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Original Research Full Report: Basic and Translational—Pancreas| Volume 160, ISSUE 4, P1373-1383.e6, March 01, 2021

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection

Published:December 14, 2020DOI:https://doi.org/10.1053/j.gastro.2020.11.052

      Background & Aims

      There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established.

      Methods

      CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined.

      Results

      In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection.

      Conclusion

      CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

      Keywords

      Abbreviations used in this paper:

      AUC (area under the curve), CI (confidence interval), CP (chronic pancreatitis), CUMC (Columbia University Irving Medical Center), DFCI/BWH (Dana-Farber Cancer Institute/Brigham and Women’s Hospital), ELISA (enzyme-linked immunosorbent assay), IPMN (intraductal papillary mucinous neoplasms), PDAC (pancreatic ductal adenocarcinoma), PLCO (Prostate), Lung (Colorectal and Ovarian Cancer Screening Trial), ROC (receiver operating characteristic curve)
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      References

        • Pereira S.P.
        • Oldfield L.
        • Ney A.
        • et al.
        Early detection of pancreatic cancer.
        Lancet Gastroenterol Hepatol. 2020; 5: 698-710
        • Ryan D.P.
        • Hong T.S.
        • Bardeesy N.
        Pancreatic adenocarcinoma.
        N Engl J Med. 2014; 371: 1039-1049
        • Kleeff J.
        • Korc M.
        • Apte M.
        • et al.
        Pancreatic cancer.
        Nat Rev Dis Primers. 2016; 2: 16022
        • Neoptolemos J.P.
        • Kleeff J.
        • Michl P.
        • et al.
        Therapeutic developments in pancreatic cancer: current and future perspectives.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 333-348
        • Cloyd J.M.
        • Katz M.H.
        • Prakash L.
        • et al.
        Preoperative therapy and pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a 25-year single-institution experience.
        J Gastrointest Surg. 2017; 21: 164-174
        • Murphy J.E.
        • Wo J.Y.
        • Ryan D.P.
        • et al.
        Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial.
        JAMA Oncol. 2018; 4: 963-969
        • Blackford A.L.
        • Canto M.I.
        • Klein A.P.
        • et al.
        Recent trends in the incidence and survival of Stage 1A pancreatic cancer: A Surveillance, Epidemiology, and End Results analysis.
        J Natl Cancer Inst. 2020; 112: 1162-1169
        • Steinberg W.M.
        • Gelfand R.
        • Anderson K.K.
        • et al.
        Comparison of the sensitivity and specificity of the CA19–9 and carcinoembryonic antigen assays in detecting cancer of the pancreas.
        Gastroenterology. 1986; 90: 343-349
        • Guo M.
        • Luo G.
        • Lu R.
        • et al.
        Distribution of Lewis and Secretor polymorphisms and corresponding CA19–9 antigen expression in a Chinese population.
        FEBS Open Bio. 2017; 7: 1660-1671
        • Liu C.
        • Deng S.
        • Jin K.
        • et al.
        Lewis antigen-negative pancreatic cancer: an aggressive subgroup.
        Int J Oncol. 2020; 56: 900-908
        • Kim S.
        • Park B.K.
        • Seo J.H.
        • et al.
        Carbohydrate antigen 19–9 elevation without evidence of malignant or pancreatobiliary diseases.
        Sci Rep. 2020; 10: 8820
        • Ballehaninna U.K.
        • Chamberlain R.S.
        The clinical utility of serum CA 19–9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal.
        J Gastrointest Oncol. 2012; 3: 105-119
        • Ballehaninna U.K.
        • Chamberlain R.S.
        Serum CA 19–9 as a biomarker for pancreatic cancer-a comprehensive review.
        Indian J Surg Oncol. 2011; 2: 88-100
        • Poruk K.E.
        • Gay D.Z.
        • Brown K.
        • et al.
        The clinical utility of CA 19–9 in pancreatic adenocarcinoma: diagnostic and prognostic updates.
        Curr Mol Med. 2013; 13: 340-351
        • Cohen J.D.
        • Javed A.A.
        • Thoburn C.
        • et al.
        Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers.
        Proc Natl Acad Sci U S A. 2017; 114: 10202-10207
        • Cohen J.D.
        • Li L.
        • Wang Y.
        • et al.
        Detection and localization of surgically resectable cancers with a multi-analyte blood test.
        Science. 2018; 359: 926-930
        • Fahrmann J.F.
        • Bantis L.E.
        • Capello M.
        • et al.
        A plasma-derived protein-metabolite multiplexed panel for early-stage pancreatic cancer.
        J Natl Cancer Inst. 2019; 111: 372-379
        • Capello M.
        • Bantis L.E.
        • Scelo G.
        • et al.
        Sequential validation of blood-based protein biomarker candidates for early-stage pancreatic cancer.
        J Natl Cancer Inst. 2017; 109: djw266
        • Fahrmann J.F.
        • Mao X.
        • Irajizad E.
        • et al.
        Plasma-derived extracellular vesicles convey protein signatures that reflect pathophysiology in lung and pancreatic adenocarcinomas.
        Cancers (Basel). 2020; 12: 1147
        • Kobayashi M.
        • Katayama H.
        • Irajizad E.
        • et al.
        Proteome profiling uncovers an autoimmune response signature that reflects ovarian cancer pathogenesis.
        Cancers (Basel). 2020; 12: 485
        • Jacobs E.J.
        • Chanock S.J.
        • Fuchs C.S.
        • et al.
        Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan).
        Int J Cancer. 2010; 127: 1421-1428
        • Kirkegård J.
        • Mortensen F.V.
        • Cronin-Fenton D.
        Chronic pancreatitis and pancreatic cancer risk: a systematic review and meta-analysis.
        Am J Gastroenterol. 2017; 112: 1366-1372
        • Canto M.I.
        • Almario J.A.
        • Schulick R.D.
        • et al.
        Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance.
        Gastroenterology. 2018; 155: 740-751.e2
        • Sharma 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.e3
        • Aslanian H.R.
        • Lee J.H.
        • Canto M.I.
        AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review.
        Gastroenterology. 2020; 159 (538–362)
        • Kim J.
        • Yuan C.
        • Babic A.
        • et al.
        Genetic and circulating biomarker data improve risk prediction for pancreatic cancer in the general population.
        Cancer Epidemiol Biomarkers Prev. 2020; 29: 999-1008
        • O'Brien D.P.
        • Sandanayake N.S.
        • Jenkinson C.
        • et al.
        Serum CA19–9 is significantly upregulated up to 2 years before diagnosis with pancreatic cancer: implications for early disease detection.
        Clin Cancer Res. 2015; 21: 622-631
        • Honda K.
        • Katzke V.A.
        • Hüsing A.
        • et al.
        CA19–9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation.
        Int J Cancer. 2019; 144: 1877-1887
        • Nolen B.M.
        • Brand R.E.
        • Prosser D.
        • et al.
        Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study.
        PLoS One. 2014; 9e94928
        • Prorok P.C.
        • Andriole G.L.
        • Bresalier R.S.
        • et al.
        Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.
        Control Clin Trials. 2000; 21: 273s-309s
        • Fahrmann J.F.
        • Bantis L.E.
        • Capello M.
        • et al.
        A plasma-derived protein-metabolite multiplexed panel for early-stage pancreatic cancer.
        J Natl Cancer Inst. 2019; 111: 372-379
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Schlesselman J.J.
        Case–Control Studies.
        Oxford University Press, Oxford1982
        • Kovalchik S.A.
        • Tammemagi M.
        • Berg C.D.
        • et al.
        Targeting of low-dose CT screening according to the risk of lung-cancer death.
        N Engl J Med. 2013; 369: 245-254
        • Breslow N.E.
        • Day N.E.
        • Heseltine E.
        Statistical methods in cancer research.
        1. International Agency For Research on Cancer Scientific Publications, No.82 Lyon, France1980
        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • et al.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Rawla P.
        • Sunkara T.
        • Gaduputi V.
        Epidemiology of pancreatic cancer: global trends, etiology and risk factors.
        World J Oncol. 2019; 10: 10-27
        • Petersen G.M.
        Familial pancreatic cancer.
        Semin Oncol. 2016; 43: 548-553
        • Ohno E.
        • Hirooka Y.
        • Kawashima H.
        • et al.
        Natural history of pancreatic cystic lesions: a multicenter prospective observational study for evaluating the risk of pancreatic cancer.
        J Gastroenterol Hepatol. 2018; 33: 320-328
        • Pannala R.
        • Basu A.
        • Petersen G.M.
        • et al.
        New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer.
        Lancet Oncol. 2009; 10: 88-95
        • de Jong K.
        • Nio C.Y.
        • Hermans J.J.
        • et al.
        High prevalence of pancreatic cysts detected by screening magnetic resonance imaging examinations.
        Clin Gastroenterol Hepatol. 2010; 8: 806-811
        • Kromrey M.L.
        • Bülow R.
        • Hübner J.
        • et al.
        Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study.
        Gut. 2018; 67: 138-145
        • Soroida Y.
        • Sato M.
        • Hikita H.
        • et al.
        Pancreatic cysts in general population on ultrasonography: prevalence and development of risk score.
        J Gastroenterol. 2016; 51: 1133-1140
        • Lee K.S.
        • Sekhar A.
        • Rofsky N.M.
        • et al.
        Prevalence of incidental pancreatic cysts in the adult population on MR imaging.
        Am J Gastroenterol. 2010; 105: 2079-2084
        • Laffan T.A.
        • Horton K.M.
        • Klein A.P.
        • et al.
        Prevalence of unsuspected pancreatic cysts on MDCT.
        AJR Am J Roentgenol. 2008; 191: 802-807
        • Maitra A.
        • Fukushima N.
        • Takaori K.
        • et al.
        Precursors to invasive pancreatic cancer.
        Adv Anat Pathol. 2005; 12: 81-91
        • Choi S.H.
        • Park S.H.
        • Kim K.W.
        • et al.
        Progression of unresected intraductal papillary mucinous neoplasms of the pancreas to cancer: a systematic review and meta-analysis.
        Clin Gastroenterol Hepatol. 2017; 15: 1509-1520.e4
        • Tanaka M.
        • Fernandez-del Castillo C.
        • Adsay V.
        • et al.
        International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.
        Pancreatology. 2012; 12: 183-197
        • Tang R.S.
        • Weinberg B.
        • Dawson D.W.
        • et al.
        Evaluation of the guidelines for management of pancreatic branch-duct intraductal papillary mucinous neoplasm.
        Clin Gastroenterol Hepatol. 2008; 6 (quiz 719): 815-819
        • Jang J.Y.
        • Park T.
        • Lee S.
        • et al.
        Validation of international consensus guidelines for the resection of branch duct-type intraductal papillary mucinous neoplasms.
        Br J Surg. 2014; 101: 686-692
        • Khoury R.E.
        • Kabir C.
        • Maker V.K.
        • et al.
        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. 2018; 25: 1746-1751
        • Lennon A.M.
        • Buchanan A.H.
        • Kinde I.
        • et al.
        Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention.
        Science. 2020; 369eabb9601
        • Liu M.C.
        • Oxnard G.R.
        • Klein E.A.
        • et al.
        Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA.
        Ann Oncol. 2020; 31: 745-759
        • Bhat K.
        • Wang F.
        • Ma Q.
        • et al.
        Advances in biomarker research for pancreatic cancer.
        Curr Pharm Des. 2012; 18: 2439-2451