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Bl National Academy of Clinical Biochemistry (NACB) Guidelines for the Use of Tumor Markers in Pancreatic Ductal Adenocarcinoma
Michael Goggins 1-3*, Jens Koopmann1, Dawei Yang1, Marcia I. Canto2, Ralph H. Hruban1,3
Department of Pathology1 Medicine2, and Oncology3 The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MD 21205-2196, USA
*Sub-Committee Chair, to whom all comments should be addressed via e-mail to HYPERLINK "mailto:Frank.Wians@UTSouthwestern.edu" HYPERLINK "mailto:mgoggins@jhmi.edu" mgoggins@jhmi.edu , with copies to HYPERLINK "mailto:C.Sturgeon@ed.ac.uk" C.Sturgeon@ed.ac.uk and HYPERLINK "mailto:ediamandis@mtsinai.on.ca" ediamandis@mtsinai.on.ca
Key words: pancreatic cancer, CA19-9, tumor markers, guidelines
Abbreviations: AGA, American Gastroenterological Association; EGTM, European Group on Tumor Markers; ERCP, endoscopic retrograde cholangiopancreatograph; EUS, endoscopic ultrasound; FNA, fine needle aspirate; IPMN, intraductal papillary mucinous neoplasm; NCCN, National Comprehensive Cancer Network; PanIN, pancreatic intraepithelial neoplasia.
INTRODUCTION
Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death in men and women in the USA and has the lowest survival rate for any solid cancer ADDIN EN.CITE Association1999510American Gastroenterological Association1999American Gastroenterological Association medical position statement: Epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinomaGastroenterology11761463-1484Jemal2003730Jemal, A.Murray, T.Samuels, A.Ghafoor, A.Ward, E.Thun, M. J.2003Cancer statistics 2003CA Cancer J. Clin.5315-26(1, 2). Over 31,000 individuals are diagnosed with pancreatic cancer in the USA each year, of whom ~31,000 will die of the disease. Similar mortality figures are reported in the UK, with only 2-3% of patients surviving 5 years after a diagnosis of pancreatic cancer. One important reason for this poor survival is that only 10-15% of patients are diagnosed with small, resectable cancers ADDIN EN.CITE Association1999510American Gastroenterological Association1999American Gastroenterological Association medical position statement: Epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinomaGastroenterology11761463-1484(1). The lifetime risk of developing pancreatic cancer is ~1/150, and the median age at diagnosis is the mid 60s. However, the age-specific incidence of pancreatic cancer is low prior to the age of 50 where the annual incidence in the general population is less than 10 cases per 100,000 ADDIN EN.CITE DiMagno1999360AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological AssociationDiMagno, E. P.Reber, H. A.Tempero, M. A.*Adenocarcinoma/diagnosis/epidemiology/surgeryEnvironmentHumanNeoplasm Staging*Pancreatic Ducts*Pancreatic Neoplasms/*diagnosis/epidemiology/surgeryPrognosisRandomized Controlled TrialsRisk FactorsGastroenterology199911761464-84.(3).
The diagnosis of pancreatic cancer is usually suspected from complaints of progressive obstructive jaundice, profound weight loss and pain in the abdomen or mid-back. Chronic pancreatitis can be difficult to distinguish from pancreatic cancer with the use of clinical, imaging, and biochemical parameters. Less frequently, patients with pancreatic cancer can present with diabetes mellitus, thrombophlebitis migrans, depression, or evidence of metastatic disease. Generally, the diagnosis is established using computerized tomography (CT), endoscopic ultrasound (EUS) or ERCP (endoscopic retrograde cholangiopancreatography) with histological (or cytological) confirmation. If curative resection is considered, staging investigations using EUS or angiography are performed searching for evidence of metastases to lymph nodes, peritoneum, liver and vascular invasion of the splenic or portal vein. Helical CT with contrast usually provides good visualization of the peripancreatic vasculature without the need for formal angiography. A diagnosis of pancreatic cancer may be delayed in some patients for a variety of reasons including having non-specific symptoms, having a cancer that is small or that diffusely infiltrates the pancreas without forming a mass, delay in access to diagnostic services such as endoscopic ultrasound and fine needle aspiration, or due to the sub-optimal sensitivity of fine needle aspiration cytology ADDIN EN.CITE Rosty2002440Rosty, C.Goggins, M.2002Early detection of pancreatic carcinomaHematol. Oncol. Clin. North. Am.16137-52Association1999510American Gastroenterological Association1999American Gastroenterological Association medical position statement: Epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinomaGastroenterology11761463-1484(1, 4). Imaging and endoscopy can readily be used to diagnose unresectable lesions but are less effective at diagnosing small, surgically resectable cancers.
The management of pancreatic ductal adenocarcinoma depends on several factors including the patients symptoms, the performance status of the patient, the histological classification of the cancer, the stage of the disease, and the presence of complications. Surgery (Whipple resection for tumors of the pancreatic head) remains the only realistic curative modality for pancreatic cancer. The Whipple procedure involves the resection of the head of the pancreas, the duodenum, distal common bile duct, local lymph nodes and peripancreatic tissue. Operative mortality rates vary considerably with the experience of the surgeons and the number of patients served by the treating institution ADDIN EN.CITE Sosa19983670Sosa, J. A.Bowman, H. M.Gordon, T. A.Bass, E. B.Yeo, C. J.Lillemoe, K. D.Pitt, H. A.Tielsch, J. M.Cameron, J. L.Importance of hospital volume in the overall management of pancreatic cancerAgedCosts and Cost AnalysisCross-Sectional StudiesFemaleHospital CostsHospital MortalityHospitals/*statistics & numerical dataHumanLength of StayMaleMarylandMiddle AgePancreatic Neoplasms/*economics/mortality/*surgeryRiskSurgery/manpowerSurgical Procedures, Operative/*economics/*statistics & numerical dataTreatment OutcomeAnn Surg19982283429-38(5), but rates in expert centers are as low as 1 to 3%. Unfortunately, approximately 75% of individuals who undergo Whipple operations will die of their disease within 5 years, with a median survival of ~18 months. Many patients who undergo curative resection for pancreatic adenocarcinoma are offered adjuvant or neo-chemoradiotherapy ADDIN EN.CITE Yeo1997550Yeo, C. J.Abrams, R. A.Grochow, L. B.Sohn, T. A.Ord, S. E.Hruban, R. H.Zahurak, M. L.Dooley, W. C.Coleman, J.Sauter, P. K.Pitt, H. A.Lillemoe, K. D.Cameron, J. L.Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single- institution experienceAdenocarcinoma/drug therapy/mortality/radiotherapy/*surgeryAdultAgedAged, 80 and overChemotherapy, AdjuvantCombined Modality TherapyComparative StudyFemaleHumanMaleMiddle AgeMultivariate AnalysisPancreatic Neoplasms/drug therapy/mortality/radiotherapy/*surgery*PancreaticoduodenectomyPostoperative CareProspective StudiesRadiotherapy, AdjuvantSupport, U.S. Gov't, P.H.S.Survival RateAnn Surg19972255621-33; discussion 633-6Abrams19992120Abrams, R. A.Grochow, L. B.Chakravarthy, A.Sohn, T. A.Zahurak, M. L.Haulk, T. L.Ord, S.Hruban, R. H.Lillemoe, K. D.Pitt, H. A.Cameron, J. L.Yeo, C. J.Intensified adjuvant therapy for pancreatic and periampullary adenocarcinoma: survival results and observations regarding patterns of failure, radiotherapy dose and CA19-9 levelsAdenocarcinoma/blood/*drug therapy/mortality/*radiotherapyAgedAntimetabolites, Antineoplastic/therapeutic useChemotherapy, Adjuvant/methodsCommon Bile Duct Neoplasms/blood/*drug therapy/mortality/*radiotherapyCA-19-9 Antigen/*bloodDisease-Free SurvivalDuodenal Neoplasms/blood/drug therapy/mortality/radiotherapyFemaleFluorouracil/therapeutic useHumanMaleMiddle AgePancreatic Neoplasms/blood/*drug therapy/mortality/*radiographyTreatment FailureTumor Markers, Biological/*blood*Vater's AmpullaInt J Radiat Oncol Biol Phys19994451039-46(6, 7). Recent controversial studies suggest that radiotherapy may not be effective for most patients ADDIN EN.CITE Choti200414470Adjuvant therapy for pancreatic cancer--the debate continuesChoti, M. A.Chemotherapy, AdjuvantHumansPancreatic Neoplasms/*drug therapy/*radiotherapy/surgeryRadiotherapy, AdjuvantRandomized Controlled Trials/methodsResearch DesignN Engl J Med2004350121249-51.Neoptolemos200414480A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancerNeoptolemos, J. P.Stocken, D. D.Friess, H.Bassi, C.Dunn, J. A.Hickey, H.Beger, H.Fernandez-Cruz, L.Dervenis, C.Lacaine, F.Falconi, M.Pederzoli, P.Pap, A.Spooner, D.Kerr, D. J.Buchler, M. W.AgedAntimetabolites, Antineoplastic/adverse effects/*therapeutic useChemotherapy, Adjuvant/adverse effectsFemaleFluorouracil/adverse effects/*therapeutic useHumansMaleMiddle AgedNeoplasm MetastasisNeoplasm Recurrence, LocalPancreatic Neoplasms/*drug therapy/mortality/*radiotherapy/surgeryPrognosisProportional Hazards ModelsQuality of LifeRadiotherapy DosageRadiotherapy, Adjuvant/adverse effectsResearch Support, Non-U.S. Gov'tSurvival AnalysisN Engl J Med2004350121200-10.(8, 9). Precancerous lesions can also present with symptoms and can appear as pancreatic solid and cystic masses including intraductal papillary mucinous neoplasms (IPMNs). It is important to diagnose these neoplasms which can present in the same way as invasive pancreatic cancers but are usually curable with surgery ADDIN EN.CITE Sohn200111330Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entitySohn, T. A.Yeo, C. J.Cameron, J. L.Iacobuzio-Donahue, C. A.Hruban, R. H.Lillemoe, K. D.Adenocarcinoma, Mucinous/mortality/*pathology/surgeryAdultAgedAged, 80 and overCarcinoma, Papillary/mortality/*pathology/surgeryFemaleHumanImmunohistochemistryMaleMiddle AgePancreatectomyPancreatic Neoplasms/mortality/*pathology/surgeryPancreaticoduodenectomyRetrospective StudiesSupport, U.S. Gov't, P.H.S.Survival RateAnn Surg20012343313-21; discussion 321-2.(10).
There are few chemotherapeutic agents that are active against pancreatic cancer ADDIN EN.CITE Kroep19992730Kroep, J. R.Pinedo, H. M.van Groeningen, C. J.Peters, G. J.Experimental drugs and drug combinations in pancreatic cancerAntineoplastic Agents, Combined/*therapeutic useHumanPancreatic Neoplasms/*drug therapyAnn Oncol199910Suppl 4234-8van Groeningen19992720van Groeningen, C. J.Intravenous and intra-arterial chemotherapeutic possibilities in biliopancreatic cancerAntineoplastic Agents/*administration & dosageBiliary Tract Neoplasms/*drug therapyFluorouracil/administration & dosageHumanInfusions, Intra-ArterialInfusions, IntravenousPancreatic Neoplasms/*drug therapyAnn Oncol199910Suppl 4305-7van Riel19992760van Riel, J. M.van Groeningen, C. J.Pinedo, H. M.Giaccone, G.Current chemotherapeutic possibilities in pancreaticobiliary cancerBiliary Tract Neoplasms/*drug therapyCombined Modality TherapyHumanPancreatic Neoplasms/*drug therapyAnn Oncol199910Suppl 4157-61Rich19992740Rich, T. A.Chemoradiation for pancreatic and biliary cancer: current status of RTOG studiesAntineoplastic Agents/*therapeutic useBiliary Tract Neoplasms/*therapyChemotherapy, AdjuvantCombined Modality TherapyHumanPancreatic Neoplasms/*therapyRadiotherapy, AdjuvantAnn Oncol199910Suppl 4231-3Veenhof19992750Veenhof, C. H.Pancreatic endocrine tumours, immunotherapy and gene therapy: chemotherapy and interferon therapy of endocrine tumoursApudoma/*drug therapyHumanInterferons/*therapeutic usePancreatic Neoplasms/*drug therapyAnn Oncol199910Suppl 4185-7(11-15). Agents such as gemcitabine and 5-fluorouracil (5FU) are effective in only 10-20% of patients with the disease. Other chemotherapeutics under investigation include 5FU prodrugs (capecitabine and S-1), rubitecan (9-nitrocamptothecin, RFS 2000) and taxotere. A number of experimental approaches are being tried, including tumor vaccines ADDIN EN.CITE Jaffee1998540Jaffee, E. M.Abrams, R.Cameron, J.Donehower, R.Duerr, M.Gossett, J.Greten, T. F.Grochow, L.Hruban, R.Kern, S.Lillemoe, K. D.O'Reilly, S.Pardoll, D.Pitt, H. A.Sauter, P.Weber, C.Yeo, C.A phase I clinical trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene for the treatment of pancreatic adenocarcinomaAdenocarcinoma/genetics/*therapyCancer Vaccines/*therapeutic useClinical ProtocolsGene Therapy/*methods*Granulocyte-Macrophage Colony-Stimulating Factor/geneticsHumanPancreatic Neoplasms/genetics/*therapyPatient SelectionVaccinationHum Gene Ther19989131951-71(16), but their efficacy has yet to be established.
Since most patients will die of their disease, it is important to improve patient quality of life as much as possible. Measures to alleviate pain are usually necessary, generally opiate analgesia frequently given in the form of infusion pump. Destruction of the nerves around the pancreas (celiac axis nerve block) achieved by the percutaneous, EUS-guided or intra-operative injection of 100% alcohol, provides pain relief for many patients ADDIN EN.CITE Sohn19992710Sohn, T. A.Lillemoe, K. D.Cameron, J. L.Huang, J. J.Pitt, H. A.Yeo, C. J.Surgical palliation of unresectable periampullary adenocarcinoma in the 1990sAdenocarcinoma/mortality/*surgeryAdultAgedAged, 80 and overCommon Bile Duct Neoplasms/mortality/*surgeryDuodenal Neoplasms/mortality/surgeryFemaleHumanMaleMiddle Age*Palliative CarePancreatic Neoplasms/mortality/*surgeryPancreaticoduodenectomyPostoperative ComplicationsPrognosisRetrospective StudiesSurvival Rate*Vater's AmpullaJ Am Coll Surg19991886658-66; discussion 666-9Brown19972560Brown, D. L.Caswell, R. E.Wong, G. Y.Nauss, L. A.Offord, K. P.Referral of patients with pain from pancreatic cancer for neurolytic celiac plexus blockAbdominal Pain/*etiology/*therapyAged*Autonomic Nerve Block/methods*Celiac PlexusFemaleHealth Services AccessibilityHumanMaleMedical RecordsMiddle AgePancreatic Neoplasms/*complicationsReferral and ConsultationRetrospective StudiesMayo Clin Proc1997729831-4Wiersema19962570Wiersema, M. J.Wiersema, L. M.Endosonography-guided celiac plexus neurolysisAbdominal Neoplasms/physiopathologyAged*Anesthetics, LocalAutonomic Nerve Block/*methods*Bupivacaine*Celiac Plexus*Endosonography*EthanolFemaleHumanMalePain MeasurementPain, Intractable/*therapyPancreatic Neoplasms/physiopathologyGastrointest Endosc1996446656-62Russell19992580Russell, R. C.Palliation of pain and jaundice: an overviewHumanJaundice/*therapyPain, Intractable/*therapy*Palliative CarePancreatic Neoplasms/*therapyAnn Oncol199910Suppl 4165-9(17-20). Stenting the main pancreatic duct has also been tried to relieve pain from elevated intraductal pressure in patients with pancreatic cancer ADDIN EN.CITE Tham200014460Pancreatic duct stents for "obstructive type" pain in pancreatic malignancyTham, T. C.Lichtenstein, D. R.Vandervoort, J.Wong, R. C.Slivka, A.Banks, P. A.Yim, H. B.Carr-Locke, D. L.Adenocarcinoma/radiography/*therapyAgedAged, 80 and overConstriction, Pathologic/radiography/therapyDuodenoscopesFemaleHumansMaleMelanoma/radiography/secondary/therapyMiddle AgedPain Measurement*Palliative Care*Pancreatic Ducts/radiographyPancreatic Neoplasms/radiography/secondary/*therapyProsthesis DesignSkin Neoplasms/radiography/therapy*StentsTreatment OutcomeAm J Gastroenterol2000954956-60.(21). Weight loss is a common problem which is usually multifactorial and is often refractory to treatment ADDIN EN.CITE Body19992590Body, J. J.The syndrome of anorexia-cachexiaAnorexia/etiology/pathology/*therapyCachexia/etiology/pathology/*therapyHumanNeoplasms/complicationsSyndromeCurr Opin Oncol1999114255-60(22). Anorexia, maldigestion and cachexia are important factors. Pancreatic enzymes and appetite stimulants may help. Of the many agents tried to combat cachexia, fish oils appear promising in early clinical trials ADDIN EN.CITE Barber19991620Barber, M. D.Ross, J. A.Voss, A. C.Tisdale, M. J.Fearon, K. C.The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer [In Process Citation]Br J Cancer199981180-6(23). In the laboratory, fish oils appear to block the effects of cancer on muscle and fat wasting.
Many patients with pancreatic cancer will die of the complications of common bile duct obstruction. Biliary drainage can relieve symptoms and is achieved with biliary stents introduced during ERCP or percutaneously (percutaneous transhepatic cholangiography, PTC). Biliary stents can be placed as an outpatient procedure with minimal patient discomfort. Unfortunately, these stents invariably block due to progressive tumor growth, necessitating removal and replacement of the existing stent.
Since 15-40% of patients with a resectable pancreatic cancer survive 5 years after surgical resection ADDIN EN.CITE Yeo199520Yeo, C. J.Cameron, J. L.Lillemoe, K. D.Sitzmann, J. V.1995Pancreaticoduodenectomy for cancer of the head of the pancreas:201 patientsAnn. Surg.2216721-31(24), the earlier diagnosis of pancreatic cancer could save lives. Indeed, Canto et al. have shown that EUS based screening of individuals whose family history indicates that they have an increased risk of developing pancreatic cancer can detect early (non-invasive) pancreatic neoplasms ADDIN EN.CITE Canto MI200312260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2003Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21Canto MI12260Canto MI,, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2004Screening for pancreatic neoplasia in high risk individualsClin Gastro Hepatol2606-21Canto MI12260Canto MI,, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2004Screening for pancreatic neoplasia in high risk individualsClin Gastro Hepatol2606-21Klein200412670Prospective risk of pancreatic cancer in familial pancreatic cancer kindredsKlein, A. P.Brune, K. A.Petersen, G. M.Goggins, M.Tersmette, A. C.Offerhaus, G. J.Griffin, C.Cameron, J. L.Yeo, C. J.Kern, S.Hruban, R. H.Cancer Res20046472634-8.Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55Canto MI200312260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2003Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55 ADDIN EN.CITE Canto MI200312260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2003Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21Canto MI12260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21Canto MI12260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21Klein200412670Prospective risk of pancreatic cancer in familial pancreatic cancer kindredsKlein, A. P.Brune, K. A.Petersen, G. M.Goggins, M.Tersmette, A. C.Offerhaus, G. J.Griffin, C.Cameron, J. L.Yeo, C. J.Kern, S.Hruban, R. H.Cancer Res20046472634-8.Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55Canto MI200312260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2003Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55(25-28). The role of screening using imaging tests is still under investigation. However, screening using EUS and spiral CT scanning (in the context of counseling about cancer risk and inherited susceptibility) appears to be effective at detecting, treating and probably curing early pancreatic cancers and precancerous lesions (intraductal papillary mucinous neoplasms), although this information is based on relatively small numbers of individuals ADDIN EN.CITE Canto MI200312260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2003Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21M. Canto200413250M. Canto, M. Goggins, C. Yeo, EK Fishman, S. Jagannath, S. Kantsevoy, C. Griffin, J. Axilbund, K. Brune, S. Ali, J. Richman, G. Petersen, F. Giardiello, R Hruban, AN Kalloo2004Screening for pancreatic neoplasia in asymptomatic high risk individuals: A prospective, controlled study.AACR/Lustgarten Foundation Pancreatic Cancer Research Meeting, San Francisco, June 25, 2004Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55(25, 28, 29). Potential candidates for screening include individuals who have multiple first-degree relatives with familial pancreatic cancer ADDIN EN.CITE Klein200412670Prospective risk of pancreatic cancer in familial pancreatic cancer kindredsKlein, A. P.Brune, K. A.Petersen, G. M.Goggins, M.Tersmette, A. C.Offerhaus, G. J.Griffin, C.Cameron, J. L.Yeo, C. J.Kern, S.Hruban, R. H.Cancer Res20046472634-8.(27), those with germ line mutations in the BRCA2 gene, the STK11 gene (who have the Peutz-Jeghers syndrome), or the p16 gene (with familial atypical mole melanoma syndrome), and those with hereditary pancreatitis due to germ line mutations in the cationic trypsinogen gene ADDIN EN.CITE Ulrich2001182012120218152001Pancreatic cancer in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment416-22University of Cincinnati College of Medicine, 231 Albert B. Sabin Way MSB, Room 6555, ML 0595, Cincinnati, OH 45267-0595, USA. charles.ulrich@uc.eduUlrich, C. D.PancreatologyHumanPancreatic Neoplasms/diagnosis/epidemiology/*etiology/pathologyPancreatitis/*complications/epidemiology/*genetics/pathologySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12120218(30). Currently, screening should only be considered in individuals with a significantly increased risk of developing pancreatic neoplasia and only in the context of clinical research protocols.
Better serum markers of pancreatic cancer are urgently needed to improve pancreatic cancer diagnosis. Existing tumor markers are not sufficiently sensitive nor are they specific enough to differentiate benign from malignant disease.
TUMOR MARKERS IN PANCREATIC CANCER: NACB RECOMMENDATIONS
Table 1 summarizes NACB recommendations for the use of CA19-9 in pancreatic cancer, together with those of the European Group on Tumor Markers (EGTM) and the American Gastroenterological Association (AGA). The NACB guidelines are derived from published studies of pancreatic cancer serum and tissue markers that are described below. The levels of evidence grading system used is based on that described by Hayes et al [see Section 1].
A tumor marker has been defined, as a naturally occurring molecule that is measured in serum or plasma, or other body fluids or in tissue extracts or paraffin-embedded tissue to identify the presence of cancer, to assess patient prognosis, or to monitor a patients response to therapy with the overall goal of improving the clinical management of the patient ADDIN EN.CITE Fleisher20022011Fleisher, M.Dnistrian A.M.Sturgeon, C.M.Lamerz, R.Witliff, J.L.2002Tumor markers: Physiology, Pathobiology, Technology and Clinical ApplicationsDiamandis, E.P.Fritsche, H. Schwartz, M.K.Chan, D.M.ChicagoAACC press(31). The greatest limitation of most studies of serum markers is that they fail to limit their analyses to patients with small potentially curable pancreatic cancers.
Tumor markers investigated for use in pancreatic cancer
In the discussion presented here, tumor markers have been classified according to the evidence available to support their clinical use. For markers in Category A, accepted clinical use, there is clear evidence that the marker is clinically useful and contributes to patient care, and that its use is widely accepted. For those in Category B, evaluation, there is substantial information on the marker, typically from larger cohorts, which validates its diagnostic performance, but there is no clear evidence yet that the marker is clinically useful. For markers in category C, research or discovery, typically only initial, discovery-phase data have been published; with further evaluation using larger cohorts required to determine the diagnostic potential.
Previously evaluated markers which have been demonstrated to be inferior to the current standard marker, CA19-9, include Amylin (IAPP) ADDIN EN.CITE Chari200115001152274812132001SepIslet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer640-5Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA. chari.suresh@mayo.eduChari, S. T.Klee, G. G.Miller, L. J.Raimondo, M.DiMagno, E. P.GastroenterologyAgedAmyloid/*bloodBlood GlucoseCA-19-9 Antigen/bloodDiabetes Mellitus/blood/diagnosisFemaleHumanMalePancreatic Neoplasms/*blood/*diagnosisPredictive Value of TestsSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11522748Brand2002151012622423311-32002The specificity of amylin for the diagnosis of pancreatic adenocarcinoma123-8Department of Internal Medicine, Evanston Northwestern Healthcare, Glenview, IL 60025, USA. rbrand@enh.orgBrand, R. E.Ding, X. Z.Young, C. M.Adrian, T. E.Int J Gastrointest CancerAdenocarcinoma/*diagnosis/*pathologyAdultAgedAmyloid/*bloodCholestasis/diagnosisDiabetes Mellitus, Type IIDiagnosis, DifferentialFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*diagnosis/*pathologyPancreatitis/diagnosisRadioimmunoassaySensitivity and SpecificityTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12622423(32, 33), CA 50 ADDIN EN.CITE Lucarotti1991147019953581711991FebClinical evaluation of combined use of CEA, CA19-9 and CA50 in the serum of patients with pancreatic carcinoma51-3University Department of Surgery, Bristol Royal Infirmary.Lucarotti, M. E.Habib, N. A.Kelly, S. B.Rothnie, N. D.Nelson, O.Lindholm, L.Cooper, M. J.Wood, C. B.Williamson, R. 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G.Surg OncolAdenocarcinoma/*diagnosisAntigens, Neoplasm/bloodAntigens, Tumor-Associated, Carbohydrate/bloodCA-19-9 Antigen/bloodCarcinoembryonic Antigen/bloodFollow-Up StudiesHumanPancreatic Neoplasms/*diagnosisTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8853239Gattani1996179086467277811996Jul 1Tumor markers in patients with pancreatic carcinoma57-62Division of Neoplastic Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.Gattani, A. M.Mandeli, J.Bruckner, H. W.CancerCA-125 Antigen/*analysisCA-19-9 Antigen/*analysisCarcinoembryonic Antigen/*analysisCarcinoma, Ductal, Breast/*immunology/pathology/therapyCombined Modality TherapyFemaleHumanMaleMiddle AgedNeoplasm StagingPancreatic Neoplasms/*immunology/pathology/therapyPrognosisSupport, Non-U.S. Gov'tTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8646727(61-64), CA72-4 ADDIN EN.CITE Carpelan-Holmstrom20021440121749192242002Jul-AugCEA, CA 19-9 and CA 72-4 improve the diagnostic accuracy in gastrointestinal cancers2311-6Department of Surgery, Helsinki University Central Hospital, Finland.Carpelan-Holmstrom, M.Louhimo, J.Stenman, U. H.Alfthan, H.Haglund, C.Anticancer ResAntigens, Tumor-Associated, Carbohydrate/*bloodCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/*bloodDiagnosis, DifferentialGastrointestinal Diseases/diagnosisGastrointestinal Neoplasms/*diagnosis/pathologyHumanLiver Neoplasms/diagnosis/pathologyNeoplasm StagingPancreatic Neoplasms/diagnosis/pathologyRecurrenceReproducibility of ResultsStomach Neoplasms/diagnosis/pathologySupport, Non-U.S. Gov'tTumor Markers, Biological/bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12174919Heptner1989145028143392461989AugComparison of CA 72-4 with CA 19-9 and carcinoembryonic antigen in the serodiagnostics of gastrointestinal malignancies745-50Dept. of Medicine, University of Erlangen-Nuremberg, FRG.Heptner, G.Domschke, S.Domschke, W.Scand J GastroenterolAdolescentAdultAgedAntigens, Tumor-Associated, Carbohydrate/*analysisCarcinoembryonic Antigen/*analysisColonic Neoplasms/immunologyComparative StudyEvaluation StudiesFemaleGastrointestinal Diseases/immunologyGastrointestinal Neoplasms/*immunologyHumanMaleMiddle AgedPancreatic Neoplasms/immunologyRectal Neoplasms/immunologySerologic Tests/*methodsStomach Neoplasms/immunologyhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2814339Wu199214601542085611992Low frequency and low level of elevation of serum CA 72-4 in human carcinomas in comparison with established tumor markers59-64Department of Pathology and ARUP, University of Utah Medical Center, Salt Lake City 84132.Wu, J. T.Carlisle, P.J Clin Lab AnalAntigens, Tumor-Associated, Carbohydrate/*bloodBreast Neoplasms/bloodColonic Neoplasms/bloodComparative StudyEvaluation StudiesFemaleHumanNeoplasms/*blood/diagnosisOvarian Neoplasms/bloodPancreatic Neoplasms/bloodSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1542085(65-67), DUPAN-2 ADDIN EN.CITE Satake199414807846015961994NovComparison of CA19-9 with other tumor markers in the diagnosis of cancer of the pancreas720-4First Department of Surgery, Osaka City University Medical School, Japan.Satake, K.Takeuchi, T.PancreasAntigens, Neoplasm/bloodAntigens, Tumor-Associated, Carbohydrate/bloodCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/bloodComparative StudyHumanPancreatic Elastase/bloodPancreatic Neoplasms/*blood/*diagnosisRadioimmunoassaySensitivity and SpecificitySupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7846015Kawa1991154019316126451991NovElevated serum levels of Dupan-2 in pancreatic cancer patients negative for Lewis blood group phenotype899-902Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.Kawa, S.Oguchi, H.Kobayashi, T.Tokoo, M.Furuta, S.Kanai, M.Homma, T.Br J CancerAdultAgedAntigens, Neoplasm/*bloodAntigens, Tumor-Associated, Carbohydrate/metabolismComparative StudyEnzyme-Linked Immunosorbent AssayFalse Negative ReactionsFemaleHumanLewis Blood-Group System/*genetics/immunologyMaleMiddle AgedPancreatic Neoplasms/*bloodPhenotypeSupport, Non-U.S. Gov'thttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1931612(35, 68), and SPan-1 ADDIN EN.CITE Satake1991152020497356811991Jul 1The possibility of diagnosing small pancreatic cancer (less than 4.0 cm) by measuring various serum tumor markers. A retrospective study149-52First Department of Surgery, Osaka City University Medical School, Japan.Satake, K.Chung, Y. S.Umeyama, K.Takeuchi, T.Kim, Y. S.CancerAdultAgedAged, 80 and overAntigens, Neoplasm/bloodAntigens, Tumor-Associated, Carbohydrate/bloodCarcinoembryonic Antigen/bloodFemaleHumanMaleMiddle AgedPancreatic Elastase/bloodPancreatic Neoplasms/*blood/diagnosisPredictive Value of TestsRetrospective StudiesSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2049735Frena20011530116057321632001Jul-SepSPan-1 and exocrine pancreatic carcinoma. The clinical role of a new tumor marker189-97Second Department of General Surgery, Regional Hospital of Bolzano, Italy. antonio.frena@asbz.itFrena, A.Int J Biol MarkersAdultAgedAged, 80 and overAntigens, Neoplasm/*analysisCA-19-9 Antigen/analysisCarcinoembryonic Antigen/analysisChronic DiseaseComparative StudyDigestive System Neoplasms/pathologyFemaleHumanMaleMiddle AgedNeoplasm StagingPancreatic Neoplasms/*pathologyPancreatitis/pathologyReproducibility of ResultsSensitivity and SpecificityTissue Polypeptide Antigen/analysisTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11605732(69, 70)]. None of these markers will be discussed further.
Tumor markers with accepted clinical use in pancreatic cancer (Category A)
CA 19-9
CA 19-9, the sialylated Lewisa blood group antigen, is still the current standard serum tumor marker for pancreatic adenocarcinoma, and the one against which others are compared. Recommendations regarding its use in the management of patients with pancreatic cancer have been issued from the European Group on Tumor Markers (EGTM) and the American Gastroenterological Association (AGA) ADDIN EN.CITE DiMagno1999360AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological AssociationDiMagno, E. P.Reber, H. A.Tempero, M. A.*Adenocarcinoma/diagnosis/epidemiology/surgeryEnvironmentHumanNeoplasm Staging*Pancreatic Ducts*Pancreatic Neoplasms/*diagnosis/epidemiology/surgeryPrognosisRandomized Controlled TrialsRisk FactorsGastroenterology199911761464-84.1999181010470247194A1999Jul-AugTumour markers in gastrointestinal cancers--EGTM recommendations. European Group on Tumour Markers2811-5Anticancer ResGastrointestinal Neoplasms/*diagnosisHumanLaboratory Techniques and Procedures/*standardsMass ScreeningQuality ControlTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10470247(3, 71). The clinical usefulness of CA 19-9 in the screening, diagnosis, prognosis and monitoring of therapy for pancreatic adenocarcinoma is reviewed below (see also Table 1). The US Food and Drug Administration (FDA) has approved several CA19-9 assays for monitoring patients with pancreatic cancer.
Diagnosis. The utility of serum CA19-9 in the diagnosis of pancreatic adenocarcinoma has been extensively investigated in numerous retrospective and prospective studies that have enrolled multi ple control groups (chronic pancreatitis, obstructive jaundice, abdominal pain, healthy subjects) [for review see ADDIN EN.CITE Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589Duffy19981840963510135 ( Pt 3)1998MayCA 19-9 as a marker for gastrointestinal cancers: a review364-70Department of Nuclear Medicine, St Vincent's Hospital, Dublin, Ireland.Duffy, M. J.Ann Clin BiochemCA-19-9 Antigen/*bloodDiagnosis, DifferentialGastrointestinal Neoplasms/*blood/diagnosisHumanSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9635101Ritts199818509443988711998JanCA 19-9 in pancreatic cancer93-101Mayo Medical School, Mayo Clinic Foundation, Rochester, Minnesota, USA.Ritts, R. E.Pitt, H. A.Surg Oncol Clin N AmCA-19-9 Antigen/*analysisHumanPancreatic Neoplasms/*diagnosis/therapyPrognosisTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9443988Posner199418608707771831994JunThe use of serologic tumor markers in gastrointestinal malignancies533-53Division of Hematology/Oncology, Deaconess-Dana Farber Oncology Unit, New England Deaconess Hospital, Boston, Massachusetts, USA.Posner, M. R.Mayer, R. J.Hematol Oncol Clin North AmCA-19-9 Antigen/bloodCarcinoembryonic Antigen/bloodColorectal Neoplasms/blood/diagnosisGastrointestinal Neoplasms/blood/*diagnosisHumanPancreatic Neoplasms/blood/diagnosisStomach Neoplasms/blood/diagnosisSupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodalpha-Fetoproteins/analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8707771Sawabu20041870150849682832004AprSerum tumor markers and molecular biological diagnosis in pancreatic cancer263-7Department of Internal Medicine and Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. sawabu@kenroku.kanazawa-u.ac.jpSawabu, N.Watanabe, H.Yamaguchi, Y.Ohtsubo, K.Motoo, Y.PancreasAdultAgedAntigens, Tumor-Associated, Carbohydrate/analysis/bloodCarcinoembryonic Antigen/analysis/bloodDNA Mutational AnalysisFemaleGenes, p53Genes, rasHumanMaleMiddle AgedMolecular Diagnostic TechniquesMutationPancreatic Juice/chemistryPancreatic Neoplasms/*diagnosisSensitivity and SpecificityTelomerase/metabolismTumor Markers, Biological/analysis/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15084968(72-76)]. The optimal diagnostic cutoff value of CA 19-9 has been evaluated extensively. In one study CA 19-9 levels were measured in 160 patients with pancreatic diseases (90 with pancreatic cancer, 70 with benign disease), 322 patients with biliary tract diseases (152 with biliary cancer, 170 with benign disease), and 20,035 asymptomatic controls. The mean serum concentration of CA19-9 in asymptomatic individuals was 9.42 +/- 9.95 U/ml and levels above 37 U/mL were determined to be most accurate for discriminating pancreatic cancer from benign pancreatic disease (sensitivity and specificity of 77 and 87 percent, respectively) ADDIN EN.CITE Kim1999180104062639471999JulA new strategy for the application of CA19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve1941-6Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.Kim, H. J.Kim, M. H.Myung, S. J.Lim, B. C.Park, E. T.Yoo, K. S.Seo, D. W.Lee, S. K.Min, Y. I.Am J GastroenterolBiliary Tract Diseases/diagnosisBiliary Tract Neoplasms/complications/*diagnosis/immunologyCA-19-9 Antigen/*bloodDiagnosis, DifferentialFemaleHumanMaleMiddle AgedPancreatic Diseases/diagnosisPancreatic Neoplasms/complications/*diagnosis/immunologyROC CurveSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10406263(77). Similar sensitivity and specificity values for CA19-9 have been described in other studies, but have varied depending on the study populations under investigation. Importantly, CA19-9s performance characteristics improve as a patients pancreatic cancer becomes more advanced ADDIN EN.CITE Schlieman200319001296365013892003SepUtility of tumor markers in determining resectability of pancreatic cancer951-5; discussion 955-6Department of Surgery, Division of Surgical Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA.Schlieman, M. G.Ho, H. S.Bold, R. J.Arch SurgAdenocarcinoma/*blood/pathology/radiography/surgeryAgedCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/*bloodFemaleHumanMaleMiddle AgedNeoplasm StagingPancreatic Neoplasms/*blood/pathology/radiography/surgeryPredictive Value of TestsPreoperative CareRetrospective StudiesSensitivity and SpecificityTomography, X-Ray Computedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12963650Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589(62, 72). Consequently, for small tumors (<3 cm), the sensitivity of CA19-9 decreases significantly (~55%) ADDIN EN.CITE Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589(72).
Among patients presenting with symptoms suspected to be due to pancreatic cancer, CA19-9 performs somewhat better, but still has only modest sensitivity. In a study of 261 such patients, serum CA19-9 had a sensitivity of 70%, and a specificity of 87%. In this population, the positive predictive value of an elevated CA19-9 was 59%, and the negative predictive value was 92% ADDIN EN.CITE Pleskow1989130293010811091989May 1Evaluation of a serologic marker, CA19-9, in the diagnosis of pancreatic cancer704-9New England Deaconess Hospital, Boston, Massachusetts.Pleskow, D. K.Berger, H. J.Gyves, J.Allen, E.McLean, A.Podolsky, D. K.Ann Intern MedAdenocarcinoma/immunologyAntigens, Tumor-Associated, Carbohydrate/*analysisCarcinoembryonic Antigen/analysisDigestive System Diseases/immunologyHumanNeoplasms/immunologyPancreatic Neoplasms/*diagnosis/immunologyPredictive Value of TestsProspective StudiesRadioimmunoassayhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2930108(78). A metaA meta-analysis of similar studies, performed in 1994, reported serum CA19-9 had a mean sensitivity of 81% (range 69-93%) and a specificity of 91% (range 76-99%) using a cutoff level of 37 U/L ADDIN EN.CITE Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589(72). Higher cutoff values increase the diagnostic specificity: for a cutoff level of 100 U/L, diagnostic specificity of 97% has been reported ADDIN EN.CITE Ritts199418807846013961994NovComparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease707-16Microbiology Research Laboratory, Mayo Clinic and Foundation, Rochester, Minnesota 55905.Ritts, R. E., Jr.Nagorney, D. M.Jacobsen, D. J.Talbot, R. W.Zurawski, V. R., Jr.PancreasAdolescentAdultAgedAged, 80 and overBiopsyCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/bloodComparative StudyFemaleFollow-Up StudiesGallbladder Diseases/*blood/*diagnosis/pathologyGallbladder Neoplasms/blood/diagnosis/pathologyHumanLaparotomy/methodsMaleMiddle AgedPancreatic Diseases/*blood/*diagnosis/pathologyPancreatic Neoplasms/blood/diagnosis/pathologyPredictive Value of TestsPreoperative CareProspective StudiesROC CurveRisk FactorsSensitivity and SpecificityTomography, X-Ray ComputedUltrasonographyhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7846013(79), and for CA19-9 levels >1000 U/L, specificity approaches 100% ADDIN EN.CITE Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589Forsmark199418907846016961994NovDiagnosis of pancreatic cancer and prediction of unresectability using the tumor-associated antigen CA19-9731-4Department of Medicine, University of Florida, Gainesville.Forsmark, C. E.Lambiase, L.Vogel, S. B.PancreasAdultAgedAged, 80 and overCA-19-9 Antigen/*bloodFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/*diagnosis/surgeryPredictive Value of TestsPrognosisRetrospective Studieshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7846016(72, 80). Importantly, CA19-9s performance characteristics improve as a patients pancreatic cancer becomes more advanced ADDIN EN.CITE Schlieman200319001296365013892003SepUtility of tumor markers in determining resectability of pancreatic cancer951-5; discussion 955-6Department of Surgery, Division of Surgical Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA.Schlieman, M. G.Ho, H. S.Bold, R. J.Arch SurgAdenocarcinoma/*blood/pathology/radiography/surgeryAgedCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/*bloodFemaleHumanMaleMiddle AgedNeoplasm StagingPancreatic Neoplasms/*blood/pathology/radiography/surgeryPredictive Value of TestsPreoperative CareRetrospective StudiesSensitivity and SpecificityTomography, X-Ray Computedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12963650Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589(62, 72). Consequently, for small tumors (<3 cm), the sensitivity of CA19-9 decreases significantly (~55%) ADDIN EN.CITE Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589(72). CA19-9 antigen secretion depends on Lewisa antigen status. If the Lewisa antigen status is taken into account, CA19-9s overall diagnostic sensitivity can reach 92% among patients presenting with symptoms of pancreatic cancer ADDIN EN.CITE Safi1996191090132752031996DecCA 19-9 serum course and prognosis of pancreatic cancer155-61Department of General Surgery, University Hospital of Ulm, Germany.Safi, F.Schlosser, W.Falkenreck, S.Beger, H. G.Int J PancreatolCA-19-9 Antigen/*bloodHumanNeoplasm MetastasisNeoplasm Recurrence, Local/diagnosisNeoplasm StagingPancreatic Neoplasms/*blood/diagnosis/surgeryPrognosisRadioimmunoassaySensitivity and Specificityhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9013275(81). The combination of serum CA19-9 and imaging tests (sonography, CT) increase the positive predictive value ADDIN EN.CITE Ritts199418807846013961994NovComparison of preoperative serum CA19-9 levels with results of diagnostic imaging modalities in patients undergoing laparotomy for suspected pancreatic or gallbladder disease707-16Microbiology Research Laboratory, Mayo Clinic and Foundation, Rochester, Minnesota 55905.Ritts, R. E., Jr.Nagorney, D. M.Jacobsen, D. J.Talbot, R. W.Zurawski, V. R., Jr.PancreasAdolescentAdultAgedAged, 80 and overBiopsyCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/bloodComparative StudyFemaleFollow-Up StudiesGallbladder Diseases/*blood/*diagnosis/pathologyGallbladder Neoplasms/blood/diagnosis/pathologyHumanLaparotomy/methodsMaleMiddle AgedPancreatic Diseases/*blood/*diagnosis/pathologyPancreatic Neoplasms/blood/diagnosis/pathologyPredictive Value of TestsPreoperative CareProspective StudiesROC CurveRisk FactorsSensitivity and SpecificityTomography, X-Ray ComputedUltrasonographyhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7846013(79). Unfortunately, at the current time, cure from pancreatic ductal adenocarcinoma is related to tumor stage and size ADDIN EN.CITE Yeo19985790Prognostic factors in ductal pancreatic cancerYeo, C. J.Cameron, J. L.Adenocarcinoma/*diagnosis/mortality/pathology/therapyCombined Modality TherapyHumanLymphatic MetastasisNeoplasm StagingPalliative Care*Pancreatic Ducts/pathologyPancreatic Neoplasms/*diagnosis/mortality/pathology/therapyPrognosisSurvival RateLangenbecks Arch Surg19983832129-33.(82) and thus the challenge for serum tumor markers such as CA19-9 is not simply to perform adequately among patients with advanced disease who are rarely cured of their disease, but to ensure that patients who present while they have small curative cancers can be readily identified with the help of accurate serum tumor markers. Serum CA19-9 does not have the necessary performance characteristics to meet this challenge.
Other limitations of the diagnostic usefulness of CA 19-9 include its elevation in non-pancreatic gastrointestinal malignancies as well as a variety of benign disease conditions. Biliary obstruction, cholecystitis, cholangitis, hepatic cirrhosis, acute and chronic pancreatitis are common causes of elevated CA19-9 values ADDIN EN.CITE Duffy19981840963510135 ( Pt 3)1998MayCA 19-9 as a marker for gastrointestinal cancers: a review364-70Department of Nuclear Medicine, St Vincent's Hospital, Dublin, Ireland.Duffy, M. J.Ann Clin BiochemCA-19-9 Antigen/*bloodDiagnosis, DifferentialGastrointestinal Neoplasms/*blood/diagnosisHumanSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9635101Steinberg1990183021835898541990AprThe clinical utility of the CA 19-9 tumor-associated antigen350-5Department of Medicine, George Washington University Medical Center, Washington, DC.Steinberg, W.Am J GastroenterolAntigens, Tumor-Associated, Carbohydrate/*analysisHumanPancreatic Juice/analysisPancreatic Neoplasms/*diagnosis/epidemiologySensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=2183589(72, 73). For example, in one study serum CA 19-9 values ranged from 190 to 32,000 in seven patients with acute cholangitis secondary to gallstone biliary obstruction but were normal in patients with asymptomatic cholelithiasis, common duct obstruction without cholangitis, or acute cholecystitis ADDIN EN.CITE Albert1988140316869433101988OctElevated serum levels of tumor marker CA19-9 in acute cholangitis1223-5Department of Medicine, George Washington University Medical Center, Washington, D.C. 20037.Albert, M. B.Steinberg, W. M.Henry, J. P.Dig Dis SciAntigens, Tumor-Associated, Carbohydrate/*analysisBile/immunologyCholangitis/*immunology/surgeryCholestasis/immunologyComparative StudyFemaleHumanMaleMiddle AgedProspective StudiesStatisticsTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=3168694(83).
In view of these limitations the NACB Panel does not recommend measuring serum CA19-9 for the diagnosis of pancreatic cancer. EGTM guidelines recommend a limited role for CA 19-9 in the diagnosis of pancreatic cancer as a complement to accurate pancreatic imaging procedures ADDIN EN.CITE 1999181010470247194A1999Jul-AugTumour markers in gastrointestinal cancers--EGTM recommendations. European Group on Tumour Markers2811-5Anticancer ResGastrointestinal Neoplasms/*diagnosisHumanLaboratory Techniques and Procedures/*standardsMass ScreeningQuality ControlTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10470247DiMagno1999360AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. American Gastroenterological AssociationDiMagno, E. P.Reber, H. A.Tempero, M. A.*Adenocarcinoma/diagnosis/epidemiology/surgeryEnvironmentHumanNeoplasm Staging*Pancreatic Ducts*Pancreatic Neoplasms/*diagnosis/epidemiology/surgeryPrognosisRandomized Controlled TrialsRisk FactorsGastroenterology199911761464-84.(3, 71). If measured, CA19-9 should be used in conjunction with an imaging test (CT, EUS). Appropriately interpreted CA19-9 values can guide further invasive testing (ERCP, EUS FNA, laparoscopy, laparotomy) in the appropriate clinical context.
Screening. The low prevalence of pancreatic cancer in the general population means that screening asymptomatic persons for pancreatic cancer using even highly accurate serum tumor markers would yield too many false positives and cannot be recommended. This is illustrated by a recent study in which 70,940 asymptomatic subjects were screened using CA 19-9. Four cases of pancreatic cancer were detected along with 1059 false-positives, yielding a positive predictive value of 0.9% ADDIN EN.CITE Kim200410147311281922004FebClinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population182-6Division of Gastroenterology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.Kim, J. E.Lee, K. T.Lee, J. K.Paik, S. W.Rhee, J. C.Choi, K. W.J Gastroenterol HepatolCA-19-9 Antigen/*bloodFemaleHumanImmunoradiometric AssayMale*Mass ScreeningMiddle AgedPancreatic Neoplasms/*diagnosis/ultrasonographyPredictive Value of TestsSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14731128(84).
When screening high-risk populations, many lesions detected by imaging are precancerous masses and in this setting, serum CA 19-9 is often normal ADDIN EN.CITE Canto MI200312260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2003Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21M. Canto200413250M. Canto, M. Goggins, C. Yeo, EK Fishman, S. Jagannath, S. Kantsevoy, C. Griffin, J. Axilbund, K. Brune, S. Ali, J. Richman, G. Petersen, F. Giardiello, R Hruban, AN Kalloo2004Screening for pancreatic neoplasia in asymptomatic high risk individuals: A prospective, controlled study.AACR/Lustgarten Foundation Pancreatic Cancer Research Meeting, San Francisco, June 25, 2004Brentnall19992540Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAdultAgedBiological MarkersCholangiopancreatography, Endoscopic RetrogradeEndosonographyFemaleHumanHyperplasiaMaleMiddle AgePancreas/*pathologyPancreatectomyPancreatic Neoplasms/*diagnosis/genetics/therapyPedigreePrecancerous Conditions/*diagnosis/therapyPredictive Value of TestsProspective StudiesTomography, X-Ray ComputedAnn Intern Med19991314247-55(25, 28, 29). For example, in one study CA 19-9 levels were all within normal range in 14 high-risk individuals who underwent total pancreatectomy. These 14 patients had pancreatic imaging abnormalities and were found to have histologic evidence of dysplasia in their pancreatectomy specimens ADDIN EN.CITE Brentnall1999450Brentnall, T. A.Bronner, M. P.Byrd, D. R.Haggitt, R. C.Kimmey, M. B.1999Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancerAnn. Intern. Med.1314247-55(85)(28). Similarly, since many pancreatic adenocarcinomas arise from microscopic dysplastic lesions now called PanIN (pancreatic intraepithelial neoplasia), there is concern that neither imaging nor serum tumor markers will detect many pancreatic neoplasms until they have become invasive cancers ADDIN EN.CITE Hruban20003870Hruban, R. H.Goggins, M.Parsons, J.Kern, S. E.2000Progression model for pancreatic cancerClin Cancer Res682969-72Hruban20016970Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesionsHruban, R. H.Adsay, N. V.Albores-Saavedra, J.Compton, C.Garrett, E. S.Goodman, S. N.Kern, S. E.Klimstra, D. S.Kloppel, G.Longnecker, D. S.Luttges, J.Offerhaus, G. J.Carcinoma in Situ/*classification/pathologyHumanObserver VariationPancreatic Ducts/*pathologyPancreatic Neoplasms/*classification/pathologyPrecancerous Conditions/*classification/pathologyReference StandardsSupport, U.S. Gov't, P.H.S.*TerminologyAm J Surg Pathol2001255579-86.Hruban200412900An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous NeoplasmsHruban, R. H.Takaori, K.Klimstra, D. S.Adsay, N. V.Albores-Saavedra, J.Biankin, A. V.Biankin, S. A.Compton, C.Fukushima, N.Furukawa, T.Goggins, M.Kato, Y.Kloppel, G.Longnecker, D. S.Luttges, J.Maitra, A.Offerhaus, G. J.Shimizu, M.Yonezawa, S.Am J Surg Pathol2004288977-987. ADDIN EN.CITE Hruban20003870Hruban, R. H.Goggins, M.Parsons, J.Kern, S. E.Progression model for pancreatic cancer [In Process Citation]Clin Cancer Res2000682969-72Hruban20016970Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesionsHruban, R. H.Adsay, N. V.Albores-Saavedra, J.Compton, C.Garrett, E. S.Goodman, S. N.Kern, S. E.Klimstra, D. S.Kloppel, G.Longnecker, D. S.Luttges, J.Offerhaus, G. J.Carcinoma in Situ/*classification/pathologyHumanObserver VariationPancreatic Ducts/*pathologyPancreatic Neoplasms/*classification/pathologyPrecancerous Conditions/*classification/pathologyReference StandardsSupport, U.S. Gov't, P.H.S.*TerminologyAm J Surg Pathol2001255579-86.Hruban200412900An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous NeoplasmsHruban, R. H.Takaori, K.Klimstra, D. S.Adsay, N. V.Albores-Saavedra, J.Biankin, A. V.Biankin, S. A.Compton, C.Fukushima, N.Furukawa, T.Goggins, M.Kato, Y.Kloppel, G.Longnecker, D. S.Luttges, J.Maitra, A.Offerhaus, G. J.Shimizu, M.Yonezawa, S.Am J Surg Pathol2004288977-987.(86-88)(85-87). Serum tumor markers could still be very valuable for detecting early asymptomatic invasive pancreatic cancer, but this information must await prospective studies as there is currently only limited information about the role of tumor markers in this setting. The American Gastroenterology Association recommendations published in 1999 did not recommend a screening strategy as at that time no strategy had been shown to detect early pancreatic cancers in patients with an increased risk for developing pancreatic cancer.
Prognosis. Serum CA19-9 levels carry independent predictive value for the determination of resectability of pancreatic cancer ADDIN EN.CITE Forsmark199418907846016961994NovDiagnosis of pancreatic cancer and prediction of unresectability using the tumor-associated antigen CA19-9731-4Department of Medicine, University of Florida, Gainesville.Forsmark, C. E.Lambiase, L.Vogel, S. B.PancreasAdultAgedAged, 80 and overCA-19-9 Antigen/*bloodFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/*diagnosis/surgeryPredictive Value of TestsPrognosisRetrospective Studieshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7846016Schlieman200319001296365013892003SepUtility of tumor markers in determining resectability of pancreatic cancer951-5; discussion 955-6Department of Surgery, Division of Surgical Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA.Schlieman, M. G.Ho, H. S.Bold, R. J.Arch SurgAdenocarcinoma/*blood/pathology/radiography/surgeryAgedCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/*bloodFemaleHumanMaleMiddle AgedNeoplasm StagingPancreatic Neoplasms/*blood/pathology/radiography/surgeryPredictive Value of TestsPreoperative CareRetrospective StudiesSensitivity and SpecificityTomography, X-Ray Computedhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12963650(62, 80) and of overall patient survival ADDIN EN.CITE Safi1996191090132752031996DecCA 19-9 serum course and prognosis of pancreatic cancer155-61Department of General Surgery, University Hospital of Ulm, Germany.Safi, F.Schlosser, W.Falkenreck, S.Beger, H. G.Int J PancreatolCA-19-9 Antigen/*bloodHumanNeoplasm MetastasisNeoplasm Recurrence, Local/diagnosisNeoplasm StagingPancreatic Neoplasms/*blood/diagnosis/surgeryPrognosisRadioimmunoassaySensitivity and Specificityhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9013275Grem199719209251889941997JulThe prognostic importance of tumor markers in adenocarcinomas of the gastrointestinal tract380-7NCI-Medicine Branch, National Naval Medical Center, Bethesda, MD 20889-5105, USA.Grem, J.Curr Opin OncolAdenocarcinoma/*blood/*diagnosisAntigens, Tumor-Associated, Carbohydrate/bloodCarcinoembryonic Antigen/bloodGastrointestinal Neoplasms/*blood/*diagnosisHumanPrognosisTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9251889Montgomery199719309367020471997Oct-NovPrediction of recurrence and survival by post-resection CA 19-9 values in patients with adenocarcinoma of the pancreas551-6Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.Montgomery, R. C.Hoffman, J. P.Riley, L. B.Rogatko, A.Ridge, J. A.Eisenberg, B. L.Ann Surg OncolAdenocarcinoma/*diagnosis/mortality/surgeryAdultAgedAged, 80 and overCA-19-9 Antigen/*bloodDisease-Free SurvivalFemaleFollow-Up StudiesForecastingHumanMaleMiddle AgedNeoplasm Recurrence, LocalPancreatic Neoplasms/*diagnosis/mortality/surgeryPostoperative PeriodPrognosisSurvival RateTime FactorsTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9367020Katz1998194096073564121998May 1Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy393-6Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.Katz, A.Hanlon, A.Lanciano, R.Hoffman, J.Coia, L.Int J Radiat Oncol Biol PhysAgedAnalysis of VarianceCA-19-9 Antigen/*bloodCombined Modality TherapyFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/drug therapy/mortality/*radiotherapy/surgeryPrognosisRetrospective StudiesSurvival AnalysisTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9607356(81, 89-91)(81, 88-90). For example, a retrospective review of 104 pancreatic cancer patients treated with radiotherapy found the CA 19-9 level at diagnosis to be a significant prognostic indicator, with median survival rates of 8 and 20 months for patients with a CA19-9 level above or below the median (680 U/L) ADDIN EN.CITE Katz1998194096073564121998May 1Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy393-6Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.Katz, A.Hanlon, A.Lanciano, R.Hoffman, J.Coia, L.Int J Radiat Oncol Biol PhysAgedAnalysis of VarianceCA-19-9 Antigen/*bloodCombined Modality TherapyFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/drug therapy/mortality/*radiotherapy/surgeryPrognosisRetrospective StudiesSurvival AnalysisTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9607356(91)(90). Similarly, in a cohort study of patients undergoing resection for pancreatic cancer (n=347), the median survival time for patients with the same tumor stage was significantly longer in patients whose CA19-9 levels returned to normal after resection, than in those whose CA19-9 did not normalize ADDIN EN.CITE Safi1996191090132752031996DecCA 19-9 serum course and prognosis of pancreatic cancer155-61Department of General Surgery, University Hospital of Ulm, Germany.Safi, F.Schlosser, W.Falkenreck, S.Beger, H. G.Int J PancreatolCA-19-9 Antigen/*bloodHumanNeoplasm MetastasisNeoplasm Recurrence, Local/diagnosisNeoplasm StagingPancreatic Neoplasms/*blood/diagnosis/surgeryPrognosisRadioimmunoassaySensitivity and Specificityhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9013275(81). In another study of 28 patients with advanced pancreatic cancer and elevated baseline CA 19-9 treated with gemcitabine, pretreatment CA 19-9 level was an independent, and significant predictor of survival, and was more informative than CA 19-9 response (p = .0497) ADDIN EN.CITE Saad2002390126307683212002Pretreatment CA 19-9 level as a prognostic factor in patients with advanced pancreatic cancer treated with gemcitabine35-41Centro Paulista de Oncologia, Sao Paulo, Brazil. evesaad@yahoo.comSaad, E. D.Machado, M. C.Wajsbrot, D.Abramoff, R.Hoff, P. M.Tabacof, J.Katz, A.Simon, S. D.Gansl, R. C.Int J Gastrointest CancerAdenocarcinoma/*blood/drug therapy/mortality/pathology/radiotherapyAgedAged, 80 and overAntigens, Neoplasm/*bloodAntimetabolites, Antineoplastic/*therapeutic useCA-19-9 Antigen/*bloodCarcinoma, Adenosquamous/blood/drug therapy/mortality/pathologyDeoxycytidine/*analogs & derivatives/*therapeutic useFemaleHumanLife TablesMaleMiddle AgedPancreatic Neoplasms/*blood/drug therapy/mortality/pathology/radiotherapyPrognosisRetrospective StudiesSupport, Non-U.S. Gov'thttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12630768(92)(91). Most recently, undetectable preoperative CA 19-9 levels have been shown to correlate with improved survival for patients with resectable pancreatic adenocarcinoma. The authors suggest that patients who present with undetectable preoperative CA19-9 levels and potentially resectable pancreatic cancer, regardless of advanced stage, should be considered candidates for aggressive therapy ADDIN EN.CITE Berger2004150151970141172004JulUndetectable Preoperative Levels of Serum CA 19-9 Correlate with Improved Survival for Patients with Resectable Pancreatic Adenocarcinoma644-9Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. a_berger@fccc.edu.Berger, A. C.Meszoely, I. M.Ross, E. A.Watson, J. C.Hoffman, J. P.Ann Surg Oncolhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15197014(93)(92).
While the AGA guidelines do not comment on this topic specifically, the EGTM guidelines state that CA 19-9 has the potential to assess prognosis for pancreatic cancer, but its use for that purpose is unproven ADDIN EN.CITE 1999181010470247194A1999Jul-AugTumour markers in gastrointestinal cancers--EGTM recommendations. European Group on Tumour Markers2811-5Anticancer ResGastrointestinal Neoplasms/*diagnosisHumanLaboratory Techniques and Procedures/*standardsMass ScreeningQuality ControlTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10470247(71).
The NACB Panel recommends that serum CA19-9 levels should be taken into account for risk stratification of pancreatic cancer patients. Although high levels of CA19-9 are an adverse prognostic indicator, this it is only one of many parameters that influence prognosis and decisions about therapy.
Monitoring of therapy. Substantial evidence is available regarding the role of serial CA 19-9 measurements in the monitoring of palliative chemotherapy for pancreatic cancer. In two recent studies of palliative gemcitabine chemotherapy (n=89 for the 2 studies combined), a decline in CA 19-9 of >20% compared to baseline after 8 weeks therapy (2 cycles) has been shown to be a better indicator of response and survival than CT imaging ADDIN EN.CITE Ziske20031950145620098982003Oct 20Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine1413-7Medizinische Klinik und Poliklinik I, Rheinische Friedrich-Wilhelms-Universitat, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.Ziske, C.Schlie, C.Gorschluter, M.Glasmacher, A.Mey, U.Strehl, J.Sauerbruch, T.Schmidt-Wolf, I. G.Br J CancerAdenocarcinoma/*drug therapy/pathologyAdultAgedAged, 80 and overAntimetabolites, Antineoplastic/*pharmacologyCA-19-9 Antigen/*analysis/biosynthesisDeoxycytidine/*analogs & derivatives/*pharmacologyFemaleHumanKineticsMaleMiddle AgedPancreatic Neoplasms/*drug therapy/pathologyPredictive Value of TestsPrognosisSurvival AnalysisTreatment OutcomeTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14562009Halm20001960107373828252000MarDecrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer1013-6Department of Internal Medicine II, University of Leipzig, Germany.Halm, U.Schumann, T.Schiefke, I.Witzigmann, H.Mossner, J.Keim, V.Br J CancerAdultAge FactorsAgedAntimetabolites, Antineoplastic/*therapeutic useCA-19-9 Antigen/*bloodDeoxycytidine/*analogs & derivatives/therapeutic useFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/drug therapyPrognosisProspective StudiesSex FactorsSurvival AnalysisTime FactorsTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10737382(94, 95)(93, 94). No patient had decreasing CA 19-9 levels in the presence of progressive disease and all patients with an objective response (partial or complete) had CA 19-9 reductions of >20%. The independent prognostic value of serial CA 19-9 kinetics has also been reported using different palliative combination chemotherapy regimens ADDIN EN.CITE Halm20001960107373828252000MarDecrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer1013-6Department of Internal Medicine II, University of Leipzig, Germany.Halm, U.Schumann, T.Schiefke, I.Witzigmann, H.Mossner, J.Keim, V.Br J CancerAdultAge FactorsAgedAntimetabolites, Antineoplastic/*therapeutic useCA-19-9 Antigen/*bloodDeoxycytidine/*analogs & derivatives/therapeutic useFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/drug therapyPrognosisProspective StudiesSex FactorsSurvival AnalysisTime FactorsTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10737382Stemmler20031970146054632652003OctAre serial CA 19-9 kinetics helpful in predicting survival in patients with advanced or metastatic pancreatic cancer treated with gemcitabine and cisplatin?462-7Department of Oncology, Onkologische Klinik Bad Trissl, Oberaudorf, Germany.Stemmler, J.Stieber, P.Szymala, A. M.Schalhorn, A.Schermuly, M. M.Wilkowski, R.Helmberger, T.Lamerz, R.Stoffregen, C.Niebler, K.Garbrecht, M.Heinemann, V.OnkologieAdultAgedAntineoplastic Combined Chemotherapy Protocols/adverseeffects/*therapeutic useCA-19-9 Antigen/*bloodCisplatin/*administration & dosage/adverse effectsDeoxycytidine/*administration & dosage/adverse effects/*analogs &derivativesDisease ProgressionDose-Response Relationship, DrugDrug Administration ScheduleFemaleHumanMaleMiddle AgedNeoplasm Invasiveness/pathologyNeoplasm StagingPancreas/pathologyPancreatic Neoplasms/*drug therapy/mortality/pathologyPrognosisSurvival RateTomography, X-Ray ComputedTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14605463Gogas1998198094610057721998Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas?325-8Department of Oncology, St George's Hospital, London, UK.Gogas, H.Lofts, F. J.Evans, T. R.Daryanani, S.Mansi, J. L.Br J CancerAdenocarcinoma/*diagnosis/drug therapy/immunologyAdultAgedAntineoplastic Combined Chemotherapy Protocols/therapeutic useCA-19-9 Antigen/*analysisFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*diagnosis/drug therapy/immunologyRetrospective StudiesSurvival Analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9461005Gogas1998198094610057721998Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas?325-8Department of Oncology, St George's Hospital, London, UK.Gogas, H.Lofts, F. J.Evans, T. R.Daryanani, S.Mansi, J. L.Br J CancerAdenocarcinoma/*diagnosis/drug therapy/immunologyAdultAgedAntineoplastic Combined Chemotherapy Protocols/therapeutic useCA-19-9 Antigen/*analysisFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*diagnosis/drug therapy/immunologyRetrospective StudiesSurvival Analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9461005(95-97)(94-96). In a study of 21 patients with advanced pancreatic cancer treated with gemcitabine and cisplatin, all 4 patients who achieved complete remission demonstrated a return of CA 19-9 levels into the normal range ADDIN EN.CITE Heinemann199917010470171194A1999Jul-AugCA19-9: a pedictor of response in pancreatic cancer treated with gemcitabine and cisplatin2433-5Klinikum Grosshadern, University of Munich, Germany.Heinemann, V.Schermuly, M. M.Stieber, P.Schulz, L.Jungst, D.Wilkowski, R.Schalhorn, A.Anticancer ResAdenocarcinoma/blood/*drug therapy/pathologyAdultAgedAntimetabolites, Antineoplastic/administration & dosageAntineoplastic Combined Chemotherapy Protocols/*therapeutic useCA-19-9 Antigen/*bloodCisplatin/administration & dosageDeoxycytidine/administration & dosage/analogs & derivativesDisease-Free SurvivalFemaleHumanMaleMiddle AgedPancreatic Neoplasms/blood/*drug therapy/pathologyPredictive Value of TestsTime FactorsTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10470171(98)(97), while the 4 patients who achieved partial remission showed a decrease in their CA 19-9 values ADDIN EN.CITE Heinemann199917010470171194A1999Jul-AugCA19-9: a pedictor of response in pancreatic cancer treated with gemcitabine and cisplatin2433-5Klinikum Grosshadern, University of Munich, Germany.Heinemann, V.Schermuly, M. M.Stieber, P.Schulz, L.Jungst, D.Wilkowski, R.Schalhorn, A.Anticancer ResAdenocarcinoma/blood/*drug therapy/pathologyAdultAgedAntimetabolites, Antineoplastic/administration & dosageAntineoplastic Combined Chemotherapy Protocols/*therapeutic useCA-19-9 Antigen/*bloodCisplatin/administration & dosageDeoxycytidine/administration & dosage/analogs & derivativesDisease-Free SurvivalFemaleHumanMaleMiddle AgedPancreatic Neoplasms/blood/*drug therapy/pathologyPredictive Value of TestsTime FactorsTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10470171(98)(97).
Serial CA 19-9 measurements have greater sensitivity and specificity for determining response than individual measurements. In one study, a serial drop in CA19-9 levels had a sensitivity of 67% for predicting partial response and a serial elevations a sensitivity of 86% for predicting progressive disease ADDIN EN.CITE Gogas1998198094610057721998Are serial measurements of CA19-9 useful in predicting response to chemotherapy in patients with inoperable adenocarcinoma of the pancreas?325-8Department of Oncology, St George's Hospital, London, UK.Gogas, H.Lofts, F. J.Evans, T. R.Daryanani, S.Mansi, J. L.Br J CancerAdenocarcinoma/*diagnosis/drug therapy/immunologyAdultAgedAntineoplastic Combined Chemotherapy Protocols/therapeutic useCA-19-9 Antigen/*analysisFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*diagnosis/drug therapy/immunologyRetrospective StudiesSurvival Analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9461005(97)(96). One study concluded that decreasing CA 19-9 values suggest tumor progression is unlikely and treatment should be continued, while patients with an increase of CA19-9 during chemotherapy with gemcitabine had a poor prognosis and in the absence of a significant improvement in clinical response, further chemotherapy is of questionable value ADDIN EN.CITE Ziske20031950145620098982003Oct 20Prognostic value of CA 19-9 levels in patients with inoperable adenocarcinoma of the pancreas treated with gemcitabine1413-7Medizinische Klinik und Poliklinik I, Rheinische Friedrich-Wilhelms-Universitat, Sigmund-Freud-Str. 25, 53105 Bonn, Germany.Ziske, C.Schlie, C.Gorschluter, M.Glasmacher, A.Mey, U.Strehl, J.Sauerbruch, T.Schmidt-Wolf, I. G.Br J CancerAdenocarcinoma/*drug therapy/pathologyAdultAgedAged, 80 and overAntimetabolites, Antineoplastic/*pharmacologyCA-19-9 Antigen/*analysis/biosynthesisDeoxycytidine/*analogs & derivatives/*pharmacologyFemaleHumanKineticsMaleMiddle AgedPancreatic Neoplasms/*drug therapy/pathologyPredictive Value of TestsPrognosisSurvival AnalysisTreatment OutcomeTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14562009(94)(93).
Similar studies have been performed investigating the role of CA 19-9 in predicting the response to radiotherapy for pancreatic cancer ADDIN EN.CITE Katz1998194096073564121998May 1Prognostic value of CA 19-9 levels in patients with carcinoma of the pancreas treated with radiotherapy393-6Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.Katz, A.Hanlon, A.Lanciano, R.Hoffman, J.Coia, L.Int J Radiat Oncol Biol PhysAgedAnalysis of VarianceCA-19-9 Antigen/*bloodCombined Modality TherapyFemaleHumanMaleMiddle AgedPancreatic Neoplasms/*blood/drug therapy/mortality/*radiotherapy/surgeryPrognosisRetrospective StudiesSurvival AnalysisTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9607356Micke20031990129092205712003Sep 1Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy90-7Department of Radiotherapy, Munster University Hospital, Munster, Germany. omicke@uni-muenster.deMicke, O.Bruns, F.Kurowski, R.Horst, E.deVries, A. F.Hausler, J. W.Willich, N.Schafer, U.Int J Radiat Oncol Biol PhysAdenocarcinoma/blood/diagnosis/drug therapy/radiotherapyAdultAgedAntineoplastic Combined Chemotherapy Protocols/*therapeutic useAustria/epidemiologyCA-19-9 Antigen/*bloodCombined Modality Therapy/methodsFluorouracil/therapeutic useFollow-Up StudiesHumanLeucovorin/therapeutic useMaleMiddle AgedPancreatic Neoplasms/blood/*diagnosis/drug therapy/*radiotherapyReproducibility of ResultsSensitivity and SpecificitySurvival Analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12909220Ohara200120001146294248392001May-JunUtility of serum CA 19-9 monitoring in preoperative radiotherapy for pancreatic cancer859-63Department of Radiology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba City 305-8575, Japan. ki-ohara@md.tsukuba.ac.jpOhara, K.Tatsuzaki, H.Molotkova, N. G.Oda, T.Yuzawa, K.Saida, Y.Matsuzaki, Y.Shimizu, W.Todoroki, T.Fukao, K.Tanaka, N.Itai, Y.HepatogastroenterologyAdultAgedCA-19-9 Antigen/*bloodCombined Modality TherapyFemaleHumanMaleMiddle Aged*Neoadjuvant Therapy*PancreatectomyPancreatic Neoplasms/blood/mortality/*radiotherapy/surgeryRadiotherapy DosageRetrospective StudiesSurvival RateTreatment FailureTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11462942(91, 99, 100)(90, 98, 99). Serial measurements to monitor response radiotherapy, however, are less practicable, since radiotherapy is limited by a maximum tolerated dose and is of short duration in contrast to palliative chemotherapy. When used to follow the prognosis of patients after chemoradiotherapy, serial CA 19-9 predicted disease relapse with 100% sensitivity and 88% specificity ADDIN EN.CITE Micke20031990129092205712003Sep 1Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy90-7Department of Radiotherapy, Munster University Hospital, Munster, Germany. omicke@uni-muenster.deMicke, O.Bruns, F.Kurowski, R.Horst, E.deVries, A. F.Hausler, J. W.Willich, N.Schafer, U.Int J Radiat Oncol Biol PhysAdenocarcinoma/blood/diagnosis/drug therapy/radiotherapyAdultAgedAntineoplastic Combined Chemotherapy Protocols/*therapeutic useAustria/epidemiologyCA-19-9 Antigen/*bloodCombined Modality Therapy/methodsFluorouracil/therapeutic useFollow-Up StudiesHumanLeucovorin/therapeutic useMaleMiddle AgedPancreatic Neoplasms/blood/*diagnosis/drug therapy/*radiotherapyReproducibility of ResultsSensitivity and SpecificitySurvival Analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12909220(99)(98).
Current guidelines from the AGA, NCCN and EGTM state that CA19-9 measurements cannot yet be recommended for monitoring the efficacy of treatment of pancreatic cancer.
The NACB Panel recommends that serial CA 19-9 measurements be used in conjunction with imaging to monitor patients response to therapy, particularly palliative chemotherapy. Serial CA19-9 monitoring is also recommended in the follow-up of patients after potentially curative surgery, although the utility of detecting early rises in CA19-9 and instituting therapy prior to other evidence of relapse has yet to be demonstrated.
Gene testing for inherited susceptibility
Individuals with inherited mutations of BRCA2, p16 (Familial atypical multiple mole melanoma), STK11 (Peutz-Jeghers syndrome), cationic trypsinogen (hereditary pancreatitis), FANCC, FANCG and occasionally mismatch repair gene defects (hereditary non-polyposis colorectal cancer) are at increased risk of developing inherited pancreatic cancer ADDIN EN.CITE Klein200211830Evidence for a major gene influencing risk of pancreatic cancerKlein, A. P.Beaty, T. H.Bailey-Wilson, J. E.Brune, K. A.Hruban, R. H.Petersen, G. M.Adenocarcinoma/epidemiology/*geneticsAge of OnsetAgedAged, 80 and overChi-Square DistributionFemaleGenes, DominantGenetic Predisposition to DiseaseHumanLikelihood FunctionsMaleMiddle AgeNeoplastic Syndromes, Hereditary/geneticsPancreatic Neoplasms/epidemiology/*geneticsRegistriesRetrospective StudiesRisk FactorsSmoking/epidemiologySupport, U.S. Gov't, P.H.S.United States/epidemiologyGenet Epidemiol2002232133-49.Ozcelik19979700Ozcelik, H.Schmocker, B.Di Nicola, N.Shi, X. H.Langer, B.Moore, M.Taylor, B. R.Narod, S. A.Darlington, G.Andrulis, I. L.Gallinger, S.Redston, M.1997Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patientsNat Genet16117-8Goggins19968260Goggins, M.Schutte, M.Lu, J.Moskaluk, C.A.Weinstein, C.L.Petersen, G.M.Yeo, C.J.Jackson, C.E.Lynch, H.T.Hruban, R.H.Kern, S.E.1996Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomasCancer Res565360-5364Giardiello200013030Very high risk of cancer in familial Peutz-Jeghers syndromeGiardiello, F. M.Brensinger, J. D.Tersmette, A. C.Goodman, S. N.Petersen, G. M.Booker, S. V.Cruz-Correa, M.Offerhaus, J. A.AdolescentAdultDigestive System Neoplasms/etiologyFemaleGenital Neoplasms, Female/etiologyHumanLung Neoplasms/etiologyMaleMiddle AgedNeoplasms/*etiologyPeutz-Jeghers Syndrome/*complicationsRisk FactorsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Gastroenterology200011961447-53.Lowenfels1993290Lowenfels, A. B.Maisonneuve, P.Cavallini, G.Ammann, R. W.Lankisch, P. G.Andersen, J. R.Dimagno, E. P.Andren-Sandberg, A.Domellof, L.Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group [see comments]AdultCase-Control StudiesChronic DiseaseCohort StudiesConfidence IntervalsEurope/epidemiologyFemaleHumanIncidenceMaleMiddle AgePancreatic Neoplasms/epidemiology/*etiologyPancreatitis/*complicationsProportional Hazards ModelsRisk FactorsSupport, Non-U.S. Gov'tUnited States/epidemiologyN Engl J Med1993328201433-7Lowenfels1997300Lowenfels, A. B.Maisonneuve, P.DiMagno, E. P.Elitsur, Y.Gates, L. K., Jr.Perrault, J.Whitcomb, D. C.Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study GroupAdolescenceAdultAge of OnsetChildChild, PreschoolFemaleHumanIncidenceInfantLongitudinal StudiesMaleOdds RatioPancreatic Neoplasms/*geneticsPancreatitis/*geneticsRiskSupport, Non-U.S. Gov'tJ Natl Cancer Inst1997896442-6Goggins19968260Goggins, M.Schutte, M.Lu, J.Moskaluk, C.A.Weinstein, C.L.Petersen, G.M.Yeo, C.J.Jackson, C.E.Lynch, H.T.Hruban, R.H.Kern, S.E.1996Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomasCancer Res565360-5364Goldstein19958620Goldstein, A. M.Fraser, M. C.Struewing, J. P.Hussussian, C. J.Ranade, K.Zametkin, D. P.Fontaine, L. S.Organic, S. M.Dracopoli, N. C.Clark, W. H. J.Tucker, M.A.1995Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutationsN Engl J Med333 970-974van der Heijden200311700Fanconi anemia gene mutations in young-onset pancreatic cancervan der Heijden, M. S.Yeo, C. J.Hruban, R. H.Kern, S. E.Age FactorsAllelesAnimalCarcinoma, Pancreatic Ductal/*geneticsDNA-Binding Proteins/*geneticsGene SilencingGenetic Predisposition to DiseaseHumanLoss of HeterozygosityMiceMutationNeoplasm TransplantationPancreatic Neoplasms/*geneticsProteins/*geneticsSupport, U.S. Gov't, P.H.S.Transplantation, HeterologousCancer Res200363102585-8.Petersen200312990Familial pancreatic cancer: where are we in 2003?Petersen, G. M.Hruban, R. H.Europe*Genes, BRCA2*Germ-Line MutationHumanNational Institutes of Health (U.S.)Pancreatic Neoplasms/*geneticsRegistriesUnited StatesJ Natl Cancer Inst2003953180-1.(101-109)(100-108). Most of the known inherited causes of pancreatic cancer are due to germ line BRCA2 mutations, which are found in ~10% of all familial pancreatic cancers ADDIN EN.CITE Goggins19968260Goggins, M.Schutte, M.Lu, J.Moskaluk, C.A.Weinstein, C.L.Petersen, G.M.Yeo, C.J.Jackson, C.E.Lynch, H.T.Hruban, R.H.Kern, S.E.1996Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomasCancer Res565360-5364Murphy200210830Evaluation of Candidate Genes MAP2K4, MADH4, ACVR1B, and BRCA2 in Familial Pancreatic Cancer: Deleterious BRCA2 Mutations in 17%Murphy, K. M.Brune, K. A.Griffin, C.Sollenberger, J. E.Petersen, G. M.Bansal, R.Hruban, R. H.Kern, S. E.Cancer Res200262133789-93.Hahn200312980BRCA2 germline mutations in familial pancreatic carcinomaHahn, S. A.Greenhalf, B.Ellis, I.Sina-Frey, M.Rieder, H.Korte, B.Gerdes, B.Kress, R.Ziegler, A.Raeburn, J. A.Campra, D.Grutzmann, R.Rehder, H.Rothmund, M.Schmiegel, W.Neoptolemos, J. P.Bartsch, D. K.AdultAgedDNA, Neoplasm/analysisEuropeFemaleFrameshift Mutation*Genes, BRCA2Genetic Predisposition to Disease*Germ-Line MutationGermanyHumanLymphocytesMaleMiddle AgedPancreatic Neoplasms/*geneticsPedigreePhenotypeRegistriesSequence Analysis, DNASupport, Non-U.S. Gov'tJ Natl Cancer Inst2003953214-21.Real200214690Family history of cancer and germline BRCA2 mutations in sporadic exocrine pancreatic cancerReal, F. X.Malats, N.Lesca, G.Porta, M.Chopin, S.Lenoir, G. M.Sinilnikova, O.AdultAgedBRCA2 Protein/*geneticsDNA Mutational AnalysisDNA, Neoplasm/geneticsFemaleGenetic Predisposition to Disease*Germ-Line MutationHumansMaleMiddle AgedNeoplasm Proteins/*geneticsNeoplastic Syndromes, Hereditary/*geneticsPancreatic Neoplasms/*geneticsResearch Support, Non-U.S. Gov'tGut2002505653-7.(103, 110-112)(102, 109-111) and ~5% of patients with apparently sporadic pancreatic cancer ADDIN EN.CITE Goggins19968260Goggins, M.Schutte, M.Lu, J.Moskaluk, C.A.Weinstein, C.L.Petersen, G.M.Yeo, C.J.Jackson, C.E.Lynch, H.T.Hruban, R.H.Kern, S.E.1996Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomasCancer Res565360-5364Ozcelik19979700Ozcelik, H.Schmocker, B.Di Nicola, N.Shi, X. H.Langer, B.Moore, M.Taylor, B. R.Narod, S. A.Darlington, G.Andrulis, I. L.Gallinger, S.Redston, M.1997Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patientsNat Genet16117-8(102, 103)(101, 102). Kindred with germ line BRCA2 mutations may have multiple pancreatic cancers in the absence of breast or ovarian cancer. Therefore, at many centers in the USA patients with a strong family history of pancreatic cancer are recommended to undergo genetic testing for germ line BRCA2 mutations after appropriate genetic counseling. This is based on expert opinion and applies to populations where BRCA2 mutations have been demonstrated in patients with familial pancreatic cancer ADDIN EN.CITE Goggins19968260Goggins, M.Schutte, M.Lu, J.Moskaluk, C.A.Weinstein, C.L.Petersen, G.M.Yeo, C.J.Jackson, C.E.Lynch, H.T.Hruban, R.H.Kern, S.E.1996Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomasCancer Res565360-5364Murphy200210830Evaluation of Candidate Genes MAP2K4, MADH4, ACVR1B, and BRCA2 in Familial Pancreatic Cancer: Deleterious BRCA2 Mutations in 17%Murphy, K. M.Brune, K. A.Griffin, C.Sollenberger, J. E.Petersen, G. M.Bansal, R.Hruban, R. H.Kern, S. E.Cancer Res200262133789-93.Hahn200312980BRCA2 germline mutations in familial pancreatic carcinomaHahn, S. A.Greenhalf, B.Ellis, I.Sina-Frey, M.Rieder, H.Korte, B.Gerdes, B.Kress, R.Ziegler, A.Raeburn, J. A.Campra, D.Grutzmann, R.Rehder, H.Rothmund, M.Schmiegel, W.Neoptolemos, J. P.Bartsch, D. K.AdultAgedDNA, Neoplasm/analysisEuropeFemaleFrameshift Mutation*Genes, BRCA2Genetic Predisposition to Disease*Germ-Line MutationGermanyHumanLymphocytesMaleMiddle AgedPancreatic Neoplasms/*geneticsPedigreePhenotypeRegistriesSequence Analysis, DNASupport, Non-U.S. Gov'tJ Natl Cancer Inst2003953214-21.(103, 110, 111)(102, 109, 110). In addition to considerations regarding prophylactic mastectomy and oophorectomy, patients with germ line BRCA2 mutations may benefit from screening to look for evidence of pancreatic neoplasia ADDIN EN.CITE Canto MI12260Canto MI,, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.2004Screening for pancreatic neoplasia in high risk individualsClin Gastro Hepatol2606-21 ADDIN EN.CITE Canto MI12260Canto MI, Goggins M, Yeo CJ, Griffin C, Axilbund JE, Brune K, Ali SZ, Jagannath S, Petersen GM, Fishman EK, Piantadosi S, Giardiello FM, and Hruban RH.Screening for pancreatic neoplasia in high risk individualsClinical Gastroenterology and Hepatology2606-21(26), but this is still under investigation. The other known genes cause only a very small percentage of familial pancreatic cancers. Pancreatic cancer families with a malignant melanoma will occasionally harbor germ line p16 mutations, but there is not enough evidence to recommend these patients for p16 gene testing ADDIN EN.CITE H.T.Lynch20004070H.T.Lynch, R.M. Fusaro, J.L. Lynch, C.R. Kapler, L. Fusaro, R. Brand, M. Goggins, S.E. Kern.2000Genetic counseling and testing for germline p16 mutations in two pancreatic cancer-prone families.Gastroenterologyin pressLynch20027040Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone familiesLynch, H. T.Brand, R. E.Hogg, D.Deters, C. A.Fusaro, R. M.Lynch, J. F.Liu, L.Knezetic, J.Lassam, N. J.Goggins, M.Kern, S.Cancer200294184-96.Rutter200414680Heterogeneity of risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control studyRutter, J. L.Bromley, C. M.Goldstein, A. M.Elder, D. E.Holly, E. A.Guerry, D. thHartge, P.Struewing, J. P.Hogg, D.Halpern, A.Sagebiel, R. W.Tucker, M. A.AdultAgedCase-Control StudiesFamily HealthFemaleGastrointestinal Neoplasms/*geneticsGenes, p16Genetic HeterogeneityGerm-Line MutationHumansMaleMelanoma/*geneticsMiddle AgedPancreatic Neoplasms/*geneticsRisk FactorsCancer2004101122809-16.(113-115)(112-114). Individuals with pancreatic cancer who are from families having multiple members with melanomas may have familial atypical melanoma mole syndrome (FAMM) and in this setting p16 gene testing is appropriate (Table 2).
Tissue mMarkers of pancreatic cancer
Infiltrating adenocarcinomas of the pancreas differentially express a large number of proteins and many of these proteins can be detected using commercially available antibodies (see table 3). Some of these tissue markers may aid in establishing the diagnosis of cancer, but the diagnosis of pancreatic cancer should never be based solely on immunohistochemical labeling of tissues.
All adenocarcinomas of the pancreas express cytokeratin (CK) and almost all will label with the anti-cytokeratin antibodies AE1/AE3 and CAM 5.2 ADDIN EN.CITE Solcia199714491Solcia, E., Capella, C., and Klöppel, G1997Atlas of tumor pathology: Tumors of the pancreasWashington, DC Armed Forces Institute of Pathology3rd seriesIacobuzio-Donahue200314500Iacobuzio-Donahue, CA, Hruban, R. H2003Gene expression in neoplasms of the pancreas: applications to diagnostic pathology.Adv Anat Pathol10125-134Iacobuzio-Donahue200314517Iacobuzio-Donahue, C. A, Hruban, R. H.2003Expression Profiling of Pancreatic Ductal Adenocarcinoma.M. Ladanyi and W. L. GeraldExpression Profiling of Human Tumors: Diagnostic and Research ApplicationsTotowa: Humana Press Inc. 257-275 ADDIN EN.CITE Solcia199714491Solcia, E., Capella, C., and Klöppel, G1997Atlas of tumor pathology: Tumors of the pancreasWashington, DC Armed Forces Institute of Pathology3rd seriesIacobuzio-Donahue200314500Iacobuzio-Donahue, C. A. and Hruban, R. H2003Gene expression in neoplasms of the pancreas: applications to diagnostic pathology.Adv Anat Pathol10125-134Iacobuzio-Donahue200314517Iacobuzio-Donahue, C. A. and Hruban, R. H.2003Expression Profiling of Pancreatic Ductal Adenocarcinoma.M. Ladanyi and W. L. GeraldExpression Profiling of Human Tumors: Diagnostic and Research ApplicationsTotowa: Humana Press Inc. 257-275(116-118)(115-117). Antibodies are now available to a number of cytokeratins of different molecular weights and CK 7, CK 8, CK 18 and CK 19 are expressed in 70-100% of pancreatic cancers (115). CK 17 is expressed in 50-70%, and CK 20 in <20% ADDIN EN.CITE Solcia199714491Solcia, E., Capella, C., and Klöppel, G1997Atlas of tumor pathology: Tumors of the pancreasWashington, DC Armed Forces Institute of Pathology3rd series(116)(115). The pattern of immunolabeling for cytokeratins can be diagnostically useful, as most acinar neoplasms and most well differentiated endocrine neoplasms of the pancreas do not express CK7.
Ductal adenocarcinomas of the pancreas also express epithelial membrane antigen (EMA), and a variety of tumor antigens including carcinoembryonic antigen (CEA), carcinoma antigen 19-9 (CA19-9), CA 125, and DuPan 2 ADDIN EN.CITE Solcia199714491Solcia, E., Capella, C., and Klöppel, G1997Atlas of tumor pathology: Tumors of the pancreasWashington, DC Armed Forces Institute of Pathology3rd seriesBalague199514520Balague, C., Audie, J. P., Porchet, N., and Real, F. X.1995In situ hybridization shows distinct patterns of mucin gene expression in normal, benign, and malignant pancreas tissues.Gastroenterology109953-964Shimizu199014530Shimizu, M., Saitoh, Y., Ohyanagi, H., and Itoh, H.1990Immunohistochemical staining of pancreatic cancer with CA19-9, KM01, unabsorbed CEA, and absorbed CEA.Arch Pathol Lab Med114195-200(116, 119, 120)(115, 118, 119). The expression of CEA may be particularly useful in distinguishing infiltrating adenocarcinoma from reactive glands.
Adenocarcinomas of the pancreas express several mucins including MUC1 (a pan-epithelial mucin equivalent to EMA), MUC3, MUC4, and MUC5AC (a gastric foveolar mucin) ADDIN EN.CITE Terada199614540Terada, T., Ohta, T., Sasaki, M., Nakanuma, Y., and Kim, Y. S.1996Expression of MUC apomucins in normal pancreas and pancreatic tumours.J Pathol180160-5(121)(120). A quarter of ductal adenocarcinomas will express MUC6 (a pyloric-gland mucin), but <10% will express MUC2. This pattern of mucin expression can help distinguish ductal adenocarcinomas from other tumor types in the pancreas. For example, the majority of intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) of the pancreas express MUC2 but not MUC1 ADDIN EN.CITE Terada199614540Terada, T., Ohta, T., Sasaki, M., Nakanuma, Y., and Kim, Y. S.1996Expression of MUC apomucins in normal pancreas and pancreatic tumours.J Pathol180160-5Lüttges200114550Lüttges, J., Zamboni, G., Longnecker, D. S., and Klöppel, G.2001The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma.Am.J.Surg.Pathol.25942-8Lüttges200214560Lüttges, J., Feyerabend, B., Buchelt, T., Pacena, M., and Klöppel, G.2002The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas.Am J Surg.Pathol26466-71Adsay200214620Adsay, N. V., Merati, K., Andea, A., Sarkar, F., Hruban, R. H., Wilentz, R. E., Goggins, M., Iocobuzio-Donahue, C., Longnecker, D. S., and Klimstra, D. S2002The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis.Mod Pathol151087-95(121-124)(120-123). MUC4 expression is under investigation for its utility for pancreatic cancer diagnosis and may help distinguish pancreatic cancer tissue samples from those with chronic pancreatitis ADDIN EN.CITE Andrianifahanana200116290Mucin (MUC) gene expression in human pancreatic adenocarcinoma and chronic pancreatitis: a potential role of MUC4 as a tumor marker of diagnostic significanceAndrianifahanana, M.Moniaux, N.Schmied, B. M.Ringel, J.Friess, H.Hollingsworth, M. A.Buchler, M. W.Aubert, J. P.Batra, S. K.Adenocarcinoma/*geneticsAgedAged, 80 and overChronic DiseaseComparative StudyFemaleGene Expression Regulation*Gene Expression Regulation, NeoplasticHumansMaleMiddle AgedMucins/analysis/*geneticsPancreas/chemistryPancreatic Neoplasms/*geneticsPancreatitis/*geneticsRNA/genetics/isolation & purificationRNA, Neoplasm/genetics/isolation & purificationReference ValuesResearch Support, U.S. Gov't, P.H.S.Reverse Transcriptase Polymerase Chain ReactionTumor Cells, CulturedTumor Markers, Biological/*analysisClin Cancer Res20017124033-40.(125). MUC4 expression also becomes increasingly likely in PanINs of advanced grade ADDIN EN.CITE Swartz200214720MUC4 expression increases progressively in pancreatic intraepithelial neoplasiaSwartz, M. J.Batra, S. K.Varshney, G. C.Hollingsworth, M. A.Yeo, C. J.Cameron, J. L.Wilentz, R. E.Hruban, R. H.Argani, P.Carcinoma in Situ/*metabolism/pathologyCarcinoma, Pancreatic Ductal/*metabolism/pathologyCell CountDisease ProgressionFluorescent Antibody Technique, IndirectHumansImmunohistochemistryMucins/*metabolismPancreatic Ducts/anatomy & histology/metabolismPancreatic Neoplasms/*metabolism/pathologyResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.Tumor Markers, Biological/*metabolismAm J Clin Pathol20021175791-6.(126).
The SMAD4 (DPC4/MADH4) tumor suppressor gene is genetically inactivated in 55% of pancreatic cancers and mutations in the DPC4 gene are highly correlated with loss of protein expression. Cancers showing an abnormal loss of Smad4 protein expression have a poorer prognosis ADDIN EN.CITE Tascilar20017080The SMAD4 protein and prognosis of pancreatic ductal adenocarcinomaTascilar, M.Skinner, H. G.Rosty, C.Sohn, T.Wilentz, R. E.Offerhaus, G. J.Adsay, V.Abrams, R. A.Cameron, J. L.Kern, S. E.Yeo, C. J.Hruban, R. H.Goggins, M.Clin Cancer Res20017124115-21.Wilentz20003850Wilentz, R. E.Iacobuzio-Donahue, C. A.Argani, P.McCarthy, D. M.Parsons, J. L.Yeo, C. J.Kern, S. E.Hruban, R. H.Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progressionAdenocarcinoma/*genetics/*pathology/surgeryDisease ProgressionDNA-Binding Proteins/analysis/*genetics*Gene Silencing*Genes, Suppressor, TumorHumanPancreatic Ducts/pathologyPancreatic Neoplasms/*genetics/*pathology/surgerySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Trans-Activators/analysis/*geneticsCancer Res20006072002-6(127, 128)(124, 125). Since loss of Smad4 expression is only occasionally found in other cancers and is not a feature of non-neoplastic pancreatic conditions, Smad4 expression has been demonstrated to facilitate the interpretation of diagnostically difficult cytological specimens ADDIN EN.CITE Tascilar20017070Immunohistochemical labeling for the Dpc4 gene product is a specific marker for adenocarcinoma in biopsy specimens of the pancreas and bile ductTascilar, M.Offerhaus, G. J.Altink, R.Argani, P.Sohn, T. A.Yeo, C. J.Cameron, J. L.Goggins, M.Hruban, R. H.Wilentz, R. E.Adenocarcinoma/*chemistryAgedBile Duct Neoplasms/*chemistry/pathologyBile Ducts, Extrahepatic/pathologyDNA-Binding Proteins/*analysisFemaleFluorescent Antibody Technique, IndirectHumanMaleMiddle AgeNeoplasm Proteins/*analysisPancreatic Neoplasms/*chemistry/pathologyReproducibility of ResultsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Trans-Activators/*analysisTumor Markers, Biological/*analysisAm J Clin Pathol20011166831-7.(129)(126).
Tumor markers under evaluation for use in pancreatic cancer [Category B (Table 4)]
CA242.
CA242, the non-fucosylated precursor sialyl-Lewisc antigen, is a mucin-based serum marker. The serum levels of this marker are not dependent on Lewisa secretor status ADDIN EN.CITE Lamerz199913901043680910 Suppl 41999Role of tumour markers, cytogenetics145-9Medical Department II, Klinikum Grosshadern, University of Munich, Germany. lamerz@med2.med.uni-muenchen.deLamerz, R.Ann OncolAntigens, Tumor-Associated, Carbohydrate/analysisCA-19-9 Antigen/analysisCarcinoembryonic Antigen/analysis*Chromosome AberrationsDNA Repair/geneticsGenes, Tumor SuppressorHumanPancreatic Neoplasms/*diagnosis/geneticsTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10436809(61). Substantial published data are available on the diagnostic utility of CA242 as a pancreatic cancer marker. Depending on the population studied, sensitivities of 41%-75% and specificities of 85-95% for the diagnosis of pancreatic cancer have been described ADDIN EN.CITE Haglund1994131080807357031994SepCA 242, a new tumour marker for pancreatic cancer: a comparison with CA 19-9, CA 50 and CEA487-92Fourth Department of Surgery, Helsinki University Central Hospital, Finland.Haglund, C.Lundin, J.Kuusela, P.Roberts, P. J.Br J CancerAntigens, Tumor-Associated, Carbohydrate/*bloodBiliary Tract Diseases/bloodBilirubin/bloodCarcinoembryonic Antigen/*bloodComparative StudyHumanLiver Diseases/bloodNeoplasm StagingPancreatic Diseases/bloodPancreatic Neoplasms/*blood/pathologySensitivity and SpecificitySupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8080735Ventrucci1998132095898073631998MarSerum CA 242: the search for a valid marker of pancreatic cancer179-84Dipartimento di Medicina Interna e Gastroenterologia, Universita di Bologna, Italy. Ventrucc@med.unibo.itVentrucci, M.Ubalducci, G. M.Cipolla, A.Panella, M. A.Ligabue, A.Clin Chem Lab MedAdolescentAdultAgedAged, 80 and overAntigens, Tumor-Associated, Carbohydrate/*bloodCA-19-9 Antigen/*bloodComparative StudyFemaleHumanMaleMiddle AgedPancreatic Neoplasms/blood/*diagnosisPancreatitis/blood/diagnosisSupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9589807Ozkan200313301457181350532003Sep-OctComparison of tumor marker CA 242 with CA 19-9 and carcinoembryonic antigen (CEA) in pancreatic cancer1669-74Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.Ozkan, H.Kaya, M.Cengiz, A.HepatogastroenterologyAntigens, Tumor-Associated, Carbohydrate/*bloodBile Duct Neoplasms/diagnosisBile Ducts, IntrahepaticCA-19-9 Antigen/*bloodCarcinoembryonic Antigen/*bloodCholangiocarcinoma/diagnosisCholedocholithiasis/diagnosisComparative StudyHumanLiver Cirrhosis/diagnosisPancreatic Neoplasms/*diagnosisSensitivity and Specificityhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14571813(130-132)(127-129). Overall, the reported diagnostic performance is similar to that of CA19.9 ADDIN EN.CITE Haglund1994131080807357031994SepCA 242, a new tumour marker for pancreatic cancer: a comparison with CA 19-9, CA 50 and CEA487-92Fourth Department of Surgery, Helsinki University Central Hospital, Finland.Haglund, C.Lundin, J.Kuusela, P.Roberts, P. J.Br J CancerAntigens, Tumor-Associated, Carbohydrate/*bloodBiliary Tract Diseases/bloodBilirubin/bloodCarcinoembryonic Antigen/*bloodComparative StudyHumanLiver Diseases/bloodNeoplasm StagingPancreatic Diseases/bloodPancreatic Neoplasms/*blood/pathologySensitivity and SpecificitySupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8080735Kawa1994134080807347031994SepComparative study of CA242 and CA19-9 for the diagnosis of pancreatic cancer481-6Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.Kawa, S.Tokoo, M.Hasebe, O.Hayashi, K.Imai, H.Oguchi, H.Kiyosawa, K.Furuta, S.Homma, T.Br J CancerAntigens, Tumor-Associated, Carbohydrate/*bloodChronic DiseaseComparative StudyHepatitis/blood/diagnosisHumanLewis Blood-Group SystemLiver Cirrhosis/blood/diagnosisNeoplasm StagingPancreatic Neoplasms/*blood/*diagnosisPancreatitis/blood/diagnosisReference ValuesRetrospective StudiesSensitivity and SpecificitySupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8080734Nilsson1992135017396206521992FebSensitivity and specificity of CA242 in gastro-intestinal cancer. A comparison with CEA, CA50 and CA 19-9215-21Pharmacia CanAg, Goteborg, Sweden.Nilsson, O.Johansson, C.Glimelius, B.Persson, B.Norgaard-Pedersen, B.Andren-Sandberg, A.Lindholm, L.Br J CancerAnimalsAntigens, Tumor-Associated, Carbohydrate/*bloodCarcinoembryonic Antigen/*bloodColorectal Neoplasms/bloodComparative StudyGastrointestinal Diseases/bloodGastrointestinal Neoplasms/*blood/pathologyHumanMiceMice, Inbred BALB CNeoplasm StagingPancreatic Neoplasms/bloodROC CurveSensitivity and SpecificityTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1739620Plebani1995136078003375211995Jan-FebIs CA242 really a new tumour marker for pancreatic adenocarcinoma?19-23Institute of Laboratory Medicine, University of Padua, Italy.Plebani, M.Basso, D.Navaglia, F.D'Angeli, F.Panozzo, M. P.Del Giudice, G.Battistel, M.Meggiato, T.Del Favero, G.OncologyAdenocarcinoma/*bloodAdolescentAdultAgedAged, 80 and overAntigens, Tumor-Associated, Carbohydrate/*bloodCA-19-9 Antigen/bloodFemaleGastrointestinal Neoplasms/bloodHumanMaleMiddle AgedPancreatic Neoplasms/*bloodSupport, Non-U.S. Gov'tTumor Cells, CulturedTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7800337(130, 133-135)(127, 130-132). In a study of 42 consecutive patients with pancreatic carcinoma, CA19.9 (at a cut-off value of 37 U/ml) and CA242 (cut-off value 20 U/ml) had essentially the same performance characteristics. CA242 was better than CA19.9 with respect to specificity (>90%), whereas CA19.9 had better sensitivity (>70%) ADDIN EN.CITE Banfi19963087766071121996Apr-JunCA 19.9, CA 242 and CEA in the diagnosis and follow-up of pancreatic cancer77-81Servizio Integrato di Medicina di Laboratorio, Istituto Scientifico H. S. Raffaele, Milano, Italy.Banfi, G.Bravi, S.Ardemagni, A.Zerbi, A.Int J Biol MarkersAntigens, Tumor-Associated, Carbohydrate/*analysisCA-19-9 Antigen/*analysisCarcinoembryonic Antigen/*analysisHumanPancreatic Neoplasms/*diagnosisSensitivity and Specificityhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8776607(136)(133). CA242 levels also carry prognostic significance. In one study, patients with resected pancreatic cancer and a preoperative CA242 <25 U/ml had a significantly better prognosis than those with higher CA242 levels, independent of resectability and of CA19-9 levels ADDIN EN.CITE Lundin199513808572621155B1995Sep-OctPrognostic significance of serum CA 242 in pancreatic cancer. A comparison with CA 19-92181-6Fourth Department of Surgery, Helsinki University Central Hospital, Finland.Lundin, J.Roberts, P. J.Kuusela, P.Haglund, C.Anticancer ResAntigens, Tumor-Associated, Carbohydrate/*bloodCA-19-9 Antigen/*bloodComparative StudyHumanMultivariate AnalysisNeoplasm StagingPancreatic Neoplasms/*immunology/mortality/pathologyPrognosisSupport, Non-U.S. Gov'tSurvival RateTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8572621(137)(134). The advantages of CA242 over CA19-9 include its independence of Lewis antigen status and that its levels are less influenced by cholestasis ADDIN EN.CITE Kawa1994134080807347031994SepComparative study of CA242 and CA19-9 for the diagnosis of pancreatic cancer481-6Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.Kawa, S.Tokoo, M.Hasebe, O.Hayashi, K.Imai, H.Oguchi, H.Kiyosawa, K.Furuta, S.Homma, T.Br J CancerAntigens, Tumor-Associated, Carbohydrate/*bloodChronic DiseaseComparative StudyHepatitis/blood/diagnosisHumanLewis Blood-Group SystemLiver Cirrhosis/blood/diagnosisNeoplasm StagingPancreatic Neoplasms/*blood/*diagnosisPancreatitis/blood/diagnosisReference ValuesRetrospective StudiesSensitivity and SpecificitySupport, Non-U.S. Gov'tTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8080734(133)(130). In conclusion, CA242 has been shown to have similar, but not superior diagnostic performance compared to CA19-9. In selected situations, such as Lewisa non-secretor status, its determination may be clinically useful.
CAM 17.1
CAM 17.1, a sialylated blood group type-1 antigen, probably sialyl-I ADDIN EN.CITE Lamerz199913901043680910 Suppl 41999Role of tumour markers, cytogenetics145-9Medical Department II, Klinikum Grosshadern, University of Munich, Germany. lamerz@med2.med.uni-muenchen.deLamerz, R.Ann OncolAntigens, Tumor-Associated, Carbohydrate/analysisCA-19-9 Antigen/analysisCarcinoembryonic Antigen/analysis*Chromosome AberrationsDNA Repair/geneticsGenes, Tumor SuppressorHumanPancreatic Neoplasms/*diagnosis/geneticsTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10436809Eccleston1998140098133915961998Nov-DecPancreatic tumour marker anti-mucin antibody CAM 17.1 reacts with a sialyl blood group antigen, probably I, which is expressed throughout the human gastrointestinal tract665-70Department of Histopathology, Walton Hospital, Liverpool, UK.Eccleston, D. W.Milton, J. D.Hoffman, J.Bara, J.Rhodes, J. M.DigestionAdultAntibodies, Monoclonal/immunologyAntigen-Antibody ReactionsBiopsyComparative StudyHemagglutination/immunologyHumanI Blood-Group System/*immunologyImmunoblottingImmunoenzyme TechniquesIntestinal Diseases/immunologyIntestinal Mucosa/*immunologyMucins/*immunologyPancreatic Neoplasms/*immunology/pathologySialic Acids/*immunologyTumor Markers, Biological/*immunologyhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9813391(61, 138)(61, 135), is also a mucin-based marker. Initial reports using sera from patients with pancreatic cancer and various controls (chronic pancreatitis, healthy controls, those with other GI cancers) describe sensitivities of 67-78% and specificities of 76-91% ADDIN EN.CITE Gansauge19961410898040374121996DecCAM 17.1--a new diagnostic marker in pancreatic cancer1997-2002Department of General Surgery, University of Ulm, Germany.Gansauge, F.Gansauge, S.Parker, N.Beger, M. I.Poch, B.Link, K. H.Safi, F.Beger, H. G.Br J CancerAdultAgedAntibodies, Monoclonal/analysis/bloodCarcinoma/chemistry/*diagnosis/metabolismFemaleFlow Cytometry/methodsHumanImmunohistochemistry/methodsMaleMiddle AgedNeoplasm StagingPancreas/chemistry/metabolism/pathologyPancreatic Diseases/metabolism/pathologyPancreatic Neoplasms/chemistry/*diagnosis/metabolismPancreatitis/metabolism/pathologySensitivity and SpecificitySurvival AnalysisTumor Cells, CulturedTumor Markers, Biological/*analysis/bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8980403Parker1992142015159827051992Sep 1A new enzyme-linked lectin/mucin antibody sandwich assay (CAM 17.1/WGA) assessed in combination with CA 19-9 and peanut lectin binding assay for the diagnosis of pancreatic cancer1062-8University Department of Medicine, Liverpool University, United Kingdom.Parker, N.Makin, C. A.Ching, C. K.Eccleston, D.Taylor, O. M.Milton, J. D.Rhodes, J. M.CancerAdolescentAdultAntibodies, Monoclonal/*diagnostic useAntigens, Tumor-Associated, Carbohydrate/*analysisFemaleGlycoproteins/*bloodHumanImmunoenzyme TechniquesJaundice/blood/diagnosis/etiology*LectinsMaleMiddle AgedPancreatic Neoplasms/blood/complications/*diagnosisPeanut AgglutininRadioimmunoassayReproducibility of ResultsSensitivity and SpecificitySupport, Non-U.S. Gov't*Wheat Germ Agglutininshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1515982(139, 140)(136, 137). The diagnostic sensitivity of CAM 17.1 is similar to that of CA19-9, but CAM 17.1 may have higher specificity ADDIN EN.CITE Gansauge19961410898040374121996DecCAM 17.1--a new diagnostic marker in pancreatic cancer1997-2002Department of General Surgery, University of Ulm, Germany.Gansauge, F.Gansauge, S.Parker, N.Beger, M. I.Poch, B.Link, K. H.Safi, F.Beger, H. G.Br J CancerAdultAgedAntibodies, Monoclonal/analysis/bloodCarcinoma/chemistry/*diagnosis/metabolismFemaleFlow Cytometry/methodsHumanImmunohistochemistry/methodsMaleMiddle AgedNeoplasm StagingPancreas/chemistry/metabolism/pathologyPancreatic Diseases/metabolism/pathologyPancreatic Neoplasms/chemistry/*diagnosis/metabolismPancreatitis/metabolism/pathologySensitivity and SpecificitySurvival AnalysisTumor Cells, CulturedTumor Markers, Biological/*analysis/bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8980403(139)(136). One large prospective cohort study of serum CAM 17.1 in 250 patients suspected to have pancreatic cancer demonstrated a sensitivity for predicting pancreatic cancer of 86% and specificity of 91%; with 89% sensitivity and 94% specificity for patients who did not have jaundice ADDIN EN.CITE Yiannakou19971430903346534990491997Feb 8Prospective study of CAM 17.1/WGA mucin assay for serological diagnosis of pancreatic cancer389-92Department of Medicine, University of Liverpool, UK.Yiannakou, J. Y.Newland, P.Calder, F.Kingsnorth, A. N.Rhodes, J. M.LancetAntibodies, Monoclonal/*diagnostic useAntigens, Tumor-Associated, Carbohydrate/*analysisHumanImmunoassayJaundice/etiologyPancreatic Neoplasms/blood/complications/*diagnosisProspective StudiesSensitivity and SpecificitySupport, Non-U.S. Gov'thttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9033465(141)(138). The combination of CAM 17.1 and abdominal sonography further increased the sensitivity to 94%. In the same study, high CAM17.1 levels (>200U/L) also predicted non-resectability. Expression of CAM 17.1 is influenced by Lewisa antigen status ADDIN EN.CITE Eccleston1998140098133915961998Nov-DecPancreatic tumour marker anti-mucin antibody CAM 17.1 reacts with a sialyl blood group antigen, probably I, which is expressed throughout the human gastrointestinal tract665-70Department of Histopathology, Walton Hospital, Liverpool, UK.Eccleston, D. W.Milton, J. D.Hoffman, J.Bara, J.Rhodes, J. M.DigestionAdultAntibodies, Monoclonal/immunologyAntigen-Antibody ReactionsBiopsyComparative StudyHemagglutination/immunologyHumanI Blood-Group System/*immunologyImmunoblottingImmunoenzyme TechniquesIntestinal Diseases/immunologyIntestinal Mucosa/*immunologyMucins/*immunologyPancreatic Neoplasms/*immunology/pathologySialic Acids/*immunologyTumor Markers, Biological/*immunologyhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9813391(138)(135); consequently the same limitation (7-10% non-secretor in the general population) seen with CA19-9 applies. The potential superiority to CA19-9 in terms of specificity has not been confirmed in other studies.
Tissue polypeptide specific antigen (TPS)
Two retrospective cohort studies have investigated the role of tissue polypeptide specific antigen (TPS), an epitope from soluble cytokeratin 18 fragments, in the monitoring of palliative chemotherapy for advanced pancreatic cancer. One of these studies showed a superior performance in comparison with CA 19-9 ADDIN EN.CITE Glimelius1996174086393083521996Monitoring palliative chemotherapy in advanced gastrointestinal cancer using serial tissue polypeptide specific antigen (TPS) measurements141-8Department of Oncology, Uppsala University, Sweden.Glimelius, B.Hoffman, K.Einarsson, R.Pahlman, L.Graf, W.Acta OncolAdultAgedAged, 80 and overAntineoplastic Agents/*therapeutic useDisease ProgressionFemaleGastrointestinal Neoplasms/*drug therapy/*immunologyHumanMaleMiddle Aged*Palliative CarePeptides/*bloodPredictive Value of TestsSensitivity and SpecificityTreatment OutcomeTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8639308Kornek1995170075295277111995JanTissue polypeptide-specific antigen (TPS) in monitoring palliative treatment response of patients with gastrointestinal tumours182-5Department of Internal Medicine I, Vienna University Medical School, Austria.Kornek, G.Schenk, T.Raderer, M.Djavarnmad, M.Scheithauer, W.Br J CancerAdultAgedAntigens, Tumor-Associated, Carbohydrate/analysisCA-19-9 Antigen/analysisFemaleGastrointestinal Neoplasms/*chemistry/therapyHumanMaleMiddle Aged*Palliative CarePeptides/*analysisTissue Polypeptide AntigenTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7529527(41, 142)(41, 139). However, both studies only included a limited number of patients (n=9 and 20). TPS has also been investigated for its ability to differentiate patients with chronic pancreatitis from those with pancreatic cancer but results are inconclusive ADDIN EN.CITE Kornek1995170075295277111995JanTissue polypeptide-specific antigen (TPS) in monitoring palliative treatment response of patients with gastrointestinal tumours182-5Department of Internal Medicine I, Vienna University Medical School, Austria.Kornek, G.Schenk, T.Raderer, M.Djavarnmad, M.Scheithauer, W.Br J CancerAdultAgedAntigens, Tumor-Associated, Carbohydrate/analysisCA-19-9 Antigen/analysisFemaleGastrointestinal Neoplasms/*chemistry/therapyHumanMaleMiddle Aged*Palliative CarePeptides/*analysisTissue Polypeptide AntigenTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7529527Plebani1993175082332835061993Nov-DecClinical utility of TPS, TPA and CA 19-9 measurement in pancreatic cancer436-40Institute of Laboratory Medicine, University of Padua, Italy.Plebani, M.Basso, D.Del Favero, G.Ferrara, C.Meggiato, T.Fogar, P.Mangano, F.Ricciardi, G.Burlina, A.OncologyAdultAgedAged, 80 and overAntigens, Tumor-Associated, Carbohydrate/bloodFemaleHumanLiver Function TestsMaleMiddle AgedPancreatic Neoplasms/blood/*diagnosisPeptides/*bloodReference ValuesTissue Polypeptide AntigenTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8233283Banfi1993176084488513931993MarBehavior of tumor markers CA19.9, CA195, CAM43, CA242, and TPS in the diagnosis and follow-up of pancreatic cancer420-3Laboratorio Analisi, Istituto Scientifico H. S. Raffaele, Milano, Italy.Banfi, G.Zerbi, A.Pastori, S.Parolini, D.Di Carlo, V.Bonini, P.Clin ChemAdultAgedAntigens, Tumor-Associated, Carbohydrate/*blood/classificationFalse Positive ReactionsFemaleHumanMaleMiddle AgedNeoplasm StagingPancreatic Neoplasms/*blood/diagnosis/pathologyPeptides/*bloodTissue Polypeptide AntigenTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=8448851(41, 143, 144)(41, 140, 141). In one study of 122 patients with suspected pancreatic carcinoma or chronic pancreatitis an elevated TPS level (>100 U/L) was found in 100% (46/46) of the patients with pancreatic cancer, whereas an elevated CA 19-9 (>37U/ mL) was seen in 32/46 (70%) patients. Elevations of TPS and CA 19-9 levels were found in 22% and 19% of 74 patients with chronic pancreatitis, respectively. If a cut-off value of 200 U/L was used, TPS had a sensitivity of 97% and specificity of 98% in discriminating pancreatic cancer from chronic pancreatitis ADDIN EN.CITE Slesak200050108970048912000Jul 1Tissue polypeptide specific antigen (TPS), a marker for differentiation between pancreatic carcinoma and chronic pancreatitis. A comparative study with CA 19-983-8Department of Tumor Immunology, Wroclaw Medical University, Wroclaw, Poland.Slesak, B.Harlozinska-Szmyrka, A.Knast, W.Sedlaczek, P.van Dalen, A.Einarsson, R.CancerAdultAgedCA-19-9 Antigen/*analysisCarcinoma/*diagnosis/immunologyChronic DiseaseDiagnosis, DifferentialFemaleHumanImmunoassayMaleMiddle AgedPancreatic Neoplasms/*diagnosis/immunologyPancreatitis/*diagnosis/immunologyProspective StudiesSensitivity and SpecificityTissue Polypeptide Antigen/*analysisTumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10897004(145)(142). These data suggest that TPS may have a role in the detection of early pancreatic cancer and in the monitoring of responses to therapy, but further study is warranted before definitive recommendations can be made.
Potential tumor markers for pancreatic cancer still in the research or discovery stage [Category C (Table 4)]
Serum macrophage inhibitory cytokine 1 (MIC-1)
Serum macrophage inhibitory cytokine 1 (MIC-1) was initially identified as being over expressed in pancreatic and colorectal cancer by gene expression studies ADDIN EN.CITE Buckhaults20018601158572361192001Oct 1Secreted and cell surface genes expressed in benign and malignant colorectal tumors6996-7001Howard Hughes Medical Institute, Johns Hopkins Medical Institution, Baltimore, Maryland 21231, USA.Buckhaults, P.Rago, C.St Croix, B.Romans, K. E.Saha, S.Zhang, L.Vogelstein, B.Kinzler, K. W.Cancer ResAdenomatous Polyposis Coli/genetics/metabolismColorectal Neoplasms/*genetics/metabolism/secretionGene Expression Profiling/methodsGene Expression Regulation, NeoplasticHumanIn Situ HybridizationMembrane Proteins/biosynthesis/*genetics/secretionPolymerase Chain Reaction/methodsRNA, Messenger/geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11585723Koopmann20041210150731151072004Apr 1Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers2386-92Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.Koopmann, J.Buckhaults, P.Brown, D. A.Zahurak, M. L.Sato, N.Fukushima, N.Sokoll, L. J.Chan, D. W.Yeo, C. J.Hruban, R. H.Breit, S. N.Kinzler, K. W.Vogelstein, B.Goggins, M.Clin Cancer Reshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15073115(146, 147)(143, 144) and is also over expressed in prostate and other cancers ADDIN EN.CITE Welsh200114370Analysis of gene expression identifies candidate markers and pharmacological targets in prostate cancerWelsh, J. B.Sapinoso, L. M.Su, A. I.Kern, S. G.Wang-Rodriguez, J.Moskaluk, C. A.Frierson, H. F., Jr.Hampton, G. M.Adenocarcinoma/drug therapy/*genetics/metabolism/pathologyAdultAgedCytokines/biosynthesis/geneticsFatty Acid Synthetase Complex/biosynthesis/genetics*Gene Expression ProfilingGene Expression Regulation, NeoplasticHumanMaleMiddle AgedProstate-Specific Antigen/biosynthesis/geneticsProstatic Neoplasms/drug therapy/*genetics/metabolism/pathologySerine Endopeptidases/biosynthesis/geneticsTumor Cells, CulturedTumor Markers, Biological/biosynthesis/*geneticsTumor Stem Cell AssayCancer Res200161165974-8.(148)(145). Serum MIC-1 level and genotype has been associated with progression and prognosis of colorectal carcinoma ADDIN EN.CITE Brown200319012855642972003JulMIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma2642-50Centre for Immunology, St. Vincent's Hospital and University of New South Wales, Sydney NSW, Australia.Brown, D. A.Ward, R. L.Buckhaults, P.Liu, T.Romans, K. E.Hawkins, N. J.Bauskin, A. R.Kinzler, K. W.Vogelstein, B.Breit, S. N.Clin Cancer ResAdenoma/genetics/metabolismAdenomatous Polyps/metabolismAllelesCarcinoma/genetics/*metabolismCell Line, TumorCohort StudiesColorectal Neoplasms/genetics/*metabolismCytokines/*blood/*geneticsDisease-Free SurvivalFemaleGenotypeHumanImmunohistochemistryLogistic ModelsLymphocytes/metabolismMaleNeoplasm MetastasisPrognosisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Time FactorsTransforming Growth Factor beta/metabolismTreatment OutcomeUp-Regulationhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12855642(149)(146). Recently, the diagnostic performance of MIC-1 was investigated using a custom-designed ELISA to assay 326 sera samples from patients with resectable pancreatic cancer (n=80), resectable ampullary and cholangiocarcinoma (n=30), other pancreatic neoplasms (n=42), chronic pancreatitis (n=77) and healthy controls (n=97). Serum MIC-1 had a sensitivity of 71% and specificity of 78% (cutoff 1070 pg/ml). CA19-9 had similar diagnostic utility in this cohort (ROC AUC 0.81 for MIC-1 and 0.77 for CA 19-9). The combination of MIC-1 and CA19-9 significantly improved the diagnostic accuracy compared to each single marker (ROC 0.87). More recently, MIC-1 was compared to CA19-9 and other investigational markers after some minor modifications in assay performance. Serum MIC-1 was elevated in 96% of individuals with resectable pancreatic cancer, as well as in 42% of those with chronic pancreatitis. The diagnostic accuracy of MIC-1 by ROC curve analysis was significantly better than CA19-9 (Koopmann et al, unpublished).
Osteopontin
Since first identified as a transformation-associated protein, osteopontin (OPN) has been recognized as important in the processes of tumorigenicity and metastasis ADDIN EN.CITE Rittling20042501513846490102004May 17Role of osteopontin in tumour progression1877-81Department of Genetics, Rutgers University, Piscataway, NJ, USA. rittling@biology.rutgers.eduRittling, S. R.Chambers, A. F.Br J CancerAnimals*Cell Transformation, NeoplasticDisease Models, AnimalDisease ProgressionGene Expression Regulation, NeoplasticGlycoproteins/*pharmacologyHumanMiceNeoplasms/*pathologyPrognosisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15138464(150)(147). OPN is over expressed in lung, breast, prostate, gastric, esophageal and ovarian cancers ADDIN EN.CITE Furger200126011899236152001NovThe functional and clinical roles of osteopontin in cancer and metastasis621-32London Regional Cancer Centre, Ontario, Canada.Furger, K. A.Menon, R. K.Tuckl, A. B.Bramwelll, V. H.Chambers, A. F.Curr Mol MedAnimalsBreast Neoplasms/etiology/physiopathologyCell SurvivalFemaleHumanNeoplasm Metastasis/*physiopathologyNeoplasms/etiology/pathology/*physiopathologyNeovascularization, PathologicPrognosisReceptors, Cell Surface/physiologyReceptors, Growth Factor/physiologySialoglycoproteins/blood/*physiologySupport, Non-U.S. Gov'tSupport, U.S. Gov't, Non-P.H.S.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11899236(151)(148). Gene expression profiling technology has also been used to demonstrate increased osteopontin (OPN) mRNA expression in pancreatic cancers ADDIN EN.CITE Iacobuzio-Donahue200280Iacobuzio-Donahue, C.A.Maitra, A.Shen-Ong, G.L.Van Heek, T.Ashfaq, R.Meyer, R.Walter, K.Berg,K.Hollingsworth, M.A.Cameron, J. L.Yeo, C. J.Kern, S.E.Goggins, M.Hruban, R.H.2002Discovery of novel tumor markers of pancreatic cancer using global gene expression technologyAm. J. Pathol.16041239-1249(152)(149). As a secreted molecule, serum OPN can be measured using an ELISA assay designed to limit osteopontin factor H interactions in the serum. Serum OPN was measured in patients with resectable pancreatic cancer (n=50) and in normal controls (n=22) and found to outperform CA19-9, with 97% specificity and 80% sensitivity for OPN (cutoff 334 ng/ mL).
Tissue inhibitor of metalloproteinase type 1 (TIMP-1)
Tissue inhibitor of metalloproteinase type 1 (TIMP-1) was first identified as a potential marker of pancreatic cancer following the discovery that it was over expressed in pancreatic cancer tissues ADDIN EN.CITE Zhou1998110Zhou, W.Sokoll, L. J.Bruzek, D. J.Zhang, L.Velculescu, V. E.Goldin, S. B.Hruban, R. H.Kern, S. E.Hamilton, S. R.Chan, D.W.Vogelstein, B.Kinzler, K. W.1998Identifying markers for pancreatic cancer by gene expression analysisCancer Epidemiol. Biomarkers Prev.72109-112(153)(150). Plasma TIMP-1 levels have been reported to be increased in patients with colorectal cancers, with levels having prognostic significance in patients with colorectal carcinoma ADDIN EN.CITE Yukawa200423015274408243b2004May-JunPrognostic impact of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with colorectal cancer2101-5Gastroenterological Center, Yokohama City University Medical Center, 4-57 urafunecho, Minami-ku, Yokohama 232-0024, Japan. nryukawa@mac.comYukawa, N.Yoshikawa, T.Akaike, M.Sugimasa, Y.Takemiya, S.Yanoma, S.Imada, T.Noguchi, Y.Anticancer ResAgedColorectal Neoplasms/*blood/pathologyFemaleHumanMaleMiddle AgedMultivariate AnalysisNeoplasm MetastasisNeoplasm StagingPrognosisTissue-Inhibitor of Metalloproteinase-1/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15274408(154)(151) and primary breast cancer ADDIN EN.CITE Schrohl2004240150731041072004Apr 1Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer2289-98The Royal Veterinary and Agricultural University, Department of Pharmacology and Pathobiology, Frederiksberg C, Denmark. sofie@kvl.dkSchrohl, A. S.Holten-Andersen, M. N.Peters, H. A.Look, M. P.Meijer-van Gelder, M. E.Klijn, J. G.Brunner, N.Foekens, J. A.Clin Cancer Reshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15073104(155)(152). Evaluation of TIMP-1 using a commercial ELISA that detects free and complexed forms showed significantly higher levels in the sera of patients with pancreatic cancer (n=85) compared to normal controls (n=98). While serum TIMP-1 did not outperform CA19-9, in one study the combined measurement of TIMP-1, CEA and CA19-9 levels achieved 100% specificity at 60% sensitivity (specificity optimized cutoff values) and 95% specificity at 81% sensitivity (sensitivity optimized cutoff values), illustrating the potential utility of combining markers ADDIN EN.CITE Zhou199813260Identifying markers for pancreatic cancer by gene expression analysisZhou, W.Sokoll, L. J.Bruzek, D. J.Zhang, L.Velculescu, V. E.Goldin, S. B.Hruban, R. H.Kern, S. E.Hamilton, S. R.Chan, D. W.Vogelstein, B.Kinzler, K. W.Blotting, NorthernCA-19-9 Antigen/bloodCarcinoembryonic Antigen/bloodEnzyme-Linked Immunosorbent Assay*Gene ExpressionHumanPancreatic Neoplasms/*blood/*diagnosis/geneticsSensitivity and SpecificitySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tissue-Inhibitor of Metalloproteinase-1/*blood/geneticsTumor Markers, Biological/*bloodCancer Epidemiol Biomarkers Prev199872109-12.(153)(150). Further study of the diagnostic utility of TIMP-1 measurement for pancreatic cancer diagnosis is required including further evaluation of assays and the best body fluid for analysis (plasma vs. serum).
Serum Proteomic markers
Since the serum proteome contains many potential biomarkers for disease detection, several proteomic approaches are being used to identify novel protein markers of disease. One of the most commonly used analytical platform for high-throughput proteomic studies uses a ProteinChip Biomarker System-II, also known as surface-enhanced laser desorption/ionization (SELDI), and a low-resolution time-of-flight ([TOF)] mass spectrometer. Pilot studies utilizing SELDI have identified candidate biomarkers in ovarian, breast, prostate and pancreatic cancers ADDIN EN.CITE Petricoin2002300301186711235993062002Feb 16Use of proteomic patterns in serum to identify ovarian cancer572-7Food and Drug Administration/National Institutes of Health Clinical Proteomics Program, Department of Therapeutic Proteins/Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA. petricoin@cber.fda.govPetricoin, E. F.Ardekani, A. M.Hitt, B. A.Levine, P. J.Fusaro, V. A.Steinberg, S. M.Mills, G. B.Simone, C.Fishman, D. A.Kohn, E. C.Liotta, L. A.LancetCA-125 Antigen/bloodFemaleHumanMass Screening/methodsOvarian Neoplasms/*blood/diagnosisPredictive Value of TestsProteome/*isolation & purificationSupport, U.S. Gov't, Non-P.H.S.http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11867112Petricoin2002310311238171194202002Oct 16Serum proteomic patterns for detection of prostate cancer1576-8Food and Drug Administration (FDA)-National Cancer Institute (NCI) Clinical Proteomics Program, Department of Therapeutic Proteins/Center for Biologics Evaluation and Research (CBER), Bethesda, MD, USA. petricoin@cber.fda.govPetricoin, E. F., 3rdOrnstein, D. K.Paweletz, C. P.Ardekani, A.Hackett, P. S.Hitt, B. A.Velassco, A.Trucco, C.Wiegand, L.Wood, K.Simone, C. B.Levine, P. J.Linehan, W. M.Emmert-Buck, M. R.Steinberg, S. M.Kohn, E. C.Liotta, L. A.J Natl Cancer InstCase-Control StudiesChi-Square DistributionDiagnosis, DifferentialHumanMalePredictive Value of TestsProstate-Specific Antigen/bloodProstatic Diseases/blood/diagnosisProstatic Neoplasms/*blood/*diagnosis/immunologyProteome/*analysisSpectrum Analysis, MassTumor Markers, Biological/*bloodhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12381711Koopmann200432032148719611032004Feb 1Serum diagnosis of pancreatic adenocarcinoma using surface-enhanced laser desorption and ionization mass spectrometry860-8Department of Pathology, Johns Hopkins Medical Institutions, 632 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA.Koopmann, J.Zhang, Z.White, N.Rosenzweig, J.Fedarko, N.Jagannath, S.Canto, M. I.Yeo, C. J.Chan, D. W.Goggins, M.Clin Cancer Reshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14871961Koopmann200433033150069281332004MarEvaluation of osteopontin as biomarker for pancreatic adenocarcinoma487-91Department of Pathology and Surgery, Johns Hopkins Medical Institutions, Baltimore, MD, USA.Koopmann, J.Fedarko, N. S.Jain, A.Maitra, A.Iacobuzio-Donahue, C.Rahman, A.Hruban, R. H.Yeo, C. J.Goggins, M.Cancer Epidemiol Biomarkers PrevAdenocarcinoma/*pathologyAdultAgedAged, 80 and overCase-Control StudiesEnzyme-Linked Immunosorbent AssayFemale*Gene Expression ProfilingHumanIn Situ HybridizationMacrophagesMaleMiddle AgedOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*pathologySensitivity and SpecificitySialoglycoproteins/*analysis/*biosynthesisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Markers, Biological/*analysishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15006928Koopmann200434034150731151072004Apr 1Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers2386-92Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.Koopmann, J.Buckhaults, P.Brown, D. A.Zahurak, M. L.Sato, N.Fukushima, N.Sokoll, L. J.Chan, D. W.Yeo, C. J.Hruban, R. H.Breit, S. N.Kinzler, K. W.Vogelstein, B.Goggins, M.Clin Cancer Reshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15073115Rosty200235035119121676262002Mar 15Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology1868-75Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.Rosty, C.Christa, L.Kuzdzal, S.Baldwin, W. M.Zahurak, M. L.Carnot, F.Chan, D. W.Canto, M.Lillemoe, K. D.Cameron, J. L.Yeo, C. J.Hruban, R. H.Goggins, M.Cancer ResAdultAgedAged, 80 and over*Antigens, NeoplasmBiosensing TechniquesCalcium-Binding Proteins/*biosynthesisCarcinoma, Pancreatic Ductal/*metabolismEnzyme-Linked Immunosorbent AssayFemaleHumanImmunohistochemistryLectins/*biosynthesis*Lectins, C-TypeMaleMiddle AgedPancreatic Juice/metabolismPancreatic Neoplasms/*metabolismReverse Transcriptase Polymerase Chain ReactionSpectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methodsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Markers, Biological/*biosynthesishttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11912167(156-161)(153-158). In addition, recently a large multicenter study of ovarian cancer sera identified three peptides that were diagnostically useful in discriminating ovarian cancer from control sera. These markers, having been discovered in patients from one center were validated using patients from other centers ADDIN EN.CITE Zhang200414660Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancerZhang, Z.Bast, R. C., Jr.Yu, Y.Li, J.Sokoll, L. J.Rai, A. J.Rosenzweig, J. M.Cameron, B.Wang, Y. Y.Meng, X. Y.Berchuck, A.Van Haaften-Day, C.Hacker, N. F.de Bruijn, H. W.van der Zee, A. G.Jacobs, I. J.Fung, E. T.Chan, D. W.Amino Acid SequenceApolipoprotein A-I/bloodCA-125 Antigen/bloodFemaleHumansImmunoassayMiddle AgedMolecular Sequence DataNeoplasm StagingOvarian Neoplasms/*blood/diagnosis/pathologyPrealbumin/metabolismPredictive Value of TestsProtein Array AnalysisProteomics/*methodsResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.Retrospective StudiesTumor Markers, Biological/*bloodCancer Res200464165882-90.(162)(159). In a case-control study, Koopmann et al. compared serum samples from patients with resectable pancreatic adenocarcinoma using SELDI to those of a variety of disease and healthy controls ADDIN EN.CITE Koopmann200432032148719611032004Feb 1Serum diagnosis of pancreatic adenocarcinoma using surface-enhanced laser desorption and ionization mass spectrometry860-8Department of Pathology, Johns Hopkins Medical Institutions, 632 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA.Koopmann, J.Zhang, Z.White, N.Rosenzweig, J.Fedarko, N.Jagannath, S.Canto, M. I.Yeo, C. J.Chan, D. W.Goggins, M.Clin Cancer Reshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14871961(158)(155). They found two discriminating peptide peaks could differentiate patients with pancreatic cancer from healthy controls with a sensitivity of 78% and specificity of 97%, outperforming CA19-9 (p<0.05). The diagnostic accuracy of these two peptides was improved by using them in combination with CA 19-9. SELDI markers were also better than CA19-9 in distinguishing patients with pancreatic cancer from those with pancreatitis. Although these results indicate the potential diagnostic utility of assaying small serum peptide markers of pancreatic cancer, large multicenter studies are needed to confirm these findings and to precisely identify peptide markers so that more specific assays can be designed for their detection.
Markers of pancreatic neoplasia detectable in pancreatic juice (Table 5)
Serum markers play an important role in the diagnosis of many cancers, but they are less useful for identifying non-invasive neoplasms. The need to identify very small non-invasive pancreatic neoplasms has led to interest in identifying novel markers of pancreatic neoplasia that can be applied to pancreatic juice specimens. Accurate molecular markers of pancreatic neoplasia that could be applied to test inconclusive cytological or biopsy specimens would be valuable for evaluating patients with suspected pancreatic cancer. Samples of pancreatic secretions (pancreatic juice) are also attractive diagnostic specimens because they have high concentrations of neoplastic DNA and proteins and could be a useful clinical specimen to use when diagnosing symptomatic patients as well as when screening high-risk individuals for evidence of early pancreatic cancer or of precancerous neoplasms of the pancreas, an approach analogous to using nipple aspirates for breast cancer diagnosis.
Multiple studies have determined the utility of using pancreatic juice samples to detect DNA methylation changes, DNA mutations, and protein over expression. For example, mutant K-ras genes are readily detected in pancreatic juice, but in plasma these mutations are usually detectable only after patients have inoperable cancer ADDIN EN.CITE Yamada199814080Yamada, T.Nakamori, S.Ohzato, H.Oshima, S.Aoki, T.Higaki, N.Sugimoto, K.Akagi, K.Fujiwara, Y.Nishisho, I.Sakon, M.Gotoh, M.Monden, M.Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological featuresClinical Cancer Research1998461527-32Mulcahy199814090Mulcahy, H. E.Lyautey, J.Lederrey, C.qi Chen, X.Anker, P.Alstead, E. M.Ballinger, A.Farthing, M. J.Stroun, M.A prospective study of K-ras mutations in the plasma of pancreatic cancer patientsClinical Cancer Research199842271-5Castells1999940Castells, A.Puig, P.Mora, J.Boadas, J.Boix, L.Urgell, E.Sole, M.Capella, G.Lluis, F.Fernandez-Cruz, L.Navarro, S.Farre, A.K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significanceAdenocarcinoma/blood/*diagnosis/geneticsAdultAgedChronic DiseaseDNA, Neoplasm/blood/*geneticsFemaleFollow-Up Studies*Genes, rasHumanMaleMiddle Age*MutationNeoplasm Circulating Cells/chemistry/pathologyPancreatic Neoplasms/blood/*diagnosis/geneticsPancreatitis/blood/geneticsPrognosisProspective StudiesSupport, Non-U.S. Gov'tJ Clin Oncol1999172578-84(163-165)(160-162). Pure pancreatic juice collection requires ERCP, but pancreatic juice can also be collected in the duodenum and assayed for the presence of cancer DNA during routine upper-gastrointestinal endoscopy after secretin stimulation without the need for ERCP. Pancreatic juice markers and the assays designed for their detection are currently still undergoing evaluation and have not yet been demonstrated to be useful in clinical practice.
DNA alterations in pancreatic juice as markers of pancreatic cancer
Mutant DNA
The diagnostic potential of DNA-based markers has improved in recent years, with technological developments including chip-based technology, and quantitative polymerase chain reaction (PCR) ADDIN EN.CITE Harden200312320Quantitative GSTP1 methylation and the detection of prostate adenocarcinoma in sextant biopsiesHarden, S. V.Sanderson, H.Goodman, S. N.Partin, A. A.Walsh, P. C.Epstein, J. I.Sidransky, D.Adenocarcinoma/*diagnosis/*metabolism/pathology/surgeryBiopsy, NeedleDNA, Neoplasm/metabolismGlutathione Transferase/*metabolismHumanIsoenzymes/*metabolismMaleMethylationPolymerase Chain ReactionPromoter Regions (Genetics)Prostatic Neoplasms/*diagnosis/*metabolism/pathology/surgerySensitivity and SpecificitySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Markers, Biological/*metabolismJ Natl Cancer Inst200395211634-7.(166)(163). DNA mutations can be detected at very low concentrations, even when a mutant allele is admixed with many hundreds or even thousands of wild-type alleles. Despite the accuracy of many DNA-based detection methods, and the multiple genes targeted for mutation in pancreatic cancers ADDIN EN.CITE Jaffee200213260Focus on pancreas cancerJaffee, E. M.Hruban, R. H.Canto, M.Kern, S. E.ForecastingHumanPancreatic Neoplasms/diagnosis/epidemiology/*genetics/therapyTherapies, InvestigationalCancer Cell20022125-8.(167)(164), few somatic mutations have been identified that have ideal diagnostic characteristics. An ideal genetic marker would be present in virtually all pancreatic cancers and would be readily detectable. The easiest mutations to detect are those that are limited to a single codon or to a very specific portion of the targeted gene such as K-ras or BRAF ADDIN EN.CITE Yamada199814080Yamada, T.Nakamori, S.Ohzato, H.Oshima, S.Aoki, T.Higaki, N.Sugimoto, K.Akagi, K.Fujiwara, Y.Nishisho, I.Sakon, M.Gotoh, M.Monden, M.Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological featuresClinical Cancer Research1998461527-32Mulcahy199814090Mulcahy, H. E.Lyautey, J.Lederrey, C.qi Chen, X.Anker, P.Alstead, E. M.Ballinger, A.Farthing, M. J.Stroun, M.A prospective study of K-ras mutations in the plasma of pancreatic cancer patientsClinical Cancer Research199842271-5Castells1999940Castells, A.Puig, P.Mora, J.Boadas, J.Boix, L.Urgell, E.Sole, M.Capella, G.Lluis, F.Fernandez-Cruz, L.Navarro, S.Farre, A.K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significanceAdenocarcinoma/blood/*diagnosis/geneticsAdultAgedChronic DiseaseDNA, Neoplasm/blood/*geneticsFemaleFollow-Up Studies*Genes, rasHumanMaleMiddle Age*MutationNeoplasm Circulating Cells/chemistry/pathologyPancreatic Neoplasms/blood/*diagnosis/geneticsPancreatitis/blood/geneticsPrognosisProspective StudiesSupport, Non-U.S. Gov'tJ Clin Oncol1999172578-84Calhoun200312100BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targetsCalhoun, E. S.Jones, J. B.Ashfaq, R.Adsay, V.Baker, S. J.Valentine, V.Hempen, P. M.Hilgers, W.Yeo, C. J.Hruban, R. H.Kern, S. E.Adenocarcinoma/*genetics/metabolism/therapyAmino Acid Sequence/geneticsAnimalBase Sequence/geneticsCell Cycle Proteins/*geneticsCyclin E/genetics/metabolismGene AmplificationGene DosageHumanImmunohistochemistryMiceMolecular Sequence DataMutationOncogene Proteins/*geneticsPancreatic Neoplasms/*genetics/metabolism/therapySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedAm J Pathol200316341255-60.Cohen200312090BRAF mutation in papillary thyroid carcinomaCohen, Y.Xing, M.Mambo, E.Guo, Z.Wu, G.Trink, B.Beller, U.Westra, W. H.Ladenson, P. W.Sidransky, D.AdenineCarcinoma, Papillary/*geneticsCase-Control StudiesHead and Neck Neoplasms/geneticsHumanLung Neoplasms/genetics*Mutation, MissensePolymerase Chain ReactionProto-Oncogene Proteins c-raf/*geneticsThymineThyroid Neoplasms/*geneticsTumor Cells, CulturedJ Natl Cancer Inst2003958625-7.Davies200212080Mutations of the BRAF gene in human cancerDavies, H.Bignell, G. R.Cox, C.Stephens, P.Edkins, S.Clegg, S.Teague, J.Woffendin, H.Garnett, M. J.Bottomley, W.Davis, N.Dicks, E.Ewing, R.Floyd, Y.Gray, K.Hall, S.Hawes, R.Hughes, J.Kosmidou, V.Menzies, A.Mould, C.Parker, A.Stevens, C.Watt, S.Hooper, S.Wilson, R.Jayatilake, H.Gusterson, B. A.Cooper, C.Shipley, J.Hargrave, D.Pritchard-Jones, K.Maitland, N.Chenevix-Trench, G.Riggins, G. J.Bigner, D. D.Palmieri, G.Cossu, A.Flanagan, A.Nicholson, A.Ho, J. W.Leung, S. Y.Yuen, S. T.Weber, B. L.Seigler, H. F.Darrow, T. L.Paterson, H.Marais, R.Marshall, C. J.Wooster, R.Stratton, M. R.Futreal, P. A.3T3 CellsAmino Acid SequenceAnimalBase SequenceCell DivisionCell Transformation, Neoplastic/geneticsDNA Mutational AnalysisEnzyme ActivationHumanMAP Kinase Signaling SystemMelanoma/enzymology/*genetics/metabolism/pathologyMiceMitogen-Activated Protein Kinases/metabolismMolecular Sequence DataMutation, Missense/*geneticsNeoplasms/enzymology/*genetics/metabolism/pathologyProtein Structure, TertiaryProto-Oncogene Proteins c-raf/chemistry/*genetics/metabolismSupport, Non-U.S. Gov'tTumor Cells, Culturedras Proteins/immunology/metabolismNature20024176892949-54.(163-165, 168-170)(160-162, 165-167). Unfortunately K-ras mutations are not specific for invasive pancreatic cancer; studies of K-ras gene mutations in pancreatic tissues, pancreatic juice and stool find they occur in patients with chronic pancreatitis, in individuals who smoke, and in PanINs from patients without pancreatic cancer ADDIN EN.CITE Berger1999140Berger, D. H.Chang, H.Wood, M.Huang, L.Heath, C. W.Lehman, T.Ruggeri, B. A.Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status [In Process Citation]Cancer1999852326-32Caldas1994570Caldas, C.Hahn, S. A.da Costa, L. T.Redston, M. S.Schutte, M.Seymour, A. B.Weinstein, C. L.Hruban, R. H.Yeo, C. J.Kern, S. E.Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma [published erratum appears in Nat Genet 1994 Dec;8(4):410]Adenocarcinoma/*geneticsBase SequenceCarrier Proteins/*geneticsChromosome DeletionChromosomes, Human, Pair 9Gene DeletionGenes, p53HumanMolecular Sequence DataMutationPancreatic Neoplasms/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedNat Genet19948127-32Kalthoff199312330p53 and K-RAS alterations in pancreatic epithelial cell lesionsKalthoff, H.Schmiegel, W.Roeder, C.Kasche, D.Schmidt, A.Lauer, G.Thiele, H. G.Honold, G.Pantel, K.Riethmuller, G.et al.,Base SequenceBlotting, Western*Genes, p53*Genes, rasHumanImmunoenzyme TechniquesImmunohistochemistryMolecular Sequence DataMutationPancreas/chemistryPancreatic Neoplasms/*geneticsPoint MutationProtein p53/analysisRNA, Messenger/analysisSupport, Non-U.S. Gov'tTumor Cells, CulturedOncogene199382289-98.Moskaluk19979580Moskaluk, C.A.Hruban, R.H.Kern, S.E.1997p16 and K-ras mutations in the intraductal precursors of human pancreatic adenocarcinoma.Cancer Res572140-2143Tada199314270Tada, M.Omata, M.Kawai, S.Saisho, H.Ohto, M.Saiki, R. K.Sninsky, J. J.Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinomaCancer Research199353112472-4(171-175)(168-172).
TP53 gene mutations generally occur relatively late in the neoplastic to invasive pancreatic cancer, and the detection of TP53 gene mutations has been widely investigated as a potentially specific diagnostic marker in various cancers. In pancreatic ductal adenocarcinoma, TP53 gene mutations are found in ~70% of invasive cancers ADDIN EN.CITE Redston19945020Redston, M.S.Caldas, C.Seymour, A.B.Hruban, R.H.da Costa, L.Yeo, C.J.Kern, S.E.1994p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletionsCancer Res543025-3033(176)(173). Although a few nucleotide hot spots of TP53 gene mutation are known to exist, mutations occur throughout the gene ADDIN EN.CITE Hollstein199111730Hollstein, M.Sidransky, D.Vogelstein, B.Harris, C. C.p53 mutations in human cancersScience1991253501549-53(177)(174). In one study, assaying for eight common TP53 gene mutations in stool with the use of a mismatch ligation, investigators identified 59% of stool samples from patients with colon cancer ADDIN EN.CITE Dong200112290Detecting colorectal cancer in stool with the use of multiple genetic targetsDong, S. M.Traverso, G.Johnson, C.Geng, L.Favis, R.Boynton, K.Hibi, K.Goodman, S. N.D'Allessio, M.Paty, P.Hamilton, S. R.Sidransky, D.Barany, F.Levin, B.Shuber, A.Kinzler, K. W.Vogelstein, B.Jen, J.AgedColonic Neoplasms/*diagnosis/*genetics/pathologyColorectal Neoplasms/*diagnosis/*genetics/pathologyDNA/*genetics/isolation & purificationFeces/*chemistry*Genes, p53*Genes, rasGenetic MarkersGerm-Line MutationHumanMiddle Aged*MutationNeoplasm StagingPolymerase Chain Reaction/methodsReproducibility of ResultsSequence DeletionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.J Natl Cancer Inst20019311858-65.(178)(175), but other studies have found a much lower percentage of recurrent TP53 gene mutations ADDIN EN.CITE Ahrendt200312450p53 mutations and survival in stage I non-small-cell lung cancer: results of a prospective studyAhrendt, S. A.Hu, Y.Buta, M.McDermott, M. P.Benoit, N.Yang, S. C.Wu, L.Sidransky, D.AdultAgedCarcinoma, Non-Small-Cell Lung/*genetics/*mortality/pathologyDideoxynucleosides/analysisFemale*Genes, p53Genetic MarkersHumanLung Neoplasms/*genetics/*mortality/pathologyMaleMiddle Aged*MutationNeoplasm StagingOligonucleotide Array Sequence AnalysisPredictive Value of TestsPrognosisProportional Hazards ModelsProspective StudiesRegression AnalysisSupport, U.S. Gov't, P.H.S.Survival AnalysisJ Natl Cancer Inst20039513961-70.(179)(176). Hot spots of TP53 gene mutation arise because of specific environmental factors, such as smoking or aflatoxin exposure, thus the prevalence of TP53 mutational hotspots vary with the population under study., Most studies of TP53 mutations as a cancer marker have used assays such as chip technologies, single-strand conformational polymorphism, and temperature gradient capillary electrophoresis that have the potential to identify the complete spectrum of TP53 gene mutations. The sensitivity and limit of detection of these technologies are not as good as strategies that detect single nucleotide mutations. Assays such as single-strand conformational polymorphism (SSCP) and temperature gradient capillary electrophoresis can detect mutations that are present in at least 1% and more often 5-10% of the total DNA ADDIN EN.CITE Yamaguchi199912530Detection of mutations of p53 tumor suppressor gene in pancreatic juice and its application to diagnosis of patients with pancreatic cancer: comparison with K-ras mutationYamaguchi, Y.Watanabe, H.Yrdiran, S.Ohtsubo, K.Motoo, Y.Okai, T.Sawabu, N.AgedCodon/geneticsDNA Mutational AnalysisDNA, Neoplasm/*geneticsDuodenoscopy*Genes, p53*Genes, rasHumanMalePancreatic Juice/*chemistryPancreatic Neoplasms/*diagnosis/geneticsPolymerase Chain ReactionPolymorphism, Restriction Fragment LengthPolymorphism, Single-Stranded ConformationalSensitivity and SpecificitySupport, Non-U.S. Gov'tClin Cancer Res1999551147-53.Kaino199912520Detection of K-ras and p53 gene mutations in pancreatic juice for the diagnosis of intraductal papillary mucinous tumorsKaino, M.Kondoh, S.Okita, S.Hatano, S.Shiraishi, K.Kaino, S.Okita, K.Adenocarcinoma, Mucinous/*diagnosis/geneticsAdultAgedCarcinoma, Intraductal, Noninfiltrating/*diagnosis/geneticsDNA/analysisDNA Mutational AnalysisFemale*Genes, p53*Genes, rasHumanImmunohistochemistryMaleMiddle Aged*MutationPancreatic Juice/chemistryPancreatic Neoplasms/*diagnosis/geneticsPoint MutationPolymerase Chain ReactionPolymorphism, Single-Stranded ConformationalSequence Analysis, DNAPancreas1999183294-9.(180, 181)(177, 178). Using SSCP, investigators have reported the presence of TP53 gene mutations, within exons 5-8, in pancreatic juice samples and in brush cytology specimens of 40%--50% of patients with pancreatic cancers ADDIN EN.CITE Sturm199812380The potential diagnostic use of K-ras codon 12 and p53 alterations in brush cytology from the pancreatic head regionSturm, P. D.Hruban, R. H.Ramsoekh, T. B.Noorduyn, L. A.Tytgat, G. N.Gouma, D. J.Offerhaus, G. J.AgedAmpulla of Vater/pathologyBiopsyCodon*Genes, p53*Genes, rasHumanHyperplasia/geneticsImmunohistochemistryIn Situ HybridizationMiddle AgedMutationPancreatic Neoplasms/*diagnosis/geneticsPolymerase Chain ReactionProtein p53/analysisSupport, Non-U.S. Gov't*Tumor Markers, BiologicalJ Pathol19981863247-53.(182)(179). This figure is close to the number of mutations that one would expect to find in the primary pancreatic cancers from these patients ADDIN EN.CITE Sturm199812380The potential diagnostic use of K-ras codon 12 and p53 alterations in brush cytology from the pancreatic head regionSturm, P. D.Hruban, R. H.Ramsoekh, T. B.Noorduyn, L. A.Tytgat, G. N.Gouma, D. J.Offerhaus, G. J.AgedAmpulla of Vater/pathologyBiopsyCodon*Genes, p53*Genes, rasHumanHyperplasia/geneticsImmunohistochemistryIn Situ HybridizationMiddle AgedMutationPancreatic Neoplasms/*diagnosis/geneticsPolymerase Chain ReactionProtein p53/analysisSupport, Non-U.S. Gov't*Tumor Markers, BiologicalJ Pathol19981863247-53.(182)(179). One study using temperature gradient gel electrophoresis demonstrated that pancreatic juice from patients with chronic pancreatitis rarely harbors TP53 gene mutations ADDIN EN.CITE Lohr200111470p53 and K-ras mutations in pancreatic juice samples from patients with chronic pancreatitisLohr, M.Muller, P.Mora, J.Brinkmann, B.Ostwald, C.Farre, A.Lluis, F.Adam, U.Stubbe, J.Plath, F.Nizze, H.Hopt, U. T.Barten, M.Capella, G.Liebe, S.AdolescenceAdultAgedAged, 80 and overBase SequenceChi-Square DistributionChronic DiseaseComparative StudyFemaleGenes, p53/*geneticsGenes, ras/*geneticsGenetic MarkersHumanMaleMiddle AgeMolecular Sequence Data*MutationPancreatic Juice/*metabolismPancreatitis/diagnosis/*geneticsPolymerase Chain ReactionProbabilityProspective StudiesSensitivity and SpecificityStatistics, NonparametricSupport, Non-U.S. Gov'tGastrointest Endosc2001537734-43.(183)(180). Gene chip technology has also been used for TP53 gene mutation detection and it has the advantage that it can identify, in a single assay, a large percentage of possible TP53 gene mutations in a given DNA sample as long as the mutation is present in the sample at sufficient concentration relative to normal DNA (>1% of DNA) ADDIN EN.CITE Wikman200014640Evaluation of the performance of a p53 sequencing microarray chip using 140 previously sequenced bladder tumor samplesWikman, F. P.Lu, M. L.Thykjaer, T.Olesen, S. H.Andersen, L. D.Cordon-Cardo, C.Orntoft, T. F.Bladder Neoplasms/*geneticsHumansMutationOligonucleotide Array Sequence AnalysisPolymerase Chain ReactionProtein p53/*geneticsResearch Support, Non-U.S. Gov'tTumor Cells, CulturedClin Chem200046101555-61.(184)(181). Although these gene chips are very effective in identifying mis-sense mutations, they may miss the small deletions and insertions that represent ~10%--20% of all TP53 gene mutations. In studies using Affymetrix( p53 gene chips, investigators were able to identify ~80% of all TP53 gene mutations in non--small cell lung cancer tissues ADDIN EN.CITE Ahrendt200312450p53 mutations and survival in stage I non-small-cell lung cancer: results of a prospective studyAhrendt, S. A.Hu, Y.Buta, M.McDermott, M. P.Benoit, N.Yang, S. C.Wu, L.Sidransky, D.AdultAgedCarcinoma, Non-Small-Cell Lung/*genetics/*mortality/pathologyDideoxynucleosides/analysisFemale*Genes, p53Genetic MarkersHumanLung Neoplasms/*genetics/*mortality/pathologyMaleMiddle Aged*MutationNeoplasm StagingOligonucleotide Array Sequence AnalysisPredictive Value of TestsPrognosisProportional Hazards ModelsProspective StudiesRegression AnalysisSupport, U.S. Gov't, P.H.S.Survival AnalysisJ Natl Cancer Inst20039513961-70.Ahrendt199912460Rapid p53 sequence analysis in primary lung cancer using an oligonucleotide probe arrayAhrendt, S. A.Halachmi, S.Chow, J. T.Wu, L.Halachmi, N.Yang, S. C.Wehage, S.Jen, J.Sidransky, D.HumanLung Neoplasms/*geneticsMutation*Oligonucleotide ProbesProtein p53/*geneticsSequence Analysis/*methodsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Proc Natl Acad Sci U S A199996137382-7.(179, 185)(176, 182). The concentration of mutant DNA in the pancreatic juice of patients with pancreatic cancer can be less than 1% of total DNA ADDIN EN.CITE Shi C200413480Shi C, Eshleman S, Jones D, Fukushima N, Hua L, Parker AR, Yeo CJ, Hruban RH, Goggins MG, Eshleman JR.2004LigAmp for sensitive detection of single-nucleotide differencesNature Methods1141-7(186)(183) so the utility of using TP53 gene chip assays for pancreatic cancer diagnosis remains to be determined.
The emergence of chip technologies has also facilitated investigations into the diagnostic utility of mitochondrial mutations. Mitochondrial mutations are commonly found in multiple cancers types ADDIN EN.CITE Polyak19981370Polyak, K.Li, Y.Zhu, H.Lengauer, C.Willson, J. K.Markowitz, S. D.Trush, M. A.Kinzler, K. W.Vogelstein, B.Somatic mutations of the mitochondrial genome in human colorectal tumoursBase SequenceCell FusionColorectal Neoplasms/*genetics/metabolismDNA DamageDNA, Mitochondrial/*geneticsDNA, Neoplasm/*genetics*Genome, HumanHuman*MutationReactive Oxygen Species/metabolismSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedNat Genet1998203291-3Jones200112180Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutationsJones, J. B.Song, J. J.Hempen, P. M.Parmigiani, G.Hruban, R. H.Kern, S. E.Adenocarcinoma/*geneticsAnimalBlotting, SouthernComparative StudyDNA Mutational AnalysisDNA, Mitochondrial/*geneticsDNA, Neoplasm/*geneticsGene Frequency/*geneticsGenome, HumanHumanModels, GeneticMutation/*physiologyNeoplasm TransplantationPancreatic Neoplasms/*geneticsPolymerase Chain ReactionSuperoxide Dismutase/geneticsSupport, U.S. Gov't, P.H.S.Transplantation, HeterologousCancer Res20016141299-304.Maitra200412930The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detectionMaitra, A.Cohen, Y.Gillespie, S. E.Mambo, E.Fukushima, N.Hoque, M. O.Shah, N.Goggins, M.Califano, J.Sidransky, D.Chakravarti, A.Genome Res2004145812-9.Fliss200012170Facile detection of mitochondrial DNA mutations in tumors and bodily fluidsFliss, M. S.Usadel, H.Caballero, O. L.Wu, L.Buta, M. R.Eleff, S. M.Jen, J.Sidransky, D.Amino Acid SubstitutionBladder Neoplasms/diagnosis/geneticsBody Fluids/*chemistryBronchoalveolar Lavage Fluid/chemistryDNA, Mitochondrial/analysis/*genetics/urineDNA, Neoplasm/analysis/*genetics/urineGenes, p53Head and Neck Neoplasms/diagnosis/geneticsHumanLung Neoplasms/diagnosis/genetics*MutationNeoplasms/diagnosis/*geneticsPoint MutationPolymerase Chain ReactionPolymorphism (Genetics)Saliva/chemistrySequence DeletionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Science200028754602017-9.Sanchez-Cespedes200112150Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumorsSanchez-Cespedes, M.Parrella, P.Nomoto, S.Cohen, D.Xiao, Y.Esteller, M.Jeronimo, C.Jordan, R. C.Nicol, T.Koch, W. M.Schoenberg, M.Mazzarelli, P.Fazio, V. M.Sidransky, D.Carcinoma, Squamous Cell/blood/geneticsDNA, Mitochondrial/*geneticsFemaleGerm-Line MutationHead and Neck Neoplasms/blood/geneticsHumanLung Neoplasms/geneticsLymphocytes/physiologyMaleMicrosatellite Repeats/*geneticsNeoplasms/blood/*geneticsPolymorphism (Genetics)Precancerous Conditions/blood/geneticsSequence Analysis, DNASupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Cancer Res200161197015-9.(187-191)(184-188). One advantage of mitochondrial DNA as a marker for cancer is that each cell has many more copies of the mitochondrial genome than of nuclear DNA, and the amount of mitochondrial DNA in cancer cells is several times more abundant than it is in normal tissues ADDIN EN.CITE Fliss200012170Facile detection of mitochondrial DNA mutations in tumors and bodily fluidsFliss, M. S.Usadel, H.Caballero, O. L.Wu, L.Buta, M. R.Eleff, S. M.Jen, J.Sidransky, D.Amino Acid SubstitutionBladder Neoplasms/diagnosis/geneticsBody Fluids/*chemistryBronchoalveolar Lavage Fluid/chemistryDNA, Mitochondrial/analysis/*genetics/urineDNA, Neoplasm/analysis/*genetics/urineGenes, p53Head and Neck Neoplasms/diagnosis/geneticsHumanLung Neoplasms/diagnosis/genetics*MutationNeoplasms/diagnosis/*geneticsPoint MutationPolymerase Chain ReactionPolymorphism (Genetics)Saliva/chemistrySequence DeletionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Science200028754602017-9.Polyak19981370Polyak, K.Li, Y.Zhu, H.Lengauer, C.Willson, J. K.Markowitz, S. D.Trush, M. A.Kinzler, K. W.Vogelstein, B.Somatic mutations of the mitochondrial genome in human colorectal tumoursBase SequenceCell FusionColorectal Neoplasms/*genetics/metabolismDNA DamageDNA, Mitochondrial/*geneticsDNA, Neoplasm/*genetics*Genome, HumanHuman*MutationReactive Oxygen Species/metabolismSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedNat Genet1998203291-3Jones200112180Detection of mitochondrial DNA mutations in pancreatic cancer offers a "mass"-ive advantage over detection of nuclear DNA mutationsJones, J. B.Song, J. J.Hempen, P. M.Parmigiani, G.Hruban, R. H.Kern, S. E.Adenocarcinoma/*geneticsAnimalBlotting, SouthernComparative StudyDNA Mutational AnalysisDNA, Mitochondrial/*geneticsDNA, Neoplasm/*geneticsGene Frequency/*geneticsGenome, HumanHumanModels, GeneticMutation/*physiologyNeoplasm TransplantationPancreatic Neoplasms/*geneticsPolymerase Chain ReactionSuperoxide Dismutase/geneticsSupport, U.S. Gov't, P.H.S.Transplantation, HeterologousCancer Res20016141299-304.Nomoto200212130Mitochondrial D-loop mutations as clonal markers in multicentric hepatocellular carcinoma and plasmaNomoto, S.Yamashita, K.Koshikawa, K.Nakao, A.Sidransky, D.AdultAgedCarcinoma, Hepatocellular/*blood/*genetics*DNA, MitochondrialFemaleHumanLiver Neoplasms/*blood/*geneticsMaleMiddle Age*MutationOligonucleotides/metabolismPolymerase Chain ReactionSupport, Non-U.S. Gov't*Tumor Markers, BiologicalClin Cancer Res200282481-7.(187, 188, 190, 192)(184, 185, 187, 189). To efficiently interrogate the mitochondrial genome, a MitoChip has been developed ADDIN EN.CITE Maitra200412930The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detectionMaitra, A.Cohen, Y.Gillespie, S. E.Mambo, E.Fukushima, N.Hoque, M. O.Shah, N.Goggins, M.Califano, J.Sidransky, D.Chakravarti, A.Genome Res2004145812-9.(189)(186), and initial studies suggest that this chip can be used to detect mitochondrial mutations in pancreatic juice samples obtained from patients with pancreatic cancer as well as from the urine of patients with urinary tract cancers ADDIN EN.CITE Maitra200412930The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detectionMaitra, A.Cohen, Y.Gillespie, S. E.Mambo, E.Fukushima, N.Hoque, M. O.Shah, N.Goggins, M.Califano, J.Sidransky, D.Chakravarti, A.Genome Res2004145812-9.(189)(186). These results are preliminary and require confirmation in larger prospective studies.
Methylated DNA
Since aberrant hypermethylation of tumor suppressor genes is common during carcinogenesis, DNA methylation abnormalities may be particularly suitable for use in early-detection strategies ADDIN EN.CITE Jones200210730The fundamental role of epigenetic events in cancerJones, P. A.Baylin, S. B.Chromosome MappingDNA MethylationGenome, HumanHumanMass Screening/methodsNeoplasms/*geneticsSignal Transduction/geneticsSupport, U.S. Gov't, P.H.S.Nat Rev Genet200236415-28.Sato200311560SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactionsSato, N.Fukushima, N.Maehara, N.Matsubayashi, H.Koopmann, J.Su, G. H.Hruban, R. H.Goggins, M.Oncogene200322325021-30.(193, 194)(190, 191). Several dozen genes, such as SPARC, ppENK, p16, TSLC1 and TFPI-2, have been identified as aberrantly methylated in pancreatic carcinomas: some of these markers are aberrantly methylated in ~90% of pancreatic cancers ADDIN EN.CITE Sato200311560SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactionsSato, N.Fukushima, N.Maehara, N.Matsubayashi, H.Koopmann, J.Su, G. H.Hruban, R. H.Goggins, M.Oncogene200322325021-30.Sato14400Sato, N.Parker, A. R.Fukushima, N.Miyagi, Y.Iacobuzio-Donahue, C. A.Eshleman, J. R.Goggins, M.2005Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinomaOncogenein press.Sato200311600Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarraysSato, N.Fukushima, N.Maitra, A.Matsubayashi, H.Yeo, C. J.Cameron, J. L.Hruban, R. H.Goggins, M.AdultAgedAged, 80 and over*Chromosome Aberrations*DNA MethylationDNA PrimersGene Expression ProfilingHumanMiddle AgeNeoplasm Proteins/genetics*Oligonucleotide Array Sequence Analysis/methodsPancreatic Neoplasms/*geneticsReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedCancer Res200363133735-42.Jansen200211640Aberrant Methylation of the 5' CpG Island of TSLC1 Is Common in Pancreatic Ductal Adenocarcinoma and Is First Manifest in High-Grade PanlNsJansen, M.Fukushima, N.Rosty, C.Walter, K.Altink, R.Heek, T. V.Hruban, R.Offerhaus, J. G.Goggins, M.Cancer Biol Ther200213293-6.Sato N200210660 Sato N,, Ueki T, Fukushima N, Iacobuzio-Donahue CA, Yeo CJ, Cameron JL, Hruban RH, Goggins M.2002Aberrant Methylation of CpG Islands in Intraductal Papillary Mucinous Neoplasms of the Pancreas Increases with Histological GradeGastroenterology1231365-72 ADDIN EN.CITE Sato200311560SPARC/osteonectin is a frequent target for aberrant methylation in pancreatic adenocarcinoma and a mediator of tumor-stromal interactionsSato, N.Fukushima, N.Maehara, N.Matsubayashi, H.Koopmann, J.Su, G. H.Hruban, R. H.Goggins, M.Oncogene200322325021-30.Sato14400Sato, N.Parker, A. R.Fukushima, N.Miyagi, Y.Iacobuzio-Donahue, C. A.Eshleman, J. R.Goggins, M.2005Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinomaOncogenein press.Sato200311600Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarraysSato, N.Fukushima, N.Maitra, A.Matsubayashi, H.Yeo, C. J.Cameron, J. L.Hruban, R. H.Goggins, M.AdultAgedAged, 80 and over*Chromosome Aberrations*DNA MethylationDNA PrimersGene Expression ProfilingHumanMiddle AgeNeoplasm Proteins/genetics*Oligonucleotide Array Sequence Analysis/methodsPancreatic Neoplasms/*geneticsReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedCancer Res200363133735-42.Jansen200211640Aberrant Methylation of the 5' CpG Island of TSLC1 Is Common in Pancreatic Ductal Adenocarcinoma and Is First Manifest in High-Grade PanlNsJansen, M.Fukushima, N.Rosty, C.Walter, K.Altink, R.Heek, T. V.Hruban, R.Offerhaus, J. G.Goggins, M.Cancer Biol Ther200213293-6.Sato N200210660 Sato N, Ueki T, Fukushima N, Iacobuzio-Donahue CA, Yeo CJ, Cameron JL, Hruban RH, Goggins M.2002Aberrant Methylation of CpG Islands in Intraductal Papillary Mucinous Neoplasms of the Pancreas Increases with Histological GradeGastroenterology1231365-72(194-198)(191-195). The detection of such aberrant methylation changes in clinical samples is feasible with methylation-specific PCR (MSP) ADDIN EN.CITE Herman1996800Herman, J. G.Graff, J. R.Myohanen, S.Nelkin, B. D.Baylin, S. B.Methylation-specific PCR: a novel PCR assay for methylation status of CpG islandsAntisense Elements (Genetics)/chemistryBase SequenceCadherins/geneticsCarrier Proteins/geneticsCell Line*CpG IslandsDNA Primers/chemical synthesisGenes, Suppressor, TumorHumanMethylationMolecular Sequence DataPolymerase Chain Reaction/*methodsProteins/geneticsRestriction MappingSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Proc Natl Acad Sci U S A199693189821-6(199)(196). MSP requires bisulfite modification of the DNA to convert all unmethylated cytosines to uracils. MSP has been used successfully to identify methylated DNA in most biologic fluids, including blood, fine needle aspirates, saliva, and sputum from cancer patients ADDIN EN.CITE Esteller20018690A gene hypermethylation profile of human cancerEsteller, M.Corn, P. G.Baylin, S. B.Herman, J. G.*DNA MethylationGene Expression Regulation, NeoplasticGene SilencingGenes, Tumor SuppressorGenetic MarkersHumanNeoplasms/*geneticsPromoter Regions (Genetics)Support, U.S. Gov't, P.H.S.Cancer Res20016183225-9.(200)(197). In addition, quantification of methylated DNA using real-time MSP is being employed in an attempt to distinguish more accurately cancers from non-neoplastic diseases. Initial studies in patients with pancreatic disease have demonstrated that aberrant DNA methylation patterns can be detected in pancreatic juice samples from patients with pancreatic cancer ADDIN EN.CITE Fukushima200311620Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juiceFukushima, N.Walter, K. M.Uek, T.Sato, N.Matsubayashi, H.Cameron, J. L.Hruban, R. H.Canto, M.Yeo, C. J.Goggins, M.Adenocarcinoma, Mucinous/diagnosis/genetics/pathologyAdultAgedAged, 80 and overCarcinoma, Intraductal, Noninfiltrating/diagnosis/genetics/pathologyCarcinoma, Pancreatic Ductal/*diagnosis/genetics/pathologyComparative Study*DNA MethylationDNA Primers/chemistryDNA, Neoplasm/genetics/metabolismDuodenum/pathologyEnkephalins/*geneticsFemaleHumanMaleMiddle AgePancreas/pathology/secretionPancreatic Diseases/diagnosis/genetics/pathologyPancreatic Neoplasms/*diagnosis/genetics/pathologyPolymerase Chain ReactionProtein Precursors/*geneticsProtein p16/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Cancer Biol Ther20032178-83.Sato200311600Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarraysSato, N.Fukushima, N.Maitra, A.Matsubayashi, H.Yeo, C. J.Cameron, J. L.Hruban, R. H.Goggins, M.AdultAgedAged, 80 and over*Chromosome Aberrations*DNA MethylationDNA PrimersGene Expression ProfilingHumanMiddle AgeNeoplasm Proteins/genetics*Oligonucleotide Array Sequence Analysis/methodsPancreatic Neoplasms/*geneticsReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedCancer Res200363133735-42.Sato200514400Sato, N.Parker, A. R.Fukushima, N.Miyagi, Y.Iacobuzio-Donahue, C. A.Eshleman, J. R.Goggins, M.2005Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinomaOncogenein press.(195, 196, 201)(192, 193, 198), and are only rarely found in pancreatic juice samples from patients without pancreatic cancer. Although these data are promising, several biologic features of DNA methylation require consideration when DNA methylation markers are considered for use in clinical practice as cancer markers. These include tissue-specific differences in normal methylation patterns, increases in DNA methylation with patient age, limitations of bisulfite modification, and the potential for methylated DNA markers to detect early neoplasia with little propensity for cancer ADDIN EN.CITE Matsubayashi200311610Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissuesMatsubayashi, H.Sato, N.Fukushima, N.Yeo, C. J.Walter, K. M.Brune, K.Sahin, F.Hruban, R. H.Goggins, M.Clin Cancer Res2003941446-52.Matsubayashi H et al12610Matsubayashi H et al, , Sato N, Brune K, Blackford AL, Hruban RH, Canto M, Yeo CJ, Goggins M.2005Age- and Disease-Related Methylation of Multiple Genes in Non-neoplastic Duodenal tissuesClin Cancer Res11573-83Issa199411530Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colonIssa, J. P.Ottaviano, Y. L.Celano, P.Hamilton, S. R.Davidson, N. E.Baylin, S. B.Aging/*genetics/*metabolismBase SequenceColon/*metabolismColonic Neoplasms/etiology/*genetics/*metabolismColorectal Neoplasms/etiology/genetics/metabolismGene ExpressionHumanMethylationOligodeoxyribonucleotides/chemistry/geneticsReceptors, Estrogen/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Nat Genet199474536-40.Pao20016950The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cellsPao, M. M.Tsutsumi, M.Liang, G.Uzvolgyi, E.Gonzales, F. A.Jones, P. A.Bladder Neoplasms/*genetics/metabolismColonic Neoplasms/*genetics/metabolismComparative StudyCpG Islands/*genetics*DNA MethylationDNA Primers/chemistryDNA, Neoplasm/analysisDinucleoside Phosphates/genetics/metabolismHumanMale*Promoter Regions (Genetics)Prostatic Neoplasms/*genetics/metabolismReceptors, Endothelin/*genetics/metabolismRegulatory Sequences, Nucleic AcidReverse Transcriptase Polymerase Chain ReactionSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedHum Mol Genet2001109903-10.Nguyen20016910Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cellsNguyen, C.Liang, G.Nguyen, T. T.Tsao-Wei, D.Groshen, S.Lubbert, M.Zhou, J. H.Benedict, W. F.Jones, P. A.J Natl Cancer Inst200193191465-72. ADDIN EN.CITE Matsubayashi200311610Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissuesMatsubayashi, H.Sato, N.Fukushima, N.Yeo, C. J.Walter, K. M.Brune, K.Sahin, F.Hruban, R. H.Goggins, M.Clin Cancer Res2003941446-52.Matsubayashi H et al12610Matsubayashi H et al, , Sato N, Brune K, Blackford AL, Hruban RH, Canto M, Yeo CJ, Goggins M.Age- and Disease-Related Methylation of Multiple Genes in Non-neoplastic Duodenal tissuesClin Cancer Resin pressIssa199411530Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colonIssa, J. P.Ottaviano, Y. L.Celano, P.Hamilton, S. R.Davidson, N. E.Baylin, S. B.Aging/*genetics/*metabolismBase SequenceColon/*metabolismColonic Neoplasms/etiology/*genetics/*metabolismColorectal Neoplasms/etiology/genetics/metabolismGene ExpressionHumanMethylationOligodeoxyribonucleotides/chemistry/geneticsReceptors, Estrogen/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Nat Genet199474536-40.Pao20016950The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cellsPao, M. M.Tsutsumi, M.Liang, G.Uzvolgyi, E.Gonzales, F. A.Jones, P. A.Bladder Neoplasms/*genetics/metabolismColonic Neoplasms/*genetics/metabolismComparative StudyCpG Islands/*genetics*DNA MethylationDNA Primers/chemistryDNA, Neoplasm/analysisDinucleoside Phosphates/genetics/metabolismHumanMale*Promoter Regions (Genetics)Prostatic Neoplasms/*genetics/metabolismReceptors, Endothelin/*genetics/metabolismRegulatory Sequences, Nucleic AcidReverse Transcriptase Polymerase Chain ReactionSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedHum Mol Genet2001109903-10.Nguyen20016910Susceptibility of nonpromoter CpG islands to de novo methylation in normal and neoplastic cellsNguyen, C.Liang, G.Nguyen, T. T.Tsao-Wei, D.Groshen, S.Lubbert, M.Zhou, J. H.Benedict, W. F.Jones, P. A.J Natl Cancer Inst200193191465-72.(202-206)(199-203). For example, some genes normally unmethylated in the pancreas and commonly methylated in pancreatic cancers undergo low-level methylation in non-neoplastic duodenal tissues. Some methylation in normal tissues such as duodenum is more likely to be present in older patients ADDIN EN.CITE Fukushima200311620Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juiceFukushima, N.Walter, K. M.Uek, T.Sato, N.Matsubayashi, H.Cameron, J. L.Hruban, R. H.Canto, M.Yeo, C. J.Goggins, M.Adenocarcinoma, Mucinous/diagnosis/genetics/pathologyAdultAgedAged, 80 and overCarcinoma, Intraductal, Noninfiltrating/diagnosis/genetics/pathologyCarcinoma, Pancreatic Ductal/*diagnosis/genetics/pathologyComparative Study*DNA MethylationDNA Primers/chemistryDNA, Neoplasm/genetics/metabolismDuodenum/pathologyEnkephalins/*geneticsFemaleHumanMaleMiddle AgePancreas/pathology/secretionPancreatic Diseases/diagnosis/genetics/pathologyPancreatic Neoplasms/*diagnosis/genetics/pathologyPolymerase Chain ReactionProtein Precursors/*geneticsProtein p16/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Cancer Biol Ther20032178-83.(201)(198). This suggests that assaying for DNA methylation in pure pancreatic juice collected directly from the pancreatic duct will be preferable as it avoids possible duodenal contamination ADDIN EN.CITE Fukushima200311620Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juiceFukushima, N.Walter, K. M.Uek, T.Sato, N.Matsubayashi, H.Cameron, J. L.Hruban, R. H.Canto, M.Yeo, C. J.Goggins, M.Adenocarcinoma, Mucinous/diagnosis/genetics/pathologyAdultAgedAged, 80 and overCarcinoma, Intraductal, Noninfiltrating/diagnosis/genetics/pathologyCarcinoma, Pancreatic Ductal/*diagnosis/genetics/pathologyComparative Study*DNA MethylationDNA Primers/chemistryDNA, Neoplasm/genetics/metabolismDuodenum/pathologyEnkephalins/*geneticsFemaleHumanMaleMiddle AgePancreas/pathology/secretionPancreatic Diseases/diagnosis/genetics/pathologyPancreatic Neoplasms/*diagnosis/genetics/pathologyPolymerase Chain ReactionProtein Precursors/*geneticsProtein p16/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Cancer Biol Ther20032178-83.(201)(198). Because MSP requires a bisulfite modification step that causes DNA degradation, MSP is not as sensitive as simple PCR, and has a lower limit of detection of ~10-20 copies ADDIN EN.CITE Fukushima200311620Diagnosing pancreatic cancer using methylation specific PCR analysis of pancreatic juiceFukushima, N.Walter, K. M.Uek, T.Sato, N.Matsubayashi, H.Cameron, J. L.Hruban, R. H.Canto, M.Yeo, C. J.Goggins, M.Adenocarcinoma, Mucinous/diagnosis/genetics/pathologyAdultAgedAged, 80 and overCarcinoma, Intraductal, Noninfiltrating/diagnosis/genetics/pathologyCarcinoma, Pancreatic Ductal/*diagnosis/genetics/pathologyComparative Study*DNA MethylationDNA Primers/chemistryDNA, Neoplasm/genetics/metabolismDuodenum/pathologyEnkephalins/*geneticsFemaleHumanMaleMiddle AgePancreas/pathology/secretionPancreatic Diseases/diagnosis/genetics/pathologyPancreatic Neoplasms/*diagnosis/genetics/pathologyPolymerase Chain ReactionProtein Precursors/*geneticsProtein p16/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Cancer Biol Ther20032178-83.(201)(198). Even at this level of detection, MSP may detect low-level methylation that arises either from normal aging or in lesions of low malignant potential. For example, low-grade PanINs develop with increasing frequency in the pancreas with increasing age, and some of these PanINs harbor methylation changes that are not found in normal pancreatic epithelium. For this reason, genes that only undergo methylation in high grade PanINs and invasive cancers are likely to have more diagnostic accuracy for detecting pancreatic cancer as opposed to those that are methylated in early PanIN ADDIN EN.CITE Sato N200412600Sato N,, Parker AR, Fukushima N, Miyagi Y, Iacobuzio-Donahue C, Eshleman JR, Goggins M.2004Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinomaOncogenein press(207)(204).
Tissue Markers under investigation
Many proteins that are differentially expressed in pancreatic cancer have been identified through global analyses of gene expression ADDIN EN.CITE Iacobuzio-Donahue CA20029480Iacobuzio-Donahue CA, Anirban Maitra, Shen-Ong GL, van Heek T, Ashfaq R, Meyer R, Walter K, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH.2002Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression TechnologyAm J Pathol1601239-49Iacobuzio-Donahue200311630Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarraysIacobuzio-Donahue, C. A.Maitra, A.Olsen, M.Lowe, A. W.van Heek, N. T.Rosty, C.Walter, K.Sato, N.Parker, A.Ashfaq, R.Jaffee, E.Ryu, B.Jones, J.Eshleman, J. R.Yeo, C. J.Cameron, J. L.Kern, S. E.Hruban, R. H.Brown, P. O.Goggins, M.Adenocarcinoma/*genetics/pathologyDNA MethylationDNA, Complementary/genetics*Gene Expression Regulation, NeoplasticHumanMultigene FamilyNeoplasm Invasiveness*Oligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/pathologyPolymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedTumor Markers, Biological/analysisAm J Pathol200316241151-62.Iacobuzio-Donahue200312540Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologiesIacobuzio-Donahue, C. A.Ashfaq, R.Maitra, A.Adsay, N. V.Shen-Ong, G. L.Berg, K.Hollingsworth, M. A.Cameron, J. L.Yeo, C. J.Kern, S. E.Goggins, M.Hruban, R. H.Cancer Res200363248614-22.Byungwoo Ryu200210650Byungwoo Ryu, Jessa Jones, Natalie J. Blades, Giovanni Parmigiani, Michael A. Hollingsworth, Ralph H. Hruban, and Scott E. Kern2002Relationships and Differentially Expressed Genes among Pancreatic Cancers Examined by Large-scale Serial Analysis of Gene ExpressionCancer Res62819-826Iacobuzio-Donahue200311630Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarraysIacobuzio-Donahue, C. A.Maitra, A.Olsen, M.Lowe, A. W.van Heek, N. T.Rosty, C.Walter, K.Sato, N.Parker, A.Ashfaq, R.Jaffee, E.Ryu, B.Jones, J.Eshleman, J. R.Yeo, C. J.Cameron, J. L.Kern, S. E.Hruban, R. H.Brown, P. O.Goggins, M.Adenocarcinoma/*genetics/pathologyDNA MethylationDNA, Complementary/genetics*Gene Expression Regulation, NeoplasticHumanMultigene FamilyNeoplasm Invasiveness*Oligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/pathologyPolymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedTumor Markers, Biological/analysisAm J Pathol200316241151-62.Ryu B20016210Ryu B,, Jones J, Hollingsworth MA, Hruban RH, Kern SE.2001Invasion-specific Genes in Malignancy Serial Analysis of Gene Expression Comparisons of Primary and Passaged CancersCancer Res611833-1838Crnogorac-Jurcevic200111010Gene expression profiles of pancreatic cancer and stromal desmoplasiaCrnogorac-Jurcevic, T.Efthimiou, E.Capelli, P.Blaveri, E.Baron, A.Terris, B.Jones, M.Tyson, K.Bassi, C.Scarpa, A.Lemoine, N. R.Adenocarcinoma/*genetics/metabolism/pathologyBiopsy, NeedleCell CountCollagen/biosynthesis/geneticsComputer SystemsFibrosis*Gene Expression ProfilingGene LibraryHumanInternetMembrane Proteins/biosynthesis/geneticsMitogen-Activated Protein Kinases/biosynthesis/geneticsNeoplasm Proteins/*biosynthesis/geneticsOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/metabolism/pathologyPhosphoproteins/biosynthesis/geneticsPhosphoric Monoester Hydrolases/biosynthesis/geneticsProtein Isoforms/biosynthesis/geneticsProteoglycans/biosynthesis/geneticsReceptors, Cell Surface/biosynthesis/geneticsReverse Transcriptase Polymerase Chain ReactionRibosomal Proteins/biosynthesis/geneticsSialoglycoproteins/biosynthesis/geneticsStromal Cells/metabolism/pathologySupport, Non-U.S. Gov'tTumor Markers, Biological/*biosynthesis/geneticsTumor Stem Cells/metabolism/pathologyrac1 GTP-Binding Protein/biosynthesis/geneticsOncogene200120507437-46.Crnogorac-Jurcevic200210980Expression profiling of microdissected pancreatic adenocarcinomasCrnogorac-Jurcevic, T.Efthimiou, E.Nielsen, T.Loader, J.Terris, B.Stamp, G.Baron, A.Scarpa, A.Lemoine, N. R.Adenocarcinoma/*genetics/pathology/surgeryComparative Study*Dissection*Gene Expression Profiling*Gene Expression Regulation, NeoplasticHumanImmunohistochemistryOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/pathology/surgeryRNA, Messenger/genetics/metabolismRNA, Neoplasm/genetics/metabolismReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tTumor Cells, CulturedOncogene200221294587-94.Han200210990Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarrayHan, H.Bearss, D. J.Browne, L. W.Calaluce, R.Nagle, R. B.Von Hoff, D. D.Blotting, NorthernDNA, Complementary/genetics/metabolismDNA-Binding Proteins/biosynthesis/geneticsGene Expression ProfilingHela CellsHumanOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/metabolismProto-Oncogene Proteins c-myc/biosynthesis/geneticsRNA, Messenger/genetics/metabolismReproducibility of ResultsReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tTumor Cells, CulturedTumor Markers, Biological/geneticsCancer Res200262102890-6.Cao13300Cao, D.Hustinx, S. R.Sui, G.Bala, P.Sato, N.Martin, S.Maitra, A.Murphy, K. M.Cameron, J. L.Yeo, C. J.Kern, S. E.Goggins, M.Pandey, A.Hruban, R. H.2004Identification of Novel Highly Expressed Genes in Pancreatic Ductal Adenocarcinomas through a Bioinformatics Analysis of Expressed Sequence TagsCancer Biol Ther31081-9Hustinx13280Hustinx, S. R.Cao, D.Maitra, A.Sato, N.Martin, S. T.Sudhir, D.Iacobuzio-Donahue, C.Cameron, J. L.Yeo, C. J.Kern, S. E.Goggins, M.Mollenhauer, J.Pandey, A.Hruban, R. H.2004Differentially Expressed Genes in Pancreatic Ductal Adenocarcinomas Identified Through Serial Analysis of Gene ExpressionCancer Biol Ther31254-61 ADDIN EN.CITE Iacobuzio-Donahue CA20029480Iacobuzio-Donahue CA, Anirban Maitra, Shen-Ong GL, van Heek T, Ashfaq R, Meyer R, Walter K, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH.2002Discovery of Novel Tumor Markers of Pancreatic Cancer using Global Gene Expression TechnologyAm J Pathol1601239-49Iacobuzio-Donahue200311630Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarraysIacobuzio-Donahue, C. A.Maitra, A.Olsen, M.Lowe, A. W.van Heek, N. T.Rosty, C.Walter, K.Sato, N.Parker, A.Ashfaq, R.Jaffee, E.Ryu, B.Jones, J.Eshleman, J. R.Yeo, C. J.Cameron, J. L.Kern, S. E.Hruban, R. H.Brown, P. O.Goggins, M.Adenocarcinoma/*genetics/pathologyDNA MethylationDNA, Complementary/genetics*Gene Expression Regulation, NeoplasticHumanMultigene FamilyNeoplasm Invasiveness*Oligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/pathologyPolymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedTumor Markers, Biological/analysisAm J Pathol200316241151-62.Iacobuzio-Donahue200312540Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologiesIacobuzio-Donahue, C. A.Ashfaq, R.Maitra, A.Adsay, N. V.Shen-Ong, G. L.Berg, K.Hollingsworth, M. A.Cameron, J. L.Yeo, C. J.Kern, S. E.Goggins, M.Hruban, R. H.Cancer Res200363248614-22.Byungwoo Ryu200210650Byungwoo Ryu, Jessa Jones, Natalie J. Blades, Giovanni Parmigiani, Michael A. Hollingsworth, Ralph H. Hruban, and Scott E. Kern2002Relationships and Differentially Expressed Genes among Pancreatic Cancers Examined by Large-scale Serial Analysis of Gene ExpressionCancer Res62819-826Iacobuzio-Donahue200311630Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarraysIacobuzio-Donahue, C. A.Maitra, A.Olsen, M.Lowe, A. W.van Heek, N. T.Rosty, C.Walter, K.Sato, N.Parker, A.Ashfaq, R.Jaffee, E.Ryu, B.Jones, J.Eshleman, J. R.Yeo, C. J.Cameron, J. L.Kern, S. E.Hruban, R. H.Brown, P. O.Goggins, M.Adenocarcinoma/*genetics/pathologyDNA MethylationDNA, Complementary/genetics*Gene Expression Regulation, NeoplasticHumanMultigene FamilyNeoplasm Invasiveness*Oligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/pathologyPolymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, CulturedTumor Markers, Biological/analysisAm J Pathol200316241151-62.Ryu B20016210Ryu B, Jessa Jones, Michael A. Hollingsworth, Ralph H. Hruban and Scott E. Kern2001Invasion-specific Genes in Malignancy
Serial Analysis of Gene Expression Comparisons of Primary and Passaged CancersCancer Res611833-1838Crnogorac-Jurcevic200111010Gene expression profiles of pancreatic cancer and stromal desmoplasiaCrnogorac-Jurcevic, T.Efthimiou, E.Capelli, P.Blaveri, E.Baron, A.Terris, B.Jones, M.Tyson, K.Bassi, C.Scarpa, A.Lemoine, N. R.Adenocarcinoma/*genetics/metabolism/pathologyBiopsy, NeedleCell CountCollagen/biosynthesis/geneticsComputer SystemsFibrosis*Gene Expression ProfilingGene LibraryHumanInternetMembrane Proteins/biosynthesis/geneticsMitogen-Activated Protein Kinases/biosynthesis/geneticsNeoplasm Proteins/*biosynthesis/geneticsOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/metabolism/pathologyPhosphoproteins/biosynthesis/geneticsPhosphoric Monoester Hydrolases/biosynthesis/geneticsProtein Isoforms/biosynthesis/geneticsProteoglycans/biosynthesis/geneticsReceptors, Cell Surface/biosynthesis/geneticsReverse Transcriptase Polymerase Chain ReactionRibosomal Proteins/biosynthesis/geneticsSialoglycoproteins/biosynthesis/geneticsStromal Cells/metabolism/pathologySupport, Non-U.S. Gov'tTumor Markers, Biological/*biosynthesis/geneticsTumor Stem Cells/metabolism/pathologyrac1 GTP-Binding Protein/biosynthesis/geneticsOncogene200120507437-46.Crnogorac-Jurcevic200210980Expression profiling of microdissected pancreatic adenocarcinomasCrnogorac-Jurcevic, T.Efthimiou, E.Nielsen, T.Loader, J.Terris, B.Stamp, G.Baron, A.Scarpa, A.Lemoine, N. R.Adenocarcinoma/*genetics/pathology/surgeryComparative Study*Dissection*Gene Expression Profiling*Gene Expression Regulation, NeoplasticHumanImmunohistochemistryOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/pathology/surgeryRNA, Messenger/genetics/metabolismRNA, Neoplasm/genetics/metabolismReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tTumor Cells, CulturedOncogene200221294587-94.Han200210990Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarrayHan, H.Bearss, D. J.Browne, L. W.Calaluce, R.Nagle, R. B.Von Hoff, D. D.Blotting, NorthernDNA, Complementary/genetics/metabolismDNA-Binding Proteins/biosynthesis/geneticsGene Expression ProfilingHela CellsHumanOligonucleotide Array Sequence AnalysisPancreatic Neoplasms/*genetics/metabolismProto-Oncogene Proteins c-myc/biosynthesis/geneticsRNA, Messenger/genetics/metabolismReproducibility of ResultsReverse Transcriptase Polymerase Chain ReactionSupport, Non-U.S. Gov'tTumor Cells, CulturedTumor Markers, Biological/geneticsCancer Res200262102890-6.Cao13300Cao, D.Hustinx, S. R.Sui, G.Bala, P.Sato, N.Martin, S.Maitra, A.Murphy, K. M.Cameron, J. L.Yeo, C. J.Kern, S. E.Goggins, M.Pandey, A.Hruban, R. H.Identification of Novel Highly Expressed Genes in Pancreatic Ductal Adenocarcinomas through a Bioinformatics Analysis of Expressed Sequence TagsCancer Biol Therin pressHustinx13280Hustinx, S. R.Cao, D.Maitra, A.Sato, N.Martin, S. T.Sudhir, D.Iacobuzio-Donahue, C.Cameron, J. L.Yeo, C. J.Kern, S. E.Goggins, M.Mollenhauer, J.Pandey, A.Hruban, R. H.Differentially Expressed Genes in Pancreatic Ductal Adenocarcinomas Identified Through Serial Analysis of Gene ExpressionCancer Biol Therin press(208-217)(205-214). For example, mesothelin (expressed in nearly 100% of pancreatic cancers) may prove to be a useful tumor antigen ADDIN EN.CITE Thomas200413330Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patientsThomas, A. M.Santarsiero, L. M.Lutz, E. R.Armstrong, T. D.Chen, Y. C.Huang, L. Q.Laheru, D. A.Goggins, M.Hruban, R. H.Jaffee, E. M.Antigen-Presenting Cells/*physiologyCD8-Positive T-Lymphocytes/*immunologyCancer Vaccines/*immunologyCell LineGranulocyte-Macrophage Colony-Stimulating Factor/secretionHLA-A2 Antigen/analysisHLA-A3 Antigen/analysis/physiologyHumanHypersensitivity, Delayed/etiologyMembrane Glycoproteins/*immunologyPancreatic Neoplasms/*immunology/therapySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.VaccinationJ Exp Med20042003297-306.(218)(215). Other over expressed proteins include prostate stem cell antigen (expressed in 60%), sea urchin fascin homolog (95%), claudin-4, 14-3-3-sigma, transglutaminase 2, CDC25B, ADAM9, cdc2/p34, heat shock protein 47, trefoil factor-2 ADDIN EN.CITE Terris200211000Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreasTerris, B.Blaveri, E.Crnogorac-Jurcevic, T.Jones, M.Missiaglia, E.Ruszniewski, P.Sauvanet, A.Lemoine, N. R.Adenocarcinoma, Mucinous/genetics/*pathologyBile Ducts, Intrahepatic/metabolism/*pathologyCarcinoma, Papillary/genetics/*pathologyCell Line, Transformed*Gene Expression ProfilingHumanOligonucleotide Array Sequence AnalysisPancreas/metabolism/pathologyPancreatic Neoplasms/genetics/*pathologyRNA, Neoplasm/genetics/metabolismAm J Pathol200216051745-54.(219)(216) and topoisomerase II alpha (95%) ADDIN EN.CITE Argani20016530Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinomaArgani, P.Rosty, C.Reiter, R. E.Wilentz, R. E.Murugesan, S. R.Leach, S. D.Ryu, B.Skinner, H. G.Goggins, M.Jaffee, E. M.Yeo, C. J.Cameron, J. L.Kern, S. E.Hruban, R. H.Cancer Res200161114320-4.Argani20017090Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE)Argani, P.Iacobuzio-Donahue, C.Ryu, B.Rosty, C.Goggins, M.Wilentz, R. E.Murugesan, S. R.Leach, S. D.Jaffee, E.Yeo, C. J.Cameron, J. L.Kern, S. E.Hruban, R. H.Clin Cancer Res20017123862-8.Swierczynski200414570Swierczynski, S. L., Maitra, A., Abraham, S. C., Iacobuzio-Donahue, C. A., Ashfaq, R., Cameron, J. L., Schulick, R. D., Yeo, C. J., Rahman, A., Hinkle, D. A., Hruban, R. H., and Argani, P.2004Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays.Hum.Pathol35357-366Maitra200211140Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: sea urchin fascin homolog and heat shock protein 47Maitra, A.Iacobuzio-Donahue, C.Rahman, A.Sohn, T. A.Argani, P.Meyer, R.Yeo, C. J.Cameron, J. L.Goggins, M.Kern, S. E.Ashfaq, R.Hruban, R. H.Wilentz, R. E.AdultAgedAged, 80 and overAnimalCarcinoma in Situ/*genetics/metabolism/pathologyCarcinoma, Pancreatic Ductal/*genetics/metabolism/secondaryCarrier Proteins/*genetics/metabolismCell CountFemaleGene Expression*Gene Expression ProfilingHeat-Shock Proteins/*genetics/metabolismHumanImmunohistochemistry/methodsMaleMicrofilament Proteins/*genetics/metabolismMiddle AgePancreatic Neoplasms/*genetics/metabolism/pathologyRNA, Neoplasm/analysisSea UrchinsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Markers, Biological/geneticsAm J Clin Pathol2002118152-9.Grutzmann200414580Grutzmann, R., Luttges, J., Sipos, B., Ammerpohl, O., Dobrowolski, F., Alldinger, I., Kersting, S., Ockert, D., Koch, R., Kalthoff, H., Schackert, H. K., Saeger, H. D., Kloppel, G., and Pilarsky, C.2004ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma.Br J Cancer901053-1058Guo200414590Guo, J., Kleeff, J., Li, J., Ding, J., Hammer, J., Zhao, Y., Giese, T., Korc, M., Buchler, M. W., and Friess, H.2004Expression and functional significance of CDC25B in human pancreatic ductal adenocarcinoma.Oncogene2371-81(220-225)(217-222). Two kallikreins, KLK6 and KLK10 are significantly up-regulated in pancreatic cancer ADDIN EN.CITE Yousef200414600Yousef, G. M., Borgono, C. A., Popalis, C., Yacoub, G. M., Polymeris, M. E., Soosaipillai, A., and Diamandis, E. P.2004In-silico analysis of kallikrein gene expression in pancreatic and colon cancers.Anticancer Res.2443-51(226)(223), as are a number of members of the S100 protein family ADDIN EN.CITE Crnogorac-Jurcevic200314610Crnogorac-Jurcevic, T., Missiaglia, E., Blaveri, E., Gangeswaran, R., Jones, M., Terris, B., Costello, E., Neoptolemos, J. P., and Lemoine, N. R.2003Molecular alterations in pancreatic carcinoma: expression profiling shows that dysregulated expression of S100 genes is highly prevalent.J Pathol20163-74Rosty20027060Overexpression of S100A4 in Pancreatic Ductal Adenocarcinomas Is Associated with Poor Differentiation and DNA HypomethylationRosty, C.Ueki, T.Argani, P.Jansen, M.Yeo, C. J.Cameron, J. L.Hruban, R. H.Goggins, M.Am J Pathol2002160145-50.(227, 228)(224, 225), and aurora kinase ADDIN EN.CITE Li200312820Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancerLi, D.Zhu, J.Firozi, P. F.Abbruzzese, J. L.Evans, D. B.Cleary, K.Friess, H.Sen, S.AgedAged, 80 and overAneuploidyBlotting, NorthernBlotting, SouthernBlotting, WesternCell DifferentiationCell Transformation, NeoplasticChromosomes, Human, Pair 20FemaleHumanLymphatic MetastasisMaleMiddle AgedNeoplasm MetastasisPancreatic Neoplasms/*enzymology/geneticsProtein-Serine-Threonine Kinases/*biosynthesis/*geneticsRNA, Messenger/metabolismSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tumor Cells, Culturedras-GRF1/biosynthesisClin Cancer Res200393991-7.(229)(226). The clinical usefulness of detecting these markers has not yet been demonstrated. Gene expression microarray analysis is being studied as a prognostic tool for several cancers, but because of the dismal prognosis of pancreatic cancer, prognostic studies of pancreatic cancer markers are not being extensively investigated. Some markers may be useful for predicting if IPMNs have an associated infiltrating pancreatic carcinoma (such as claudin 4, S100A4, and mesothelin) ADDIN EN.CITE Sato N200412190Sato N,, Fukushima N, Maitra A, Iacobuzio-Donahue CA, van Heek NT, Cameron JL, Yeo CJ, Hruban RH, Goggins M.2004Gene expression profiling identifies genes associated with invasive intraductal papillary mucinous neoplasms of the pancreasAm J Pathol164903-14(230)(227). Such markers may prove useful to assay on suspected IPMNs before surgery to help predict whether an IPMN has an associated invasive cancer to help decide on surgery. The potential therapeutic/chemoprevention target cyclooxygenase-2 is expressed in most pancreatic cancers as are mediators of the sonic hedgehog pathway including PTCH ADDIN EN.CITE Maitra200214630Maitra, A., Ashfaq, R., Gunn, C. R., Rahman, A., Yeo, C. J., Sohn, T. A., Cameron, J. L., Hruban, R. H., and Wilentz, R. E.2002Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging.Am J Clin Pathol118194-201Berman200313160Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumoursBerman, D. M.Karhadkar, S. S.Maitra, A.Montes De Oca, R.Gerstenblith, M. R.Briggs, K.Parker, A. R.Shimada, Y.Eshleman, J. R.Watkins, D. N.Beachy, P. A.AnimalsCell Division/drug effectsCell Line, TumorDigestive System/cytology/drug effects/metabolism/pathologyGastrointestinal Neoplasms/drug therapy/genetics/*metabolism/*pathologyGene Deletion*Gene Expression Regulation, NeoplasticHumanLigandsMembrane Proteins/genetics/metabolismMiceMice, NudeMutationNeoplasm TransplantationRNA, Messenger/genetics/metabolismRNA, Neoplasm/genetics/metabolism*Signal Transduction/drug effectsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Trans-Activators/antagonists & inhibitors/*genetics/*metabolismTransplantation, HeterologousVeratrum Alkaloids/pharmacology/therapeutic useNature20034256960846-51. Epub 2003 Sep 14.(231, 232)(228, 229).
Increasingly, it is becoming important to identify molecular targets of novel cancer therapies. There is considerable hope that the future of pancreatic cancer diagnosis will include molecular profiling to identify therapeutic targets for novel therapies. One example of this paradigm is the genetic inactivation of the Fanconi anemia pathway in a small percentage of pancreatic adenocarcinomas ADDIN EN.CITE van der Heijden200311700Fanconi anemia gene mutations in young-onset pancreatic cancervan der Heijden, M. S.Yeo, C. J.Hruban, R. H.Kern, S. E.Age FactorsAllelesAnimalCarcinoma, Pancreatic Ductal/*geneticsDNA-Binding Proteins/*geneticsGene SilencingGenetic Predisposition to DiseaseHumanLoss of HeterozygosityMiceMutationNeoplasm TransplantationPancreatic Neoplasms/*geneticsProteins/*geneticsSupport, U.S. Gov't, P.H.S.Transplantation, HeterologousCancer Res200363102585-8.(108)(107). Cells with inactivation of the Fanconi pathway are hypersensitive to certain chemotherapeutics, such as mitomycin, which may explain previous clinical evidence of occasional treatment responses to mitomycin ADDIN EN.CITE van der Heijden200414670Functional defects in the fanconi anemia pathway in pancreatic cancer cellsvan der Heijden, M. S.Brody, J. R.Gallmeier, E.Cunningham, S. C.Dezentje, D. A.Shen, D.Hruban, R. H.Kern, S. E.*Cell Cycle ProteinsCisplatin/pharmacologyCross-Linking Reagents/pharmacologyDNA Mutational AnalysisDNA, Neoplasm/geneticsDNA-Binding Proteins/geneticsFanconi Anemia/*genetics/metabolismG2 Phase/drug effectsGene DeletionHomozygoteHumansMitomycin/pharmacologyMitosis/drug effectsNuclear Proteins/*geneticsPancreatic Neoplasms/*genetics/pathologyProteins/geneticsResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.*Signal TransductionTumor Cells, CulturedUbiquitin/metabolismAm J Pathol20041652651-7.(233)(230). These encouraging findings highlight the need to identify which pancreatic cancers harbor inactivation of the Fanconi anemia pathway. It is expected that as additional therapeutics are identified that target specific pathways, accurate tumor markers will be needed to evaluate the status of these pathways to help determine whether a particular therapeutic is an appropriate target for an individuals pancreatic cancer.
CONCLUSIONS
In conclusion, while CA19-9 remains the most commonly used pancreatic cancer tumor marker, there are currently many additional candidate markers under investigation. Additional markers are needed not only to facilitate the early diagnosis of pancreatic cancer, but also to help diagnose pancreatic cancer precursor lesions. Our knowledge of pancreatic neoplasia has increased years, and with it the evidence from clinical studies screening individuals at high risk of developing pancreatic cancer. These studies lend support to the idea that the best way to reduce the mortality of pancreatic cancer is to use molecular markers and pancreatic imaging to identify patients with precancerous lesions of the pancreas that are likely to progress to pancreatic cancer and treat these patients while they still have best chance of being cured.Table 1. Recommendations by different Expert Groups for use of CA 19-9 as a tumor marker for pancreatic cancer
ApplicationEGTM 1999 (74)AGA 1999 (3)NACB 2005LOE [NACB]ScreeningNo specific recommendations No specific screening method for high-risk subjects recommended; best strategy perhaps CT/EUS and CA 19-9. Clinical benefit unprovenNot for screening of the general population. CA19-9 is often normal in high-risk subjects with a strong family history of pancreatic cancer undergoing EUS/CT screening of the pancreas (ref. 69-70).IIIDiagnosisIs a diagnostic aid for pancreatic malignancy, but with limited value, especially in early stages and the presence of cholestasisNo specific recommendations If it is used, CA19-9 should be used in conjunction with an imaging test (CT, EUS). Appropriately interpreted CA19-9 values can guide further invasive testing (ERCP, EUS FNA, laparoscopy, laparotomy) in the appropriate clinical context. IPrognosisRoutine use for prognostic purposes of unproven valueNo specific recommendationsHas independent prognostic value with regard to resectability and survival; Clinical decisions should be based on all available informationIMonitoringRoutine use for monitoring of unproven valueNot an accepted test for anti-tumor efficacySerial measurements during palliative chemotherapy can be used in conjunction with imaging tests to determine response. Serial measurements recommended for follow-up after potentially curative surgeryI
*CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatograph; EUS, endoscopic ultrasound; FNA, fine needle aspirate; LOE=level of evidence. I: Evidence from well-powered prospective controlled studies, or pooled or meta-analysis or level II or III studies. II: Marker evidence determined during a prospective therapeutic trial. III: Evidence from large prospective studies. IV: Evidence from small retrospective studies. V: Evidence from small pilot studies.
Table 2: Gene testing for hereditary pancreatic cancer
Gene testCharacteristics and clinical implicationsLOEReferencesBRCA2Mutated in ~5% of patients with apparently sporadic pancreatic cancer and in 5-17% of patients with familial pancreatic cancerI101,102, 109-111STK11Germ line mutations only found in those with the Peutz Jeghers syndrome phenotype. Affected patients have ~30% risk of developing pancreatic cancerI103Cationic trypsinogenGene testing in the context of hereditary pancreatitisI29,104, 105p16Considered for patients with pancreatic cancer occurring in families suspected of having familial atypical melanoma mole syndrome (FAMM). Prevalence of germ line p16 mutations not determined for families with pancreatic cancer and melanoma who do not meet criteria for FAMMII112-114
LOE=level of evidence.
Table 3: Tissue markers for pancreatic ductal adenocarcinoma.
Tissue markersCharacteristics and clinical implicationsLOEReferenceCK 7, CK 8, CK 18 and CK 19Expressed in 70-100%I115-117CK 17Expressed in 50-70%I115-117CK 20Expressed in < 20%I115-117CEADistinguish infiltrating adenocarcinoma from reactive glandsII119MUC 2Expressed in < 10% pancreatic adenocarcinoma; but in majority of IPMNII124-126MUC 6Expressed in 25%;II124-126Trefoil factor-2Expressed in minority of pancreatic adenocarcinoma, but in >90% of IPMN and MCNIV216MesothelinExpressed in close to 100%; pilot studies suggest protein expression by immunohistochemistry can aid in cytology interpretationIV215MADH4/SMAD4/DPC4 tumor suppressor geneDown-regulated in 55%; associated with poor prognosisI124-126
CK, cytokeratin; LOE=level of evidence.
Table 4: Candidate serum protein markers of pancreatic ductal adenocarcinoma
MarkerPhase of DevelopmentUses and Potential UsesLOE*ReferencesCA19-9Accepted clinical useMonitoring of disease burden, adjunct to diagnosisI70-98CA242EvaluationDiagnosis; not superior to CA19-9III126-133CAM17.1EvaluationDiagnosis; not superior to CA19-9III134-137TPSEvaluationDiagnosis; not superior to CA19-9III43, 138-141MIC-1Research/DiscoveryDiagnosis; maybe more sensitive than CA19-9, but also often elevated in patients with chronic pancreatitisIII142-145OsteopontinResearch/DiscoveryDiagnosis; studies using plasma and accurate assays requiredIV146-148TIMP-1Research/DiscoveryDiagnosis; studies using plasma and accurate assays requiredIV149-152SELDI proteomic profilingResearch/DiscoveryDiagnosis; pilot studies have identified peptide markers, but require confirmatory studiesIV155-158
LOE=level of evidence.
Table 5: Candidate DNA markers applicable to pancreatic juice analysis
MarkerPhase of DevelopmentPotential UsesLOEReferencesMutant p53EvaluationDiagnosis: Mutations thought to be highly specific for neoplasia but better assays are needed to detect the spectrum of p53 mutations, to detect them at low concentrations and to use assays that can be routinely applied in clinical labs.I173-183Mutant KRASEvaluationDiagnosis: KRAS mutations are not specific for pancreatic cancer. Further studies ongoing to evaluate the diagnostic accuracy of assays that quantify as opposed to merely detecting mutant KRAS levelsI164-172Methylated DNAEvaluationDiagnosis: Numerous candidate markers including SPARC, TFPI-2, ppENK, and others. Each are moderately sensitive and highly specific for pancreatic cancer using MSP in pure pancreatic juice. Ongoing studies are evaluating their diagnostic accuracy IV191-196-198Mitochondrial DNA mutationsEvaluationDiagnosis: Pilot studies using chip technologyIV186
LOE=level of evidence.
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NACB: Practice Guidelines And Recommendations For Use Of Tumor Markers In The Clinic
NACB First Posting Pancreatic Cancer Manuscript (3I) for Web
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