS, Pertea M, Salzberg SL (2023) Major data analysis errors invalidate cancer microbiome findings. mBio 14:e0160723. https://doi.org/10.1128/mbio.01607-23

    Article  CAS  PubMed  Google Scholar 

  89. Nagata N, Nishijima S, Kojima Y, Hisada Y, Imbe K, Miyoshi-Akiyama T, Suda W, Kimura M, Aoki R, Sekine K, Ohsugi M, Miki K, Osawa T, Ueki K, Oka S, Mizokami M, Kartal E, Schmidt TSB, Molina-Montes E, Estudillo L, Malats N, Trebicka J, Kersting S, Langheinrich M, Bork P, Uemura N, Itoi T, Kawai T (2022) Metagenomic identification of microbial signatures predicting pancreatic cancer from a multinational study. Gastroenterology 163:222–38. https://doi.org/10.1053/j.gastro.2022.03.054

    Article  CAS  PubMed  Google Scholar 

  90. Kartal E, Schmidt TSB, Molina-Montes E, Rodríguez-Perales S, Wirbel J, Maistrenko OM, Akanni WA, Alashkar Alhamwe B, Alves RJ, Carrato A, Erasmus HP, Estudillo L, Finkelmeier F, Fullam A, Glazek AM, Gómez-Rubio P, Hercog R, Jung F, Kandels S, Kersting S, Langheinrich M, Márquez M, Molero X, Orakov A, Van Rossum T, Torres-Ruiz R, Telzerow A, Zych K, Benes V, Zeller G, Trebicka J, Real FX, Malats N, Bork P (2022) A faecal microbiota signature with high specificity for pancreatic cancer. Gut 71:1359–72

    Article  CAS  PubMed  Google Scholar 

  91. Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM (2005) Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 129:504–11

    Article  PubMed  Google Scholar 

  92. Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST (2008) Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology 134:981–7

    Article  CAS  PubMed  Google Scholar 

  93. Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzese JL (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66:1103–10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Setiawan VW, Stram DO, Porcel J, Chari ST, Maskarinec G, Le Marchand L, Wilkens LR, Haiman CA, Pandol SJ, Monroe KR (2019) Pancreatic cancer following incident diabetes in African Americans and Latinos: the multiethnic cohort. J Natl Cancer Inst 111:27–33

    Article  PubMed  Google Scholar 

  95. Huang BZ, Pandol SJ, Jeon CY, Chari ST, Sugar CA, Chao CR, Zhang ZF, Wu BU, Setiawan VW (2020) New-onset diabetes, longitudinal trends in metabolic markers, and risk of pancreatic cancer in a heterogeneous population. Clin Gastroenterol Hepatol 18:1812–21.e7

    Article  CAS  PubMed  Google Scholar 

  96. Sharma A, Kandlakunta H, Nagpal SJS, Feng Z, Hoos W, Petersen GM, Chari ST (2018) Model to determine risk of pancreatic cancer in patients with new-onset diabetes. Gastroenterology 155:730–9.e3

    Article  PubMed  Google Scholar 

  97. Wu BU, Lustigova E, Chen Q, Dong EY, Maitra A, Chari ST, Feng Z, Rinaudo JA, Matrisian LM, Parker RA (2022) Imaging of the pancreas in new-onset diabetes: a prospective pilot study. Clin Transl Gastroenterol 13:e00478. https://doi.org/10.14309/ctg.0000000000000478

    Article  PubMed  PubMed Central  Google Scholar 

  98. Maitra A, Sharma A, Brand RE, Van Den Eeden SK, Fisher WE, Hart PA, Hughes SJ, Mather KJ, Pandol SJ, Park WG, Feng Z, Serrano J, Rinaudo JAS, Srivastava S, Chari ST (2018) Consortium for the Study of Chronic Pancreatitis D, Pancreatic C: a prospective study to establish a new-onset diabetes cohort: from the consortium for the study of chronic pancreatitis, diabetes, and pancreatic cancer. Pancreas 47:1244–8

    Article  PubMed  PubMed Central  Google Scholar 

  99. Yuan C, Kim J, Wang QL, Lee AA, Babic A, Amundadottir LT, Klein AP, Li D, McCullough ML, Petersen GM, Risch HA, Stolzenberg-Solomon RZ, Perez K, Ng K, Giovannucci EL, Stampfer MJ, Kraft P, Wolpin BM (2022) The age-dependent association of risk factors with pancreatic cancer. Ann Oncol 33:693–701. https://doi.org/10.1016/j.annonc.2022.03.276

    Article  CAS  PubMed  Google Scholar 

  100. Zhang Y, Wang QL, Yuan C, Lee AA, Babic A, Ng K, Perez K, Nowak JA, Lagergren J, Stampfer MJ, Giovannucci EL, Sander C, Rosenthal MH, Kraft P, Wolpin BM (2023) Pancreatic cancer is associated with medication changes prior to clinical diagnosis. Nat Commun 14:2437. https://doi.org/10.1038/s41467-023-38088-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Chen W, Zhou B, Jeon CY, Xie F, Lin YC, Butler RK, Zhou Y, Luong TQ, Lustigova E, Pisegna JR, Wu BU (2023) Machine learning versus regression for prediction of sporadic pancreatic cancer. Pancreatology 27:00103–5

    Google Scholar 

  102. Placido D, Yuan B, Hjaltelin JX, Zheng C, Haue AD, Chmura PJ, Yuan C, Kim J, Umeton R, Antell G, Chowdhury A, Franz A, Brais L, Andrews E, Marks DS, Regev A, Ayandeh S, Brophy MT, Do NV, Kraft P, Wolpin BM, Rosenthal MH, Fillmore NR, Brunak S, Sander C (2023) A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories. Nat Med 8:023–02332

    Google Scholar 

  103. Jia K, Kundrot S, Palchuk MB, Warnick J, Haapala K, Kaplan ID, Rinard M, Appelbaum L (2023) A pancreatic cancer risk prediction model (Prism) developed and validated on large-scale US clinical data. EBioMedicine 98:104888. https://doi.org/10.1016/j.ebiom.2023.104888

    Article  PubMed  PubMed Central  Google Scholar 

  104. Springer S, Masica DL, Dal Molin M, Douville C, Thoburn CJ, Afsari B, Li L, Cohen JD, Thompson E, Allen PJ, Klimstra DS, Schattner MA, Schmidt CM, Yip-Schneider M, Simpson RE, Fernandez-Del Castillo C, Mino-Kenudson M, Brugge W, Brand RE, Singhi AD, Scarpa A, Lawlor R, Salvia R, Zamboni G, Hong SM, Hwang DW, Jang JY, Kwon W, Swan N, Geoghegan J, Falconi M, Crippa S, Doglioni C, Paulino J, Schulick RD, Edil BH, Park W, Yachida S, Hijioka S, van Hooft J, He J, Weiss MJ, Burkhart R, Makary M, Canto MI, Goggins MG, Ptak J, Dobbyn L, Schaefer J, Sillman N, Popoli M, Klein AP, Tomasetti C, Karchin R, Papadopoulos N, Kinzler KW, Vogelstein B, Wolfgang CL, Hruban RH, Lennon AM (2019) A multimodality test to guide the management of patients with a pancreatic cyst. Sci Transl Med 11:4772. https://doi.org/10.1126/scitranslmed.aav4772

    Article  CAS  Google Scholar 

  105. Paniccia A, Polanco PM, Boone BA, Wald AI, McGrath K, Brand RE, Khalid A, Kubiliun N, O’Broin-Lennon AM, Park WG, Klapman J, Tharian B, Inamdar S, Fasanella K, Nasr J, Chennat J, Das R, DeWitt J, Easler JJ, Bick B, Singh H, Fairley KJ, Sarkaria S, Sawas T, Skef W, Slivka A, Tavakkoli A, Thakkar S, Kim V, Vanderveldt HD, Richardson A, Wallace MB, Brahmbhatt B, Engels M, Gabbert C, Dugum M, El-Dika S, Bhat Y, Ramrakhiani S, Bakis G, Rolshud D, Millspaugh G, Tielleman T, Schmidt C, Mansour J, Marsh W, Ongchin M, Centeno B, Monaco SE, Ohori NP, Lajara S, Thompson ED, Hruban RH, Bell PD, Smith K, Permuth JB, Vandenbussche C, Ernst W, Grupillo M, Kaya C, Hogg M, He J, Wolfgang CL, Lee KK, Zeh H, Zureikat A, Nikiforova MN, Singhi AD (2023) Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts. Gastroenterology 164:117–33 e7

    Article  Google Scholar 

  106. Hata T, Dal Molin M, Hong SM, Tamura K, Suenaga M, Yu J, Sedogawa H, Weiss MJ, Wolfgang CL, Lennon AM, Hruban RH, Goggins MG (2017) Predicting the grade of dysplasia of pancreatic cystic neoplasms using cyst fluid DNA methylation markers. Clin Cancer Res 23:3935–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yip-Schneider MT, Wu H, Dumas RP, Hancock BA, Agaram N, Radovich M, Schmidt CM (2014) Vascular endothelial growth factor, a novel and highly accurate pancreatic fluid biomarker for serous pancreatic cysts. J Am Coll Surg 218:608–17

    Article  PubMed  Google Scholar 

  108. Das KK, Geng X, Brown JW, Morales-Oyarvide V, Huynh T, Pergolini I, Pitman MB, Ferrone C, Al Efishat M, Haviland D, Thompson E, Wolfgang C, Lennon AM, Allen P, Lillemoe KD, Fields RC, Hawkins WG, Liu J, Castillo CF, Das KM, Mino-Kenudson M (2019) cross validation of the monoclonal antibody Das-1 in identification of high-risk mucinous pancreatic cystic lesions. Gastroenterology 157:720–30.e2. https://doi.org/10.1053/j.gastro.2019.05.014

    Article  CAS  PubMed  Google Scholar 

  109. Jabbar KS, Verbeke C, Hyltander AG, Sjovall H, Hansson GC, Sadik R (2014) Proteomic mucin profiling for the identification of cystic precursors of pancreatic cancer. J Natl Cancer Inst 106:439

    Article  Google Scholar 

  110. Jabbar KS, Arike L, Verbeke CS, Sadik R, Hansson GC (2017) Highly accurate identification of cystic precursor lesions of pancreatic cancer through targeted mass spectrometry: a phase IIc diagnostic study. J Clin Oncol 36:367–375

    Article  PubMed  PubMed Central  Google Scholar 

  111. Zikos T, Pham K, Bowen R, Chen AM, Banerjee S, Friedland S, Dua MM, Norton JA, Poultsides GA, Visser BC, Park WG (2015) Cyst fluid glucose is rapidly feasible and accurate in diagnosing mucinous pancreatic cysts. Am J Gastroenterol 110:909–14

    Article  PubMed  Google Scholar 

  112. Hata T, Dal Molin M, Suenaga M, Yu J, Pittman M, Weiss MJ, Canto M, Wolfgang CL, Lennon AM, Hruban RH, Goggins MG (2016) Cyst fluid telomerase activity predicts the histologic grade of cystic neoplasms of the pancreas. Clin Cancer Res 22:5141–5151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hata T, Dal Molin M, McGregor-Das A, Song TJ, Wolfgang C, Eshleman JR, Hruban RH, Goggins M (2018) Simple detection of telomere fusions in pancreatic cancer, intraductal papillary mucinous neoplasm, and pancreatic cyst fluid. J Mol Diagn 20:46–55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kwan MC, Pitman MB, Fernandez-Del Castillo C, Zhang ML (2024) Revisiting the performance of cyst fluid carcinoembryonic antigen as a diagnostic marker for pancreatic mucinous cysts: a comprehensive 20-year institutional review. Gut 9:2023–331138

    Google Scholar 

  115. Singhi AD, McGrath K, Brand RE, Khalid A, Zeh HJ, Chennat JS, Fasanella KE, Papachristou GI, Slivka A, Bartlett DL, Dasyam AK, Hogg M, Lee KK, Marsh JW, Monaco SE, Ohori NP, Pingpank JF, Tsung A, Zureikat AH, Wald AI, Nikiforova MN (2018) Preoperative next-generation sequencing of pancreatic cyst fluid is highly accurate in cyst classification and detection of advanced neoplasia. Gut 67:2131–41

    Article  CAS  PubMed  Google Scholar 

  116. Springer S, Wang Y, Dal Molin M, Masica DL, Jiao Y, Kinde I, Blackford A, Raman SP, Wolfgang CL, Tomita T, Niknafs N, Douville C, Ptak J, Dobbyn L, Allen PJ, Klimstra DS, Schattner MA, Schmidt CM, Yip-Schneider M, Cummings OW, Brand RE, Zeh HJ, Singhi AD, Scarpa A, Salvia R, Malleo G, Zamboni G, Falconi M, Jang JY, Kim SW, Kwon W, Hong SM, Song KB, Kim SC, Swan N, Murphy J, Geoghegan J, Brugge W, Fernandez-Del Castillo C, Mino-Kenudson M, Schulick R, Edil BH, Adsay V, Paulino J, van Hooft J, Yachida S, Nara S, Hiraoka N, Yamao K, Hijioka S, van der Merwe S, Goggins M, Canto MI, Ahuja N, Hirose K, Makary M, Weiss MJ, Cameron J, Pittman M, Eshleman JR, Diaz LA Jr, Papadopoulos N, Kinzler KW, Karchin R, Hruban RH, Vogelstein B, Lennon AM (2015) A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology 149:1501–10

    Article  CAS  PubMed  Google Scholar 

  117. Haeberle L, Schramm M, Goering W, Frohn L, Driescher C, Hartwig W, Preissinger-Heinzel HK, Beyna T, Neuhaus H, Fuchs K, Keitel-Anselmino V, Knoefel WT, Esposito I (2021) Molecular analysis of cyst fluids improves the diagnostic accuracy of pre-operative assessment of pancreatic cystic lesions. Sci Rep 11:2901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Paniccia A, Polanco PM, Boone BA, Wald AI, McGrath K, Brand RE, Khalid A, Kubiliun N, O’Broin-Lennon AM, Park WG, Klapman J, Tharian B, Inamdar S, Fasanella K, Nasr J, Chennat J, Das R, DeWitt J, Easler JJ, Bick B, Singh H, Fairley KJ, Sarkaria S, Sawas T, Skef W, Slivka A, Tavakkoli A, Thakkar S, Kim V, Vanderveldt HD, Richardson A, Wallace MB, Brahmbhatt B, Engels M, Gabbert C, Dugum M, El-Dika S, Bhat Y, Ramrakhiani S, Bakis G, Rolshud D, Millspaugh G, Tielleman T, Schmidt C, Mansour J, Marsh W, Ongchin M, Centeno B, Monaco SE, Ohori NP, Lajara S, Thompson ED, Hruban RH, Bell PD, Smith K, Permuth JB, Vandenbussche C, Ernst W, Grupillo M, Kaya C, Hogg M, He J, Wolfgang CL, Lee KK, Zeh H, Zureikat A, Nikiforova MN, Singhi AD (2023) Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts. Gastroenterology 164:117–33.e7. https://doi.org/10.1053/j.gastro.2022.09.028

    Article  CAS  PubMed  Google Scholar 

  119. Matsubayashi H, Sato N, Brune K, Blackford AL, Hruban RH, Canto M, Yeo CJ, Goggins M (2005) Age- and disease-related methylation of multiple genes in nonneoplastic duodenum and in duodenal juice. Clin Cancer Res 11:573–83

    Article  CAS  PubMed  Google Scholar 

  120. Suenaga M, Sadakari Y, Almario JA, Borges M, Lennon AM, Shin EJ, Canto MI, Goggins M (2017) Using an endoscopic distal cap to collect pancreatic fluid from the ampulla (with video). Gastrointest Endosc 86:1152–6.e2

    Article  PubMed  PubMed Central  Google Scholar 

  121. Sadakari Y, Kanda M, Maitani K, Borges M, Canto MI, Goggins M (2014) Mutant KRAS and GNAS DNA concentrations in secretin-stimulated pancreatic fluid collected from the pancreatic duct and the duodenal lumen. Clin Transl Gastroenterol 5:e62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Eshleman JR, Norris AL, Sadakari Y, Debeljak M, Borges M, Harrington C, Lin E, Brant A, Barkley T, Almario JA, Topazian M, Farrell J, Syngal S, Lee JH, Yu J, Hruban RH, Kanda M, Canto MI, Goggins M (2015) KRAS and guanine nucleotide-binding protein mutations in pancreatic juice collected from the duodenum of patients at high risk for neoplasia undergoing endoscopic ultrasound. Clin Gastroenterol Hepatol 13(963–9):e4

    Google Scholar 

  123. Kanda M, Sadakari Y, Borges M, Topazian M, Farrell J, Syngal S, Lee J, Kamel I, Lennon AM, Knight S, Fujiwara S, Hruban RH, Canto MI, Goggins M (2013) Mutant TP53 in duodenal samples of pancreatic juice from patients with pancreatic cancer or high-grade dysplasia. Clin Gastroenterol Hepatol 11:719–30

    Article  CAS  PubMed  Google Scholar 

  124. Kanda M, Knight S, Topazian M, Syngal S, Farrell JJ, Lee J, Kamel I, Lennon AM, Borges M, Young A, Fujiwara S, Seike J, Eshleman J, Hruban RH, Canto MI, Goggins M (2013) Mutant GNAS detected in duodenal collections of secretin-stimulated pancreatic juice indicates the presence or emergence of pancreatic cysts. Gut 62:1024–33

    Article  CAS  PubMed  Google Scholar 

  125. Suenaga M, Yu J, Shindo K, Tamura K, Almario JA, Zaykoski C, Witmer PD, Fesharakizadeh S, Borges M, Lennon AM, Shin EJ, Canto MI, Goggins M (2018) Pancreatic juice mutation concentrations can help predict the grade of dysplasia in patients undergoing pancreatic surveillance. Clin Cancer Res 24:2963–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yu J, Sadakari Y, Shindo K, Suenaga M, Brant A, Almario JAN, Borges M, Barkley T, Fesharakizadeh S, Ford M, Hruban RH, Shin EJ, Lennon AM, Canto MI, Goggins M (2017) Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms. Gut 66:1677–87

    Article  CAS  PubMed  Google Scholar 

  127. Suenaga M, Dudley B, Karloski E, Borges M, Canto M, Brand RE, Goggins M (2018) The effect of pancreatic juice collection time on the detection of KRAS mutations. Pancreas 47:35–9

    Article  PubMed  PubMed Central  Google Scholar 

  128. Majumder S, Raimondo M, Taylor WR, Yab TC, Berger CK, Dukek BA, Cao X, Foote PH, Wu CW, Devens ME, Mahoney DW, Smyrk TC, Pannala R, Chari ST, Vege SS, Topazian MD, Petersen BT, Levy MJ, Rajan E, Gleeson FC, Abu Dayyeh B, Nguyen CC, Faigel DO, Woodward TA, Wallace MB, Petersen G, Allawi HT, Lidgard GP, Kisiel JB, Ahlquist DA (2020) Methylated DNA in pancreatic juice distinguishes patients with pancreatic cancer from controls. Clin Gastroenterol Hepatol 18:676–83.e3. https://doi.org/10.1016/j.cgh.2019.07.017

    Article  CAS  PubMed  Google Scholar 

  129. Matsubayashi H, Canto M, Sato N, Klein A, Abe T, Yamashita K, Yeo CJ, Kalloo A, Hruban R, Goggins M (2006) DNA methylation alterations in the pancreatic juice of patients with suspected pancreatic disease. Cancer Res 66:1208–17

    Article  CAS  PubMed  Google Scholar 

  130. Nesteruk K, Levink IJM, de Vries E, Visser IJ, Peppelenbosch MP, Cahen DL, Fuhler GM, Bruno MJ (2022) Extracellular vesicle-derived microRNAs in pancreatic juice as biomarkers for detection of pancreatic ductal adenocarcinoma. Pancreatology 22:626–35. https://doi.org/10.1016/j.pan.2022.04.010

    Article  CAS  PubMed  Google Scholar 

  131. Radon TP, Massat NJ, Jones R, Alrawashdeh W, Dumartin L, Ennis D, Duffy SW, Kocher HM, Pereira SP (2015) Identification of a three-biomarker panel in urine for early detection of pancreatic adenocarcinoma. Clin Cancer Res 21:3512–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Debernardi S, Blyuss O, Rycyk D, Srivastava K, Jeon CY, Cai H, Cai Q, Shu XO, Crnogorac-Jurcevic T (2023) Urine biomarkers enable pancreatic cancer detection up to 2 years before diagnosis. Int J Cancer 152:769–80. https://doi.org/10.1002/ijc.34287

    Article  CAS  PubMed  Google Scholar 

  133. Klein AP (2021) Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 18:493–502. https://doi.org/10.1038/s41575-021-00457-x

    Article  PubMed  PubMed Central  Google Scholar 

  134. Saba H, Goggins M (2022) Familial pancreatic cancer. Gastroenterol Clin N Am 51:561–75. https://doi.org/10.1016/j.gtc.2022.06.006

    Article  Google Scholar 

  135. Porter N, Laheru D, Lau B, He J, Zheng L, Narang A, Roberts NJ, Canto MI, Lennon AM, Goggins MG, Hruban RH, Klein AP (2022) Risk of pancreatic cancer in the long-term prospective follow-up of familial pancreatic cancer kindreds. J Natl Cancer Inst 114:1681–8

    Article  PubMed  PubMed Central  Google Scholar 

  136. Daly MB, Pal T, Maxwell KN, Churpek J, Kohlmann W, AlHilli Z, Arun B, Buys SS, Cheng H, Domchek SM, Friedman S, Giri V, Goggins M, Hagemann A, Hendrix A, Hutton ML, Karlan BY, Kassem N, Khan S, Khoury K, Kurian AW, Laronga C, Mak JS, Mansour J, McDonnell K, Menendez CS, Merajver SD, Norquist BS, Offit K, Rash D, Reiser G, Senter-Jamieson L, Shannon KM, Visvanathan K, Welborn J, Wick MJ, Wood M, Yurgelun MB, Dwyer MA, Darlow SD (2023) NCCN Guidelines® insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, Version 2.2024. J Natl Compr Canc Netw 21:1000–10. https://doi.org/10.6004/jnccn.2023.0051

    Article  CAS  PubMed  Google Scholar 

  137. Klein AP, Lindstrom S, Mendelsohn JB, Steplowski E, Arslan AA, Bueno-de-Mesquita HB, Fuchs CS, Gallinger S, Gross M, Helzlsouer K, Holly EA, Jacobs EJ, Lacroix A, Li D, Mandelson MT, Olson SH, Petersen GM, Risch HA, Stolzenberg-Solomon RZ, Zheng W, Amundadottir L, Albanes D, Allen NE, Bamlet WR, Boutron-Ruault MC, Buring JE, Bracci PM, Canzian F, Clipp S, Cotterchio M, Duell EJ, Elena J, Gaziano JM, Giovannucci EL, Goggins M, Hallmans G, Hassan M, Hutchinson A, Hunter DJ, Kooperberg C, Kurtz RC, Liu S, Overvad K, Palli D, Patel AV, Rabe KG, Shu XO, Slimani N, Tobias GS, Trichopoulos D, Van Den Eeden SK, Vineis P, Virtamo J, Wactawski-Wende J, Wolpin BM, Yu H, Yu K, Zeleniuch-Jacquotte A, Chanock SJ, Hoover RN, Hartge P, Kraft P (2013) An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS ONE 8:e72311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ke TM, Lophatananon A, Muir KR (2023) An integrative pancreatic cancer risk prediction model in the UK biobank. Biomedicines 11:3206

    Article  PubMed  PubMed Central  Google Scholar 

  139. Tamura K, Yu J, Hata T, Suenaga M, Shindo K, Abe T, MacGregor-Das A, Borges M, Wolfgang CL, Weiss MJ, He J, Canto MI, Petersen GM, Gallinger S, Syngal S, Brand RE, Rustgi A, Olson SH, Stoffel E, Cote ML, Zogopoulos G, Potash JB, Goes FS, McCombie RW, Zandi PP, Pirooznia M, Kramer M, Parla J, Eshleman JR, Roberts NJ, Hruban RH, Klein AP, Goggins M (2018) Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci USA 115:4767–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Irajizad E, Kenney A, Tang T, Vykoukal J, Wu R, Murage E, Dennison JB, Sans M, Long JP, Loftus M, Chabot JA, Kluger MD, Kastrinos F, Brais L, Babic A, Jajoo K, Lee LS, Clancy TE, Ng K, Bullock A, Genkinger JM, Maitra A, Do KA, Yu B, Wolpin BM, Hanash S, Fahrmann JF (2023) A blood-based metabolomic signature predictive of risk for pancreatic cancer. Cell Rep Med 4:101194. https://doi.org/10.1016/j.xcrm.2023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by NIH Grants (U01210170, R01CA176828), and by a Stand Up To Cancer-Lustgarten Foundation Pancreatic Cancer Interception Translational Cancer Research Grant (Grant Number: SU2C-AACR-DT25-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. SU2C research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. MG is the Sol Goldman Professor of Pancreatic Cancer Research.

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  1. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, 1550 Orleans Street, Baltimore, MD, 21231, USA

    Michael Goggins

  2. Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael Goggins

  3. Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael Goggins

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Goggins, M. The role of biomarkers in the early detection of pancreatic cancer. Familial Cancer (2024). https://doi.org/10.1007/s10689-024-00381-4

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