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  • Primer
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Pancreatic cancer

Abstract

Pancreatic cancer is a major cause of cancer-associated mortality, with a dismal overall prognosis that has remained virtually unchanged for many decades. Currently, prevention or early diagnosis at a curable stage is exceedingly difficult; patients rarely exhibit symptoms and tumours do not display sensitive and specific markers to aid detection. Pancreatic cancers also have few prevalent genetic mutations; the most commonly mutated genes are KRAS, CDKN2A (encoding p16), TP53 and SMAD4 — none of which are currently druggable. Indeed, therapeutic options are limited and progress in drug development is impeded because most pancreatic cancers are complex at the genomic, epigenetic and metabolic levels, with multiple activated pathways and crosstalk evident. Furthermore, the multilayered interplay between neoplastic and stromal cells in the tumour microenvironment challenges medical treatment. Fewer than 20% of patients have surgically resectable disease; however, neoadjuvant therapies might shift tumours towards resectability. Although newer drug combinations and multimodal regimens in this setting, as well as the adjuvant setting, appreciably extend survival, 80% of patients will relapse after surgery and ultimately die of their disease. Thus, consideration of quality of life and overall survival is important. In this Primer, we summarize the current understanding of the salient pathophysiological, molecular, translational and clinical aspects of this disease. In addition, we present an outline of potential future directions for pancreatic cancer research and patient management.

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Figure 1: Common types of pancreatic cancer.
Figure 2: Global mortality and incidence rates of pancreatic cancer.
Figure 3: Aberrant signalling pathways in pancreatic cancer.
Figure 4: Gene alterations in pancreatic cancer.
Figure 5: Pancreatic stellate cells in pancreatic cancer.
Figure 6: Metabolic reprogramming in pancreatic cancer.
Figure 7: Models of pancreatic cancer.
Figure 8: Diagnostic imaging of pancreatic cancer.
Figure 9: The double duct sign in pancreatic cancer.
Figure 10: Infiltrating ductal adenocarcinoma of the pancreas.
Figure 11: Resectability of pancreatic cancer.
Figure 12: Surgical resection of pancreatic cancer.

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References

  1. Ferlay, J. et al. GLOBOCAN 2012: cancer incidence and mortality worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer [online] http://globocan.iarc.fr, (2013).

    Google Scholar 

  2. Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29 (2015).

    Article  PubMed  Google Scholar 

  4. He, J. et al. 2564 resected periampullary adenocarcinomas at a single institution: trends over three decades. HPB (Oxford) 16, 83–90 (2014).

    Article  Google Scholar 

  5. Rosato, V. et al. Population attributable risk for pancreatic cancer in Northern Italy. Pancreas 44, 216–220 (2015).

    Article  PubMed  Google Scholar 

  6. Boffetta, P., Boccia, S. & La Vecchia, C. (eds) A Quick Guide to Cancer Epidemiology (Springer, 2014).

    Book  Google Scholar 

  7. International Agency for Research on Cancer (IARC). Cancer incidence in five continents. Vol. X. IARC [online] http://ci5.iarc.fr, (2013).

  8. Malvezzi, M. et al. European cancer mortality predictions for the year 2015: does lung cancer have the highest death rate in EU women? Ann. Oncol. 26, 779–786 (2015). This work demonstrates that pancreatic cancer is a major neoplasm without favourable incidence and mortality trends over the past decades, and its prognosis remains dismal.

    Article  CAS  PubMed  Google Scholar 

  9. Cancer Research UK. Pancreatic cancer statistics. Cancer Research UK [online] www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer, (2015).

  10. Anderson, K., Mack, T. & Silverman, D. in Cancer of the Pancreas (eds Schottenfeld, D. & Fraumeni, J. ) 721–762 (Oxford Univ. Press, 2006).

    Google Scholar 

  11. Bosetti, C. et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case–Control Consortium (Panc4). Ann. Oncol. 23, 1880–1888 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Parkin, D. M. 2. Tobacco-attributable cancer burden in the UK in 2010. Br. J. Cancer 105, S6–S13 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Whiteman, D. C. et al. Cancers in Australia in 2010 attributable to modifiable factors: introduction and overview. Aust. N. Z. J. Public Health 39, 403–407 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Boffetta, P., Hecht, S., Gray, N., Gupta, P. & Straif, K. Smokeless tobacco and cancer. Lancet Oncol. 9, 667–675 (2008).

    Article  PubMed  Google Scholar 

  15. Behrens, G. et al. Physical activity and risk of pancreatic cancer: a systematic review and meta-analysis. Eur. J. Epidemiol. 30, 279–298 (2015).

    Article  PubMed  Google Scholar 

  16. Genkinger, J. M. et al. Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. Ann. Oncol. 26, 2257–2266 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Larsson, S. C. & Wolk, A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. Br. J. Cancer 106, 603–607 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rohrmann, S. et al. Meat and fish consumption and risk of pancreatic cancer: results from the European Prospective Investigation into Cancer and Nutrition. Int. J. Cancer 132, 617–624 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Bosetti, C. et al. Nutrient-based dietary patterns and pancreatic cancer risk. Ann. Epidemiol. 23, 124–128 (2013).

    Article  PubMed  Google Scholar 

  20. MacMahon, B., Yen, S., Trichopoulos, D., Warren, K. & Nardi, G. Coffee and cancer of the pancreas. N. Engl. J. Med. 304, 630–633 (1981).

    Article  CAS  PubMed  Google Scholar 

  21. Tramacere, I. et al. Alcohol drinking and pancreatic cancer risk: a meta-analysis of the dose–risk relation. Int. J. Cancer 126, 1474–1486 (2010).

    CAS  PubMed  Google Scholar 

  22. Lucenteforte, E. et al. Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case–Control Consortium (PanC4). Ann. Oncol. 23, 374–382 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Bosetti, C. et al. Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case–Control Consortium. Ann. Oncol. 25, 2065–2072 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chari, S. T. et al. Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134, 95–101 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Bosetti, C. et al. Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case–Control Consortium (PanC4). Ann. Oncol. 24, 2903–2910 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Turati, F. et al. Family history of cancer and the risk of cancer: a network of case–control studies. Ann. Oncol. 24, 2651–2656 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Rizzato, C. et al. ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium. Oncol. Rep. 29, 1637–1644 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & Depinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Tanaka, M. Thirty years of experience with intraductal papillary mucinous neoplasm of the pancreas: from discovery to international consensus. Digestion 90, 265–272 (2014).

    Article  PubMed  Google Scholar 

  30. Preis, M. & Korc, M. Signaling pathways in pancreatic cancer. Crit. Rev. Eukaryot. Gene Expr. 21, 115–129 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Pasca di Magliano, M. et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE 2, e1155 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tanizaki, J., Okamoto, I., Sakai, K. & Nakagawa, K. Differential roles of trans -phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification. Br. J. Cancer 105, 807–813 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gore, A. J., Deitz, S. L., Palam, L. R., Craven, K. E. & Korc, M. Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. J. Clin. Invest. 124, 338–352 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, L. et al. Whole-exome sequencing of human pancreatic cancers and characterization of genomic instability caused by MLH1 haploinsufficiency and complete deficiency. Genome Res. 22, 208–219 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015). A landmark analysis of the mutational landscape of pancreatic cancer, defining four subtypes depending on patterns of structural variation: stable, locally rearranged, scattered and unstable.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Witkiewicz, A. K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016). This comprehensive study defines four subtypes of pancreatic cancer based on expression profile: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine.

    Article  CAS  PubMed  Google Scholar 

  40. Chang, D. K., Grimmond, S. M. & Biankin, A. V. Pancreatic cancer genomics. Curr. Opin. Genet. Dev. 24, 74–81 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Blackford, A. et al. Genetic mutations associated with cigarette smoking in pancreatic cancer. Cancer Res. 69, 3681–3688 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nones, K. et al. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int. J. Cancer 135, 1110–1118 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Daemen, A. et al. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors. Proc. Natl Acad. Sci. USA 112, E4410–E4417 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gore, J. & Korc, M. Pancreatic cancer stroma: friend or foe? Cancer Cell 25, 711–712 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Biankin, A. V. & Maitra, A. Subtyping pancreatic cancer. Cancer Cell 28, 411–413 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Kottakis, F. & Bardeesy, N. Gene signatures from pancreatic cancer tumor and stromal cells predict disease outcome. Nat. Genet. 47, 1102–1103 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Seymour, A. B. et al. Allelotype of pancreatic adenocarcinoma. Cancer Res. 54, 2761–2764 (1994).

    CAS  PubMed  Google Scholar 

  51. Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Amedei, A., Niccolai, E. & Prisco, D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum. Vaccin. Immunother. 10, 3354–3368 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Inman, K. S., Francis, A. A. & Murray, N. R. Complex role for the immune system in initiation and progression of pancreatic cancer. World J. Gastroenterol. 20, 11160–11181 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Erkan, M. et al. The activated stroma index is a novel and independent prognostic marker in pancreatic ductal adenocarcinoma. Clin. Gastroenterol. Hepatol. 6, 1155–1161 (2008).

    Article  PubMed  Google Scholar 

  56. Bever, K. M. et al. The prognostic value of stroma in pancreatic cancer in patients receiving adjuvant therapy. HPB (Oxford) 17, 292–298 (2014).

    Article  Google Scholar 

  57. Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, L. M. et al. The prognostic role of desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget 7, 4183–4194 (2016).

    PubMed  Google Scholar 

  59. Apte, M. V., Wilson, J. S., Lugea, A. & Pandol, S. J. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210–1219 (2013).

    Article  PubMed  Google Scholar 

  60. Hamada, S. et al. Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem. Biophys. Res. Commun. 421, 349–354 (2012). This paper reports that enhancement of cancer cell stemness by pancreatic stellate cells influences the chemoresistance and recurrence of pancreatic cancer.

    Article  CAS  PubMed  Google Scholar 

  61. Xu, Z. et al. Role of pancreatic stellate cells in pancreatic cancer metastasis. Am. J. Pathol. 177, 2585–2596 (2010). This is the first study to demonstrate that pancreatic stellate cells can migrate from the primary tumour site to distant sites where they probably facilitate seeding and survival of metastatic cancer cells.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Patel, M. B. et al. The role of the hepatocyte growth factor/c-MET pathway in pancreatic stellate cell–endothelial cell interactions: antiangiogenic implications in pancreatic cancer. Carcinogenesis 35, 1891–1900 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Ene-Obong, A. et al. Activated pancreatic stellate cells sequester CD8+ T-cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 45, 1121–1132 (2013).

    Article  CAS  Google Scholar 

  64. Tang, D. et al. High expression of galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int. J. Cancer 130, 2337–2348 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. Mace, T. A., Bloomston, M. & Lesinski, G. B. Pancreatic cancer-associated stellate cells: a viable target for reducing immunosuppression in the tumor microenvironment. Oncoimmunology 2, e24891 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Ma, Y., Hwang, R. F., Logsdon, C. D. & Ullrich, S. E. Dynamic mast cell–stromal cell interactions promote growth of pancreatic cancer. Cancer Res. 73, 3927–3937 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Shi, C. et al. Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage–stellate cell interaction. Lab. Invest. 94, 409–421 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, X. et al. Sonic Hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin. Cancer Res. 20, 4326–4338 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Kikuta, K. et al. Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic β-cells. Biochem. Biophys. Res. Commun. 433, 292–297 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Erkan, M. et al. Cancer–stellate cell interactions perpetuate the hypoxia–fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 11, 497–508 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kong, B. et al. Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer. Oncotarget 6, 32154–32160 (2015).

    PubMed  PubMed Central  Google Scholar 

  74. Schonenberger, M. J. & Kovacs, W. J. Hypoxia signaling pathways: modulators of oxygen-related organelles. Front. Cell Dev. Biol. 3, 42 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Ye, L. Y. et al. Hypoxia-inducible factor 1α expression and its clinical significance in pancreatic cancer: a meta-analysis. Pancreatology 14, 391–397 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Yang, S. et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 25, 717–729 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Perera, R. M. et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 524, 361–365 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Commisso, C. et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Cohen, R. et al. Targeting cancer cell metabolism in pancreatic adenocarcinoma. Oncotarget 6, 16832–16847 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. Caldas, C. et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat. Genet. 8, 27–32 (1994).

    Article  CAS  PubMed  Google Scholar 

  84. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003). This paper describes the original GEMM model that demonstrated pancreatic cancer initiation and progression in a model system. Many subsequent models have been based on this GEMM model.

    Article  CAS  PubMed  Google Scholar 

  85. Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Huang, L. et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 1364–1371 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015). This is the first description of human and mouse pancreatic ductal organoids, stimulating new research areas and exploratory clinical applications for pancreatic cancer.

    Article  CAS  PubMed  Google Scholar 

  89. Huch, M. et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32, 2708–2721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bardeesy, N. et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 20, 3130–3146 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Hruban, R. H. et al. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res. 66, 95–106 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Izeradjene, K. et al. KrasG12D and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 11, 229–243 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Mann, K. M. et al. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 5934–5941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Perez-Mancera, P. A. et al. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. Nature 486, 266–270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Rad, R. et al. A conditional piggyBac transposition system for genetic screening in mice identifies oncogenic networks in pancreatic cancer. Nat. Genet. 47, 47–56 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Navas, C. et al. EGF receptor signaling is essential for K-ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Collins, M. A. et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122, 639–653 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Saborowski, M. et al. A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev. 28, 85–97 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. von Figura, G. et al. The chromatin regulator Brg1 suppresses formation of intraductal papillary mucinous neoplasm and pancreatic ductal adenocarcinoma. Nat. Cell Biol. 16, 255–267 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Bailey, J. M. et al. p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells. Oncogene http://dx.doi.org/10.1038/onc.2015.441 (2015).

    Google Scholar 

  109. Pylayeva-Gupta, Y., Lee, K. E., Hajdu, C. H., Miller, G. & Bar-Sagi, D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21, 836–847 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Bayne, L. J. et al. Tumor-derived granulocyte–macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gilabert, M. et al. Pancreatic cancer-induced cachexia is Jak2-dependent in mice. J. Cell. Physiol. 229, 1437–1443 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dawson, D. W. et al. High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model. Cancer Prev. Res. (Phila.) 6, 1064–1073 (2013).

    Article  CAS  Google Scholar 

  114. Zambirinis, C. P. et al. TLR9 ligation in pancreatic stellate cells promotes tumorigenesis. J. Exp. Med. 212, 2077–2094 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kim, E. J. et al. Pilot clinical trial of hedgehog pathway inhibitor GDC-0449 (vismodegib) in combination with gemcitabine in patients with metastatic pancreatic adenocarcinoma. Clin. Cancer Res. 20, 5937–5945 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Catenacci, D. V. et al. Randomized Phase Ib/II study of gemcitabine plus placebo or vismodegib, a Hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33, 4284–4292 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 149, 201–210 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Keenan, B. P. et al. A Listeriavaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 146, 1784–1794 (2014).

    Article  CAS  PubMed  Google Scholar 

  125. Alagesan, B. et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin. Cancer Res. 21, 396–404 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Cook, N. et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J. Exp. Med. 209, 437–444 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Bausch, D. et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clin. Cancer Res. 17, 302–309 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Neesse, A. et al. Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut 62, 1034–1043 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Faca, V. M. et al. A mouse to human search for plasma proteome changes associated with pancreatic tumor development. PLoS Med. 5, e123 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Melo, S. A. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chiou, S. H. et al. Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing. Genes Dev. 29, 1576–1585 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Lennon, A. M. et al. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res. 74, 3381–3389 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Poruk, K. E. et al. The clinical utility of CA 19–19 in pancreatic adenocarcinoma: diagnostic and prognostic updates. Curr. Mol. Med. 13, 340–351 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Sausen, M. et al. Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients. Nat. Commun. 6, 7686 (2015).

    Article  PubMed  Google Scholar 

  136. Bettegowda, C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl Med. 6, 224ra24 (2014). This paper demonstrates that mutant DNA shed from early-stage (surgically resectable) pancreatic cancers can be detected in the plasma, suggesting that circulating tumour DNA might be a useful approach for the early detection of pancreatic cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Mayers, J. R. et al. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20, 1193–1198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Mirus, J. E. et al. Cross-species antibody microarray interrogation identifies a 3-protein panel of plasma biomarkers for early diagnosis of pancreas cancer. Clin. Cancer Res. 21, 1764–1771 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Javeed, N. et al. Pancreatic cancer-derived exosomes cause paraneoplastic β-cell dysfunction. Clin. Cancer Res. 21, 1722–1733 (2015). Together with reference 133, this paper shows that advances in analytical technologies and detection capabilities will yield sensitive and specific non-invasive diagnostic tests for early-stage pancreatic cancer, thereby increasing pancreatic cancer resection rates.

    Article  CAS  PubMed  Google Scholar 

  140. Cote, G. A. et al. A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am. J. Gastroenterol. 109, 1942–1952 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Johnston, F. M. et al. Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. Clin. Cancer Res. 15, 6511–6518 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhang, S. et al. Mesothelin virus-like particle immunization controls pancreatic cancer growth through CD8+ T cell induction and reduction in the frequency of CD4+ Foxp3+ ICOS- regulatory T cells. PLoS ONE 8, e68303 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wolfgang, C. L. et al. Recent progress in pancreatic cancer. CA Cancer J. Clin. 63, 318–348 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Lee, E. S. & Lee, J. M. Imaging diagnosis of pancreatic cancer: a state-of-the-art review. World J. Gastroenterol. 20, 7864–7877 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Motosugi, U. et al. Detection of pancreatic carcinoma and liver metastases with gadoxetic acid-enhanced MR imaging: comparison with contrast-enhanced multi-detector row CT. Radiology 260, 446–453 (2011).

    Article  PubMed  Google Scholar 

  146. Tsurusaki, M., Sofue, K. & Murakami, T. Current evidence for the diagnostic value of gadoxetic acid-enhanced magnetic resonance imaging for liver metastasis. Hepatol. Res.http://dx.doi.org/10.1111/hepr.12646 (2016).

  147. Harinck, F. et al. A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals. Guthttp://dx.doi.org/10.1136/gutjnl-2014-308008 (2015).

  148. Shin, E. J. et al. Linear-array EUS improves detection of pancreatic lesions in high-risk individuals: a randomized tandem study. Gastrointest. Endosc. 82, 812–818 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Parikh, U., Marcus, C., Sarangi, R., Taghipour, M. & Subramaniam, R. M. FDG PET/CT in pancreatic and hepatobiliary carcinomas: value to patient management and patient outcomes. PET Clin. 10, 327–343 (2015).

    Article  PubMed  Google Scholar 

  150. Sah, R. P., Nagpal, S. J., Mukhopadhyay, D. & Chari, S. T. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat. Rev. Gastroenterol. Hepatol. 10, 423–433 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Hruban, R. H., Pitman, M. B. & Klimstra, D. S. Tumors of the Pancreas. Atlas of Tumor Pathology (American Registry of Pathology and Armed Forces Institute of Pathology, 2007).

    Google Scholar 

  152. Wilentz, R. E. et al. Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am. J. Pathol. 156, 37–43 (2000). This work demonstrates that immunolabelling for SMAD4 is an accurate surrogate for detecting DNA mutations in SMAD4. This paper helped to bring molecular analyses to the daily practice of pathology.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Basturk, O. et al. A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas. Am. J. Surg. Pathol. 39, 1730–1741 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Voong, K. R. et al. Resected pancreatic adenosquamous carcinoma: clinicopathologic review and evaluation of adjuvant chemotherapy and radiation in 38 patients. Hum. Pathol. 41, 113–122 (2010).

    Article  CAS  PubMed  Google Scholar 

  155. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Crippa, S. et al. Mucinous cystic neoplasm of the pancreas is not an aggressive entity: lessons from 163 resected patients. Ann. Surg. 247, 571–579 (2008).

    Article  PubMed  Google Scholar 

  157. Waters, J. A. et al. Survival after resection for invasive intraductal papillary mucinous neoplasm and for pancreatic adenocarcinoma: a multi-institutional comparison according to American Joint Committee on Cancer Stage. J. Am. Coll. Surg. 213, 275–283 (2011).

    Article  PubMed  Google Scholar 

  158. Mayo, S. C. et al. Management of patients with pancreatic adenocarcinoma: national trends in patient selection, operative management, and use of adjuvant therapy. J. Am. Coll. Surg. 214, 33–45 (2012).

    Article  PubMed  Google Scholar 

  159. Chari, S. T. et al. Early detection of sporadic pancreatic cancer: summative review. Pancreas 44, 693–712 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Klein, A. P. et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS ONE 8, e72311 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Risch, H. A., Yu, H., Lu, L. & Kidd, M. S. Detectable symptomatology preceding the diagnosis of pancreatic cancer and absolute risk of pancreatic cancer diagnosis. Am. J. Epidemiol. 182, 26–34 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Klein, A. P. et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 64, 2634–2638 (2004). This registry-based study quantifies pancreatic cancer risk in families and demonstrates that an increased risk begins as early as 45 years of age.

    Article  CAS  PubMed  Google Scholar 

  163. Al-Sukhni, W. et al. Screening for pancreatic cancer in a high-risk cohort: an eight-year experience. J. Gastrointest. Surg. 16, 771–783 (2012).

    Article  PubMed  Google Scholar 

  164. Canto, M. I. et al. International Cancer of the Pancreas Screening (CAPS) consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut 62, 339–347 (2013). This paper reports on a panel consensus from a consortium meeting regarding screening high-risk families.

    Article  PubMed  Google Scholar 

  165. Tanaka, M. et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 12, 183–197 (2012).

    Article  PubMed  Google Scholar 

  166. Pandharipande, P. V. et al. Targeted screening of individuals at high risk for pancreatic cancer: results of a simulation model. Radiology 275, 177–187 (2015).

    Article  PubMed  Google Scholar 

  167. Burris, H. A. et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).

    Article  CAS  PubMed  Google Scholar 

  168. Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a Phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).

    Article  CAS  PubMed  Google Scholar 

  169. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011). This study establishes the superiority of 5-fluorouracil, oxaliplatin and irinotecan over gemcitabine based on improved progression-free and overall survival.

  170. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013). This study establishes the superiority of gemcitabine and albumin-bound paclitaxel over gemcitabine based on improved progression-free and overall survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Tempero, M. et al. Randomized Phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J. Clin. Oncol. 21, 3402–3408 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Golan, T. et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br. J. Cancer 111, 1132–1138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Cunningham, D. et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. 27, 5513–5518 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Fine, R. L. et al. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother. Pharmacol. 61, 167–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  175. Wang-Gillam, A. et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, Phase 3 trial. Lancet 387, 545–557 (2016).

    Article  CAS  PubMed  Google Scholar 

  176. Hammel, P. et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: final results of the international Phase III LAP 07 study. J. Clin. Oncol. Abstr. 31, LBA4003 (2013).

    Article  Google Scholar 

  177. Bramhall, S. R. et al. Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study. Br. J. Surg. 82, 111–115 (1995).

    Article  CAS  PubMed  Google Scholar 

  178. van Heek, N. T. et al. Hospital volume and mortality after pancreatic resection: a systematic review and an evaluation of intervention in the Netherlands. Ann. Surg. 242, 781–788; discussion 788–790 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Carpelan-Holmstrom, M. et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut 54, 385–387 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Gudjonsson, B. Carcinoma of the pancreas: critical analysis of costs, results of resections, and the need for standardized reporting. J. Am. Coll. Surg. 181, 483–503 (1995).

    CAS  PubMed  Google Scholar 

  181. Bilimoria, K. Y. et al. National failure to operate on early stage pancreatic cancer. Ann. Surg. 246, 173–180 (2007). This article highlights that many patients with early-stage pancreatic cancer are not offered surgery as the optimal treatment option.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Amini, N., Spolverato, G., Kim, Y. & Pawlik, T. M. Trends in hospital volume and failure to rescue for pancreatic surgery. J. Gastrointest. Surg. 19, 1581–1592 (2015).

    Article  PubMed  Google Scholar 

  183. de Wilde, R. F. et al. Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality. Br. J. Surg. 99, 404–410 (2012).

    Article  CAS  PubMed  Google Scholar 

  184. Hartwig, W. et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann. Surg. 254, 311–319 (2011).

    Article  PubMed  Google Scholar 

  185. Neoptolemos, J. P. et al. Adjuvant chemotherapy with fluorouracil plus folinic acid versus gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304, 1073–1081 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Neoptolemos, J. P. et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 350, 1200–1210 (2004). This is one of the largest trials of adjuvant therapy for pancreatic cancer, firmly establishing the role of adjuvant chemotherapy for pancreatic cancer.

    Article  CAS  PubMed  Google Scholar 

  187. Oettle, H. et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310, 1473–1481 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Cameron, J. L., Riall, T. S., Coleman, J. & Belcher, K. A. One thousand consecutive pancreaticoduodenectomies. Ann. Surg. 244, 10–15 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Diener, M. K. et al. Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma. Cochrane Database Syst. Rev. 11, CD006053 (2014).

    Google Scholar 

  190. Hartwig, W. et al. Total pancreatectomy for primary pancreatic neoplasms: renaissance of an unpopular operation. Ann. Surg. 261, 537–546 (2015).

    Article  PubMed  Google Scholar 

  191. Mehrabi, A. et al. A systematic review and meta-analysis of laparoscopic versus open distal pancreatectomy for benign and malignant lesions of the pancreas: it's time to randomize. Surgery 157, 45–55 (2015).

    Article  PubMed  Google Scholar 

  192. Correa-Gallego, C. et al. Minimally-invasive versus open pancreaticoduodenectomy: systematic review and meta-analysis. J. Am. Coll. Surg. 218, 129–139 (2014).

    Article  PubMed  Google Scholar 

  193. Abdelgadir Adam, M. et al. Minimally invasive versus open pancreaticoduodenectomy for cancer: practice patterns and short-term outcomes among 7061 patients. Ann. Surg. 262, 372–377 (2015).

    Article  Google Scholar 

  194. Cirocchi, R. et al. A systematic review on robotic pancreaticoduodenectomy. Surg. Oncol. 22, 238–246 (2013).

    Article  PubMed  Google Scholar 

  195. Zureikat, A. H. et al. 250 robotic pancreatic resections: safety and feasibility. Ann. Surg. 258, 554–559; discussion 559–562 (2013).

    PubMed  Google Scholar 

  196. Bockhorn, M. et al. Borderline resectable pancreatic cancer: a consensus statement by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 155, 977–988 (2014). This is an international consensus paper defining resectability criteria for pancreatic cancer. This paper influenced subsequent patient therapy and trial design.

    Article  PubMed  Google Scholar 

  197. Tempero, M. A. et al. Pancreatic adenocarcinoma, version 2. 2014: featured updates to the NCCN guidelines. J. Natl Compr. Canc. Netw. 12, 1083–1093 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Yu, X. Z. et al. Benefit from synchronous portal-superior mesenteric vein resection during pancreaticoduodenectomy for cancer: a meta-analysis. Eur. J. Surg. Oncol. 40, 371–378 (2014).

    Article  CAS  PubMed  Google Scholar 

  199. Zhou, Y., Zhang, Z., Liu, Y., Li, B. & Xu, D. Pancreatectomy combined with superior mesenteric vein–portal vein resection for pancreatic cancer: a meta-analysis. World J. Surg. 36, 884–891 (2012).

    Article  PubMed  Google Scholar 

  200. Giovinazzo, F., Turri, G., Katz, M. H., Heaton, N. & Ahmed, I. Meta-analysis of benefits of portal-superior mesenteric vein resection in pancreatic resection for ductal adenocarcinoma. Br. J. Surg. 103, 179–191 (2016).

    Article  CAS  PubMed  Google Scholar 

  201. Mollberg, N. et al. Arterial resection during pancreatectomy for pancreatic cancer: a systematic review and meta-analysis. Ann. Surg. 254, 882–893 (2011).

    Article  PubMed  Google Scholar 

  202. Beane, J. D. et al. Distal pancreatectomy with celiac axis resection: what are the added risks? HPB (Oxford) 17, 777–784 (2015).

    Article  Google Scholar 

  203. Smoot, R. L. & Donohue, J. H. Modified Appleby procedure for resection of tumors of the pancreatic body and tail with celiac axis involvement. J. Gastrointest. Surg. 16, 2167–2169 (2012).

    Article  PubMed  Google Scholar 

  204. Hirano, S. et al. Distal pancreatectomy with en bloc celiac axis resection for locally advanced pancreatic body cancer: long-term results. Ann. Surg. 246, 46–51 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Hartwig, W. et al. Multivisceral resection for pancreatic malignancies: risk-analysis and long-term outcome. Ann. Surg. 250, 81–87 (2009).

    Article  PubMed  Google Scholar 

  206. Tol, J. A. et al. Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS). Surgery 156, 591–600 (2014).

    Article  PubMed  Google Scholar 

  207. Dasari, B. V. et al. Extended versus standard lymphadenectomy for pancreatic head cancer:meta-analysis of randomized controlled trials. J. Gastrointest. Surg. 19, 1725–1732 (2015).

    Article  PubMed  Google Scholar 

  208. Michalski, C. W. et al. Systematic review and meta-analysis of standard and extended lymphadenectomy in pancreaticoduodenectomy for pancreatic cancer. Br. J. Surg. 94, 265–273 (2007).

    Article  CAS  PubMed  Google Scholar 

  209. Gleisner, A. L. et al. Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 110, 2484–2492 (2007).

    Article  PubMed  Google Scholar 

  210. Michalski, C. W. et al. Resection of primary pancreatic cancer and liver metastasis: a systematic review. Dig. Surg. 25, 473–480 (2008).

    Article  PubMed  Google Scholar 

  211. Arnaoutakis, G. J. et al. Pulmonary resection for isolated pancreatic adenocarcinoma metastasis: an analysis of outcomes and survival. J. Gastrointest. Surg. 15, 1611–1617 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Gillen, S., Schuster, T., Friess, H. & Kleeff, J. Palliative resections versus palliative bypass procedures in pancreatic cancer — a systematic review. Am. J. Surg. 203, 496–502 (2012).

    Article  PubMed  Google Scholar 

  213. Chandrasegaram, M. D. et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br. J. Surg. 102, 1459–1472 (2015).

    Article  CAS  PubMed  Google Scholar 

  214. Esposito, I. et al. Most pancreatic cancer resections are R1 resections. Ann. Surg. Oncol. 15, 1651–1660 (2008). This is one of the first and largest studies demonstrating high R1 rates in pancreatic cancer following standardized pathological processing and reporting. This and similar work resulted in changes of several national and international guidelines.

    Article  PubMed  Google Scholar 

  215. Schlitter, A. M. & Esposito, I. Definition of microscopic tumor clearance (r0) in pancreatic cancer resections. Cancers (Basel) 2, 2001–2010 (2010).

    Article  Google Scholar 

  216. Campbell, F. et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology 55, 277–283 (2009).

    Article  PubMed  Google Scholar 

  217. Traverso, L. W. Pancreatic cancer: surgery alone is not sufficient. Surg. Endosc. 20, S446–S449 (2006).

    Article  PubMed  Google Scholar 

  218. Regine, W. F. et al. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U. S. Intergroup/RTOG 9704 Phase III trial. Ann. Surg. Oncol. 18, 1319–1326 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Gillen, S., Schuster, T., Meyer Zum Buschenfelde, C., Friess, H. & Kleeff, J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 7, e1000267 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Heinrich, S. et al. Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter Phase III study (NEOPAC study). BMC Cancer 11, 346 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Tachezy, M. et al. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery versus primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA — a randomized multicenter Phase III study (NCT01900327, DRKS00003893, ISRCTN82191749). BMC Cancer 14, 411 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Ferrone, C. R. et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann. Surg. 261, 12–17 (2015).

    Article  PubMed  Google Scholar 

  223. Nitsche, U. et al. Resectability after first-line FOLFIRINOX in initially unresectable locally advanced pancreatic cancer: a single-center experience. Ann. Surg. Oncol. 22 (Suppl. 3), 1212–1220 (2015).

    Article  Google Scholar 

  224. Katz, M. H. G. et al. Preoperative modified FOLFIRINOX (mFOLFIRINOX) followed by chemoradiation (CRT) for borderline resectable (BLR) pancreatic cancer (PDAC): initial results from Alliance Trial A021101. J. Clin. Oncol. Abstr. 33 (Suppl.), 4008 (2015).

    Article  Google Scholar 

  225. Cancer Research UK. ESPAC-5F: European study group for pancreatic cancer — trial 5F. Cancer Research UK [online] www.isrctn.com/ISRCTN89500674, (2014).

  226. Pawlik, T. M. et al. Evaluating the impact of a single-day multidisciplinary clinic on the management of pancreatic cancer. Ann. Surg. Oncol. 15, 2081–2088 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Rainbird, K., Perkins, J., Sanson-Fisher, R., Rolfe, I. & Anseline, P. The needs of patients with advanced, incurable cancer. Br. J. Cancer 101, 759–764 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Aaronson, N. K. et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J. Natl Cancer Inst. 85, 365–376 (1993).

    Article  CAS  PubMed  Google Scholar 

  229. Cella, D. F. et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J. Clin. Oncol. 11, 570–579 (1993).

    Article  CAS  PubMed  Google Scholar 

  230. Fitzsimmons, D. et al. Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life. Eur. J. Cancer 35, 939–941 (1999).

    Article  CAS  PubMed  Google Scholar 

  231. Cella, D. et al. Validity of the FACT Hepatobiliary (FACT-Hep) questionnaire for assessing disease-related symptoms and health-related quality of life in patients with metastatic pancreatic cancer. Qual. Life Res. 22, 1105–1112 (2013).

    Article  PubMed  Google Scholar 

  232. Serrano, P. E. et al. Quality of life in a prospective, multicenter Phase 2 trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 90, 270–277 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Short, M. et al. Impact of gemcitabine chemotherapy and 3-dimensional conformal radiation therapy/5-fluorouracil on quality of life of patients managed for pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 85, 157–162 (2013).

    Article  CAS  PubMed  Google Scholar 

  234. Huang, J. J. et al. Quality of life and outcomes after pancreaticoduodenectomy. Ann. Surg. 231, 890–898 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Reni, M. et al. Quality of life assessment in advanced pancreatic adenocarcinoma: results from a Phase III randomized trial. Pancreatology 6, 454–463 (2006).

    Article  CAS  PubMed  Google Scholar 

  236. Hurt, C. N. et al. Health-related quality of life in SCALOP, a randomized Phase 2 trial comparing chemoradiation therapy regimens in locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 93, 810–818 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Gaertner, J. et al. The role of end-of-life issues in the design and reporting of cancer clinical trials: a structured literature review. PLoS ONE 10, e0136640 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Biankin, A. V., Piantadosi, S. & Hollingsworth, S. J. Patient-centric trials for therapeutic development in precision oncology. Nature 526, 361–370 (2015).

    Article  CAS  PubMed  Google Scholar 

  239. Chang, D. K., Grimmond, S. M., Evans, T. R. J. & Biankin, A. V. Mining the genomes of exceptional responders. Nat. Rev. Cancer 14, 291–292 (2014).

    Article  CAS  PubMed  Google Scholar 

  240. Steenhuysen, J. Personal genome test will sell at new low price of $250. Scientific American [online] http://www.scientificamerican.com/article/craig-venter-s-company-in-deal-for-whole-exome-tests-at-new-low-cost/, (2015).

    Google Scholar 

  241. European Alliance for Personalised Medicine. Pancreatic cancer white paper 2015. Deadly ‘silent’ cancer needs a voice in EU research and investment. European Alliance for Personalised Medicine [online] http://www.euapm.eu/pdf/EAPM_Eapancreatic_cancer_white_paper_2015.pdf, (2015).

  242. Hingorani, S. R. et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: interim results of a randomized Phase II study. J. Clin. Oncol. Abstr. 33 (Suppl.), 4006 (2015).

    Article  Google Scholar 

  243. Hurwitz, H. I. et al. Randomized, double-blind, Phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J. Clin. Oncol. 33, 4039–4047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Masso-Valles, D. et al. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 75, 1675–1681 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Kleeff, J. et al. Pancreatic cancer microenvironment. Int. J. Cancer 121, 699–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  246. Soares, K. C. et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J. Immunother. 38, 1–11 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Dindo, D., Demartines, N. & Clavien, P. A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann. Surg. 240, 205–213 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  248. Bassi, C. et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 138, 8–13 (2005).

    Article  PubMed  Google Scholar 

  249. Wente, M. N. et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 142, 761–768 (2007).

    Article  PubMed  Google Scholar 

  250. Wente, M. N. et al. Postpancreatectomy hemorrhage (PPH): an International Study Group of Pancreatic Surgery (ISGPS) definition. Surgery 142, 20–25 (2007).

    Article  PubMed  Google Scholar 

  251. US National Cancer Institute. Common terminology criteria for adverse events (CTCAE), version 4.03. NCI [online] http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf, (2010).

  252. World Health Organization. WHO's cancer pain ladder for adults. WHO [online] http://www.who.int/cancer/palliative/painladder/en/, (2016).

  253. Wyse, J. M., Carone, M., Paquin, S. C., Usatii, M. & Sahai, A. V. Randomized, double-blind, controlled trial of early endoscopic ultrasound-guided celiac plexus neurolysis to prevent pain progression in patients with newly diagnosed, painful, inoperable pancreatic cancer. J. Clin. Oncol. 29, 3541–3546 (2011).

    Article  PubMed  Google Scholar 

  254. Jones, W. B., Jordan, P. & Pudi, M. Pain management of pancreatic head adenocarcinomas that are unresectable: celiac plexus neurolysis and splanchnicectomy. J. Gastrointest. Oncol. 6, 445–451 (2015).

    PubMed  PubMed Central  Google Scholar 

  255. Kitano, M. et al. Covered self-expandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreatic carcinoma: a randomized multicenter trial. Am. J. Gastroenterol. 108, 1713–1722 (2013).

    Article  PubMed  Google Scholar 

  256. Walter, D. et al. Cost efficacy of metal stents for palliation of extrahepatic bile duct obstruction in a randomized controlled trial. Gastroenterology 149, 130–138 (2015).

    Article  PubMed  Google Scholar 

  257. Jeurnink, S. M. et al. Predictors of survival in patients with malignant gastric outlet obstruction: a patient-oriented decision approach for palliative treatment. Dig. Liver Dis. 43, 548–552 (2011).

    Article  PubMed  Google Scholar 

  258. Larssen, L., Hauge, T. & Medhus, A. W. Stent treatment of malignant gastric outlet obstruction: the effect on rate of gastric emptying, symptoms, and survival. Surg. Endosc. 26, 2955–2960 (2012).

    Article  PubMed  Google Scholar 

  259. National Comprehensive Cancer Network. Distress management clinical practice guidelines in oncology, version 3.2015. NCCN [online] http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#supportive, (2015).

  260. Torgerson, S. & Wiebe, L. A. Supportive care of the patient with advanced pancreatic cancer. Oncology (Williston Park) 27, 183–190 (2013).

    Google Scholar 

  261. Del Fabbro, E. Current and future care of patients with the cancer anorexia–cachexia syndrome. Am. Soc. Clin. Oncol. Educ. Book 35, e229–e237 (2015).

    Article  Google Scholar 

  262. Le, D. T. et al. Safety and survival with GVAX pancreas prime and Listeria monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 33, 1325–1333 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Xiao, Y. & Freeman, G. J. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 5, 16–18 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Khaled, Y. S., Wright, K., Melcher, A. & Jayne, D. Anti-cancer effects of oncolytic viral therapy combined with photodynamic therapy in human pancreatic cancer cell lines. Lancet 385, S56 (2015).

    Article  PubMed  Google Scholar 

  265. Bublil, E. M. & Yarden, Y. The EGF receptor family: spearheading a merger of signaling and therapeutics. Curr. Opin. Cell Biol. 19, 124–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  266. Matsushita, A., Gotze, T. & Korc, M. Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res. 67, 10309–10316 (2007). Together with reference 33, this paper demonstrates that pancreatic cancer cells are characterized by multiple aberrant signalling pathways that enhance mitogenic signalling, underscoring the need for combinatorial therapies.

    Article  CAS  PubMed  Google Scholar 

  267. Morello, V. et al. β1 integrin controls EGFR signaling and tumorigenic properties of lung cancer cells. Oncogene 30, 4087–4096 (2011).

    Article  CAS  PubMed  Google Scholar 

  268. Kleeff, J. et al. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J. Clin. Invest. 102, 1662–1673 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Hruban, R. H., Goggins, M. & Kern, S. E. Molecular genetics and related developments in pancreatic cancer. Curr. Opin. Gastroenterol. 15, 404–409 (1999).

    Article  CAS  PubMed  Google Scholar 

  270. Doherty, J. R. & Cleveland, J. L. Targeting lactate metabolism for cancer therapeutics. J. Clin. Invest. 123, 3685–3692 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Ma, Z., Vocadlo, D. J. & Vosseller, K. Hyper-O-GlcNAcylation is anti-apoptotic and maintains constitutive NF-κB activity in pancreatic cancer cells. J. Biol. Chem. 288, 15121–15130 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).

    Article  CAS  Google Scholar 

  273. Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  274. Walter, K. et al. Serum fatty acid synthase as a marker of pancreatic neoplasia. Cancer Epidemiol. Biomarkers Prev. 18, 2380–2385 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Giardiello, F. M. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119, 1447–1453 (2000).

    Article  CAS  PubMed  Google Scholar 

  276. Lowenfels, A. B. et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J. Natl Cancer Inst. 89, 442–446 (1997).

    Article  CAS  PubMed  Google Scholar 

  277. Howes, N. et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin. Gastroenterol. Hepatol. 2, 252–261 (2004).

    Article  CAS  PubMed  Google Scholar 

  278. Goldstein, A. M. et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N. Engl. J. Med. 333, 970–974 (1995).

    Article  CAS  PubMed  Google Scholar 

  279. Borg, A. et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl Cancer Inst. 92, 1260–1266 (2000).

    Article  CAS  PubMed  Google Scholar 

  280. Kastrinos, F. et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 302, 1790–1795 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Maisonneuve, P., Marshall, B. C. & Lowenfels, A. B. Risk of pancreatic cancer in patients with cystic fibrosis. Gut 56, 1327–1328 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Iqbal, J. et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer 107, 2005–2009 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91, 1310–1316 (1999).

    Article  Google Scholar 

  284. Geoffroy-Perez, B. et al. Cancer risk in heterozygotes for ataxia-telangiectasia. Int. J. Cancer 93, 288–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  285. Ruijs, M. W. et al. TP53 germline mutation testing in 180 families suspected of Li–Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 47, 421–428 (2010).

    Article  CAS  PubMed  Google Scholar 

  286. Giardiello, F. M. et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 34, 1394–1396 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was partially supported by the COST action BM1204 “EUPancreas: An integrated European platform for pancreas cancer research: from basic science to clinical and public health interventions for a rare disease” (eupancreas.com) to J.K., C.L.V. and J.P.N. This work was also partially supported by National Cancer Institute (NCI) grants CA-075059 (to M.K.) and CA62924 (to R.H.H.); a grant from the Cancer Council New South Wales RG 13–01 (to M.A.); a grant from the Italian Foundation for Research on Cancer (to C.L.V.); a grant from the Lustgarten Foundation (to D.A.T.); a grant from the US Department of Defense (W81XWH-13-PRCRP-IA) (to D.A.T.); NIH grants 5P30CA45508-26, 5P50CA101955-07, 1U10CA180944-01, 5U01CA168409-3 and 1R01CA190092-01 (to D.A.T). R.E.N. is funded by a National Health and Medical Research Council (Australia) senior research fellowship. J.P.N. is The Owen and Ellen Evans Chair of Surgery, University of Liverpool, UK, and is a NIH Research (NIHR) Senior Investigator.

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Contributions

Introduction (J.K.); Epidemiology (C.L.V. and R.E.N.); Mechanisms/pathophysiology (M.K., A.V.B., M.A., J.K. and D.A.T.); Diagnosis, screening and prevention (M.K., R.H.H. and R.E.N.); Management (M.A., J.K., J.P.N. and M.T.); Quality of life (C.D.J.); Outlook (J.K. and A.V.B.); Overview of the Primer (J.K.). All authors read and approved the final version of the manuscript.

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Correspondence to Jorg Kleeff.

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Competing interests

R.H.H. receives royalty payments from Myriad Genetics for the PALB2 invention in a relationship that is managed by Johns Hopkins University. The remaining authors declare no competing interests.

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Kleeff, J., Korc, M., Apte, M. et al. Pancreatic cancer. Nat Rev Dis Primers 2, 16022 (2016). https://doi.org/10.1038/nrdp.2016.22

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