Early diagnosis of pancreatic cancer: challenges and new developments.

Pancreatic cancer is a lethal malignancy with its incidence almost equivalent to mortality. The complex pathophysiology, absence of early diagnostic and prognostic markers and unresponsiveness to radiation and chemotherapies are major barriers against successful therapy. Poor performance of therapeutic agents, even in the initial stage of invasive cases, emphasizes the importance of early detection for improved survival. The present review discusses the challenges and advances in biomarkers including serological signatures, circulating tumor cells, autoantibodies, epigenetic markers and miRNAs that are being explored to detect this cancer at early stages. Considering the long time gap between the development of malignant lesions and full-blown primary and metastatic pancreatic cancer, unique opportunities are being contemplated for the development of potential diagnostic and prognostic markers.

[1]  Stefan K. Maier,et al.  MALDI Imaging Mass Spectrometry for In Situ Proteomic Analysis of Preneoplastic Lesions in Pancreatic Cancer , 2012, PloS one.

[2]  C. Borrebaeck,et al.  Identification of serum biomarker signatures associated with pancreatic cancer. , 2012, Cancer research.

[3]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[4]  H. Tao,et al.  Detection of serum tumor markers in the diagnosis and treatment of patients with pancreatic cancer. , 2004, Hepatobiliary & pancreatic diseases international : HBPD INT.

[5]  R. Eeles,et al.  Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC) , 2007, Familial Cancer.

[6]  G. Petersen,et al.  New-onset diabetes in pancreatic cancer: a study in the primary care setting. , 2012, Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.].

[7]  M. de Andrade,et al.  Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. , 2008, Gastroenterology.

[8]  E. Kuipers,et al.  High Cancer Risk in Peutz–Jeghers Syndrome: A Systematic Review and Surveillance Recommendations , 2010, The American Journal of Gastroenterology.

[9]  E. Luebeck.  Cancer: Genomic evolution of metastasis , 2010, Nature.

[10]  William E Grizzle,et al.  Serum Biomarker Panels for the Detection of Pancreatic Cancer , 2011, Clinical Cancer Research.

[11]  Randall E. Brand,et al.  Transcriptional Profiling of Peripheral Blood Mononuclear Cells in Pancreatic Cancer Patients Identifies Novel Genes with Potential Diagnostic Utility , 2011, PloS one.

[12]  J. C. Houwelingen,et al.  Cancer risks in BRCA2 families: estimates for sites other than breast and ovary , 2005, Journal of Medical Genetics.

[13]  J. Solassol,et al.  Autoantibody signatures: progress and perspectives for early cancer detection , 2011, Journal of cellular and molecular medicine.

[14]  A. Basu,et al.  New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. , 2009, The Lancet. Oncology.

[15]  Ananda Basu,et al.  Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. , 2008, Gastroenterology.

[16]  E. Fishman,et al.  Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[17]  D. Goldenberg,et al.  New MUC1 serum immunoassay differentiates pancreatic cancer from pancreatitis. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  L. Jorfeldt,et al.  Pancreatic cancer is associated with impaired glucose metabolism. , 1993, The European journal of surgery = Acta chirurgica.

[19]  M. Woodward,et al.  Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies , 2005, British Journal of Cancer.

[20]  Carsten Peterson,et al.  Detection of pancreatic cancer using antibody microarray‐based serum protein profiling , 2008, Proteomics.

[21]  Dana K Andersen,et al.  Diabetes and Pancreatic Cancer: Chicken or Egg? , 2011, Pancreas.

[22]  G. Parmigiani,et al.  Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses , 2008, Science.

[23]  T. Davison,et al.  MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma , 2007, Oncogene.

[24]  P. Bracci,et al.  Serum autoantibodies to pancreatic cancer antigens as biomarkers of pancreatic cancer in a San Francisco Bay Area case–control study , 2012, Cancer.

[25]  D. Gouma,et al.  The Yield of First-Time Endoscopic Ultrasonography in Screening Individuals at a High Risk of Developing Pancreatic Cancer , 2009, The American Journal of Gastroenterology.

[26]  W. Jarnagin,et al.  Feasibility and Yield of Screening in Relatives From Familial Pancreatic Cancer Families , 2011, The American Journal of Gastroenterology.

[27]  D. Scholtens,et al.  Methylation profile of circulating plasma DNA in patients with pancreatic cancer , 2009, Journal of surgical oncology.

[28]  V. Levenson,et al.  The MethDet: a technology for biomarker development , 2011, Expert review of molecular diagnostics.

[29]  Geoffrey S. Tobias,et al.  Cigarette smoking and pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. , 2009, American journal of epidemiology.

[30]  Michael Goggins,et al.  MicroRNA Alterations of Pancreatic Intraepithelial Neoplasias , 2011, Clinical Cancer Research.

[31]  Sridhar Ramaswamy,et al.  RNA sequencing of pancreatic circulating tumour cells implicates WNT signaling in metastasis , 2012, Nature.

[32]  David E. Misek,et al.  Identification of a Specific Vimentin Isoform That Induces an Antibody Response in Pancreatic Cancer , 2006, Biomarker insights.

[33]  M. Alessio,et al.  Autoantibody signature in human ductal pancreatic adenocarcinoma. , 2007, Journal of proteome research.

[34]  R. Brand,et al.  Diverse monoclonal antibodies against the CA 19‐9 antigen show variation in binding specificity with consequences for clinical interpretation , 2012, Proteomics.

[35]  R. Tollenaar,et al.  Magnetic resonance imaging surveillance detects early-stage pancreatic cancer in carriers of a p16-Leiden mutation. , 2011, Gastroenterology.

[36]  S. Dima,et al.  Assessment of soluble angiogenic markers in pancreatic cancer. , 2008, Biomarkers in medicine.

[37]  J. Cameron,et al.  Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. , 2003, Cancer research.

[38]  E. Dimagno,et al.  Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. , 1997, Journal of the National Cancer Institute.

[39]  Xi Chen,et al.  Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. , 2012, Clinical chemistry.

[40]  P. Maisonneuve,et al.  Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. , 2010, Best practice & research. Clinical gastroenterology.

[41]  S. Gruber,et al.  Risk of pancreatic cancer in families with Lynch syndrome. , 2009, JAMA.

[42]  H. Stürzbecher,et al.  Autoantibodies in sera of pancreatic cancer patients identify recombination factor Rad51 as a tumour-associated antigen , 2002, Journal of Cancer Research and Clinical Oncology.

[43]  M. Kitagawa,et al.  Usefulness of a new tumor marker, span‐1, for the diagnosis of pancreatic cancer , 1990, Cancer.

[44]  R. Russell,et al.  Principles of MicroRNA–Target Recognition , 2005, PLoS biology.

[45]  Haojie Huang,et al.  Differential signature of fecal microRNAs in patients with pancreatic cancer. , 2012, Molecular medicine reports.

[46]  Xiaohang Zhao,et al.  Detection of apoptotic circulating tumor cells in advanced pancreatic cancer following 5-fluorouracil chemotherapy , 2011, Cancer biology & therapy.

[47]  Michelle A. Anderson,et al.  Enhanced Discrimination of Malignant from Benign Pancreatic Disease by Measuring the CA 19-9 Antigen on Specific Protein Carriers , 2011, PloS one.

[48]  P. Andrews,et al.  Identification of blood‐protein carriers of the CA 19‐9 antigen and characterization of prevalence in pancreatic diseases , 2011, Proteomics.

[49]  A. Saftoiu,et al.  Beyond conventional endoscopic ultrasound: elastography, contrast enhancement and hybrid techniques , 2011, Current opinion in gastroenterology.

[50]  M. Fukuda,et al.  Clinical utility of quantitative RT‐PCR targeted to α1,4‐N‐acetylglucosaminyltransferase mRNA for detection of pancreatic cancer , 2006, Cancer science.

[51]  J. Heverhagen,et al.  Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer , 2009, Gut.

[52]  Ruud H. Brakenhoff,et al.  Detection, clinical relevance and specific biological properties of disseminating tumour cells , 2008, Nature Reviews Cancer.

[53]  Alison P. Klein,et al.  Prospective Risk of Pancreatic Cancer in Familial Pancreatic Cancer Kindreds , 2004, Cancer Research.

[54]  D. Chan,et al.  Serum Markers in Patients with Resectable Pancreatic Adenocarcinoma: Macrophage Inhibitory Cytokine 1 versus CA19-9 , 2006, Clinical Cancer Research.

[55]  G. Petersen,et al.  Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and risk for pancreatic adenocarcinoma , 2009, Cancer.

[56]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[57]  R. Hruban,et al.  Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[58]  James W Jacobson,et al.  MicroRNA: Potential for Cancer Detection, Diagnosis, and Prognosis. , 2007, Cancer research.

[59]  L. Liotta,et al.  Circulating autoantibodies to phosphorylated α-enolase are a hallmark of pancreatic cancer. , 2011, Journal of proteome research.

[60]  J G Fletcher,et al.  Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis. , 2004, AJR. American journal of roentgenology.

[61]  David E. Misek,et al.  An Autoantibody-Mediated Immune Response to Calreticulin Isoforms in Pancreatic Cancer , 2004, Cancer Research.

[62]  Li Jiao,et al.  K-ras Mutation and p16 and Preproenkephalin Promoter Hypermethylation in Plasma DNA of Pancreatic Cancer Patients: In Relation to Cigarette Smoking , 2007, Pancreas.

[63]  J. Disario,et al.  Improved Diagnosis of Pancreatic Adenocarcinoma Using Haptoglobin and Serum Amyloid A in a Panel Screen , 2009, World Journal of Surgery.

[64]  D. McMillan,et al.  Chronic inflammation and pancreatic cancer. , 2008, Best practice & research. Clinical gastroenterology.

[65]  R. Hruban,et al.  Polymorphisms of SPINK1 N34S and CFTR in Patients with Sporadic and Familial Pancreatic Cancer , 2003, Cancer biology & therapy.

[66]  Michelle A. Anderson,et al.  A Mouse to Human Search for Plasma Proteome Changes Associated with Pancreatic Tumor Development , 2008, PLoS medicine.

[67]  M. Neagu,et al.  Tissular and soluble miRNAs for diagnostic and therapy improvement in digestive tract cancers , 2011, Expert review of molecular diagnostics.

[68]  Andrew Menzies,et al.  The patterns and dynamics of genomic instability in metastatic pancreatic cancer , 2010, Nature.

[69]  Kohzoh Imai,et al.  Circulating anti‐MUC1 IgG antibodies as a favorable prognostic factor for pancreatic cancer , 2003, International journal of cancer.

[70]  D. V. Von Hoff,et al.  Tumor-stroma interactions in pancreatic ductal adenocarcinoma , 2007, Molecular Cancer Therapeutics.

[71]  S. Batra,et al.  Current status of molecular markers for early detection of sporadic pancreatic cancer. , 2011, Biochimica et biophysica acta.

[72]  M. Kimmey,et al.  Early Diagnosis and Treatment of Pancreatic Dysplasia in Patients with a Family History of Pancreatic Cancer , 1999, Annals of Internal Medicine.

[73]  V. Egorov,et al.  Pancreatic adenocarcinoma: Outstanding problems. , 2012, World journal of gastrointestinal surgery.

[74]  W. Bamlet,et al.  Obesity adversely affects survival in pancreatic cancer patients , 2010, Cancer.

[75]  Jun Liu,et al.  Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. , 2011, European journal of cancer.

[76]  F. Giardiello,et al.  Peutz-Jeghers syndrome and management recommendations. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[77]  W. Kohlmann,et al.  Identification and screening of individuals at increased risk for pancreatic cancer with emphasis on known environmental and genetic factors and hereditary syndromes. , 2010, JOP : Journal of the pancreas.

[78]  A. Jemal,et al.  Cancer Statistics, 2009 , 2009, CA: a cancer journal for clinicians.

[79]  A. Klein.  Genetic susceptibility to pancreatic cancer , 2012, Molecular carcinogenesis.

[80]  J. Hainsworth,et al.  Introduction: unknown primary cancer. , 2009, Seminars in oncology.

[81]  L. Gullo,et al.  Diabetes and the risk of pancreatic cancer. , 1994, Annals of oncology : official journal of the European Society for Medical Oncology.

[82]  E. Kriegová,et al.  Involvement of microRNAs in physiological and pathological processes in the lung , 2010, Respiratory research.

[83]  M. Nowak,et al.  Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer , 2010, Nature.

[84]  J. Ryu,et al.  The Role of Quantitative NPTX2 Hypermethylation as a Novel Serum Diagnostic Marker in Pancreatic Cancer , 2012, Pancreas.

[85]  K. Lillemoe,et al.  Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology. , 2002, Cancer research.

[86]  F. Clavel-Chapelon,et al.  Inflammation marker and risk of pancreatic cancer: a nested case–control study within the EPIC cohort , 2012, British Journal of Cancer.

[87]  D. Landsittel,et al.  Multianalyte profiling of serum cytokines for detection of pancreatic cancer. , 2005, Cancer biomarkers : section A of Disease markers.

[88]  Sepp Kaul,et al.  Multimarker Gene Analysis of Circulating Tumor Cells in Pancreatic Cancer Patients: A Feasibility Study , 2012, Oncology.

[89]  Michelle A. Anderson,et al.  CEACAM1, a Novel Serum Biomarker for Pancreatic Cancer , 2007, Pancreas.

[90]  Martin Krapcho,et al.  SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations) , 2012 .

[91]  F. Motoi,et al.  Identification of epigenetically silenced genes in human pancreatic cancer by a novel method "microarray coupled with methyl-CpG targeted transcriptional activation" (MeTA-array). , 2011, Biochemical and biophysical research communications.

[92]  Jeffrey E. Lee,et al.  Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer , 2003, Journal of Gastrointestinal Surgery.

[93]  H. Koprowski,et al.  Detection of monoclonal antibody-defined colorectal carcinoma antigen by solid-phase binding inhibition radioimmunoassay. , 1981, Hybridoma.

[94]  Manuel Hidalgo,et al.  Disease-associated expression profiles in peripheral blood mononuclear cells from patients with advanced renal cell carcinoma. , 2003, Cancer research.

[95]  Maximilian Reichert,et al.  EMT and Dissemination Precede Pancreatic Tumor Formation , 2012, Cell.

[96]  Douglas F Easton,et al.  Cancer Incidence in BRCA1 mutation carriers. , 2002, Journal of the National Cancer Institute.

[97]  M. Porta,et al.  How useful is it clinically to analyse the K‐ras mutational status for the diagnosis of exocrine pancreatic cancer? A systematic review and meta‐analysis , 2011, European journal of clinical investigation.

[98]  Jun Wu,et al.  Serum level of TSGF, CA242 and CA19-9 in pancreatic cancer. , 2004, World journal of gastroenterology.

[99]  Huamin Wang,et al.  Ras activity levels control the development of pancreatic diseases. , 2009, Gastroenterology.

[100]  M. Goggins.  Molecular markers of early pancreatic cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[101]  Damon H. May,et al.  Protein alterations associated with pancreatic cancer and chronic pancreatitis found in human plasma using global quantitative proteomics profiling. , 2011, Journal of proteome research.

[102]  Steven Piantadosi,et al.  Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. , 2004, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[103]  R. Hruban,et al.  Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. , 1994, Cancer research.

[104]  Lynette M. Smith,et al.  Differential gene expression analysis of peripheral blood mononuclear cells reveals novel test for early detection of pancreatic cancer. , 2011, Cancer biomarkers : section A of Disease markers.

[105]  R. Abrams,et al.  Differential methylation of cell‐free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis , 2010, Cancer.

[106]  S. Kawa,et al.  Comparative study of CA-50 (time-resolved fluoroimmunoassay), Span-1, and CA19-9 in the diagnosis of pancreatic cancer. , 1991, Scandinavian journal of gastroenterology.

[107]  Wei-Yuan Zhang,et al.  Gene expression profiling of maternal blood in early onset severe preeclampsia: identification of novel biomarkers , 2009, Journal of perinatal medicine.