Table of Contents Author Guidelines Submit a Manuscript
Canadian Journal of Gastroenterology and Hepatology
Volume 2018 (2018), Article ID 1863535, 10 pages
https://doi.org/10.1155/2018/1863535
Review Article

A Contemporary Review of the Treatment Landscape and the Role of Predictive and Prognostic Biomarkers in Pancreatic Adenocarcinoma

1Division of Medical Oncology, Department of Medicine, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada
2Section of Medical Oncology, Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada

Correspondence should be addressed to Winson Y. Cheung; ac.sha@gnuehc.nosniw

Received 17 November 2017; Accepted 17 January 2018; Published 12 February 2018

Academic Editor: Kiran L. Sharma

Copyright © 2018 Irene S. Yu and Winson Y. Cheung. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. Canadian Cancer Society’s Advisory Committee on Cancer Statistics, Canadian Cancer Statistics, Canadian Cancer Society, Toronto, Canada, 2017.
  2. J. Ferlay, C. Partensky, and F. Bray, “More deaths from pancreatic cancer than breast cancer in the EU by 2017,” Acta Oncologica, vol. 55, no. 9-10, pp. 1158–1160, 2016. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Fung, T. Forte, R. Rahal, J. Niu, and H. Bryant, “Provincial rates and time trends in pancreatic cancer outcomes,” Current Oncology, vol. 20, no. 5, pp. 279–281, 2013. View at Publisher · View at Google Scholar · View at Scopus
  4. R. Wilkowski, M. Wolf, and V. Heinemann, “Primary advanced unresectable pancreatic cancer,” Recent Results in Cancer Research, vol. 177, no. 1, pp. 79–93, 2008. View at Google Scholar
  5. A. Teague, K. H. Lim, and A. Wang Gillam, “Advanced pancreatic adenocarcinoma: A review of current treatment strategies and developing therapies,” Therapeutic Advances in Medical Oncology, vol. 7, no. 2, pp. 68–84, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. S. A. Cullinan, C. G. Moertel, T. R. Fleming et al., “A Comparison of Three Chemotherapeutic Regimens in the Treatment of Advanced Pancreatic and Gastric Carcinoma: Fluorouracil vs Fluorouracil and Doxorubicin vs Fluorouracil, Doxorubicin, and Mitomycin,” Journal of the American Medical Association, vol. 253, no. 14, pp. 2061–2067, 1985. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Cullinan, C. G. Moertel, H. S. Wieand et al., “A phase III trial on the therapy of advanced pancreatic carcinoma evaluations of the mallinson regimen and combined 5‐fluorouracil, doxorubicin, and cisplatin,” Cancer, vol. 65, no. 10, pp. 2207–2212, 1990. View at Publisher · View at Google Scholar · View at Scopus
  8. H. A. Burris III, M. J. Moore, J. Andersen et al., “Improvements in survival and clinical benefit with gemcitabine as first- line therapy for patients with advanced pancreas cancer: a randomized trial,” Journal of Clinical Oncology, vol. 15, no. 6, pp. 2403–2413, 1997. View at Publisher · View at Google Scholar · View at Scopus
  9. D. Cunningham, I. Chau, D. D. Stocken et al., “Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer,” Journal of Clinical Oncology, vol. 27, no. 33, pp. 5513–5518, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. G. Colucci, R. Labianca, F. Di Costanzo et al., “Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study,” Journal of Clinical Oncology, vol. 28, no. 10, pp. 1645–1651, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. E. Poplin, Y. Feng, J. Berlin et al., “Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group,” Journal of Clinical Oncology, vol. 27, no. 23, pp. 3778–3785, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. G. P. Stathopoulos, K. Syrigos, G. Aravantinos et al., “A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer,” British Journal of Cancer, vol. 95, no. 5, pp. 587–592, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. H. Oettle, D. Richards, R. K. Ramanathan et al., “A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer,” Annals of Oncology, vol. 16, no. 10, pp. 1639–1645, 2005. View at Google Scholar
  14. R. Herrmann, G. Bodoky, T. Ruhstaller et al., “Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group,” Journal of Clinical Oncology, vol. 25, no. 16, pp. 2212–2217, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. M. J. Moore, D. Goldstein, J. Hamm 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,” Journal of Clinical Oncology, vol. 25, no. 15, pp. 1960–1966, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. R. A. Miksad, L. Schnipper, and M. Goldstein, “Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value?” Journal of Clinical Oncology, vol. 25, no. 28, pp. 4506-4507, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. T. Conroy, F. Desseigne, and M. Ychou, “FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer,” The New England Journal of Medicine, vol. 364, no. 19, pp. 1817–1825, 2011. View at Publisher · View at Google Scholar
  18. J. Long, Y. Zhang, X. Yu et al., “Overcoming drug resistance in pancreatic cancer,” Expert Opinion on Therapeutic Targets, vol. 15, no. 7, pp. 817–828, 2011. View at Publisher · View at Google Scholar · View at Scopus
  19. W. J. Gradishar, S. Tjulandin, N. Davidson et al., “Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer,” Journal of Clinical Oncology, vol. 23, no. 31, pp. 7794–7803, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. M. A. Socinski, I. N. Bondarenko, N. A. Karaseva et al., “Survival results of a randomized, phase 3 trial of nab-paclitaxel and carboplatin compared with cremophor-based paclitaxel and carboplatin as first-line therapy in advanced non-small cell lung cancer,” Journal of Clinical Oncology, vol. 28, no. 18, 2010. View at Google Scholar
  21. E. M. Hersh, S. J. O'Day, A. Ribas et al., “A phase 2 clinical trial of nab-Paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma,” Cancer, vol. 116, no. 1, pp. 155–163, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. D. D. Von Hoff, R. K. Ramanathan, M. J. Borad et al., “Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial,” Journal of Clinical Oncology, vol. 29, no. 34, pp. 4548–4554, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. D. D. Von Hoff, T. Ervin, F. P. Arena et al., “Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine,” The New England Journal of Medicine, vol. 369, no. 18, pp. 1691–1703, 2013. View at Google Scholar
  24. A. Wang-Gillam, C.-P. Li, G. Bodoky 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,” The Lancet, vol. 387, no. 10018, pp. 545–557, 2016. View at Publisher · View at Google Scholar · View at Scopus
  25. N. L. Henry and D. F. Hayes, “Cancer biomarkers,” Molecular Oncology, vol. 6, no. 2, pp. 140–146, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. K. V. Ballman, “Biomarker: Predictive or prognostic?” Journal of Clinical Oncology, vol. 33, no. 33, pp. 3968–3971, 2015. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Popat, R. Hubner, and R. S. Houlston, “Systematic review of microsatellite instability and colorectal cancer prognosis,” Journal of Clinical Oncology, vol. 23, no. 3, pp. 609–618, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. D. J. Sargent, S. Marsoni, G. Monges et al., “Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer,” Journal of Clinical Oncology, vol. 28, no. 20, pp. 3219–3226, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. F. A. Sinicrope, N. R. Foster, S. N. Thibodeau et al., “DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy,” Journal of the National Cancer Institute, vol. 103, no. 11, pp. 863–875, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Laghi, S. Beghelli, A. Spinelli et al., “Irrelevance of Microsatellite Instability in the Epidemiology of Sporadic Pancreatic Ductal Adenocarcinoma,” PLoS ONE, vol. 7, no. 9, Article ID e46002, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. J. L. Humphris, A. M. Patch, K. Nones et al., “Hypermutation in pancreatic cancer,” Gastroenterology, vol. 152, no. 1, pp. 68–74, 2017. View at Google Scholar
  32. D. T. Le, “Programmed death-1 blockade in mismatch repair deficient colorectal cancer,” Journal of Clinical Oncology, vol. 34, no. 29, pp. 3502–3510, 2016. View at Publisher · View at Google Scholar
  33. D. T. Le, J. N. Uram, H. Wang et al., “PD-1 blockade in tumors with mismatch-repair deficiency,” The New England Journal of Medicine, vol. 372, no. 26, pp. 2509–2520, 2015. View at Google Scholar
  34. M. J. Overman, R. McDermott, J. L. Leach et al., “Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): An open-label, multicentre, phase 2 study,” The Lancet Oncology, 2017. View at Publisher · View at Google Scholar · View at Scopus
  35. R. E. Royal, C. Levy, K. Turner et al., “Phase 2 trial of single agent ipilimumab (Anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma,” Journal of Immunotherapy, vol. 33, no. 8, pp. 828–833, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. D. T. Le, J. N. Durham, K. N. Smith et al., “Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade,” Science, vol. 357, no. 6349, pp. 409–413, 2017. View at Google Scholar
  37. Y. Miki, J. Swensen, D. Shattuck-Eidens et al., “A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1,” Science, vol. 266, no. 5182, pp. 66–71, 1994. View at Publisher · View at Google Scholar · View at Scopus
  38. D. Ford, D. F. Easton, D. T. Bishop, S. A. Narod, and D. E. Goldgar, “Risks of cancer in BRCA1-mutation carriers,” The Lancet, vol. 343, no. 8899, pp. 692–695, 1994. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Wooster, G. Bignell, J. Lancaster et al., “Identification of the breast cancer susceptibility gene BRCA2,” Nature, vol. 378, no. 6559, pp. 789–792, 1995. View at Publisher · View at Google Scholar · View at Scopus
  40. J. B. Greer and D. C. Whitcomb, “Role of BRCA1 and BRCA2 mutations in pancreatic cancer,” Gut, vol. 56, no. 5, pp. 601–605, 2007. View at Publisher · View at Google Scholar · View at Scopus
  41. D. Thompson and D. F. Easton, “Cancer incidence in BRCA1 mutation carriers,” Journal of the National Cancer Institute, vol. 94, no. 18, pp. 1358–1365, 2002. View at Publisher · View at Google Scholar · View at Scopus
  42. The Breast Cancer Linkage Consortium, “Cancer risks in BRCA2 mutation carriers,” Journal of the National Cancer Institute, vol. 91, no. 15, pp. 1310–1316, 1999. View at Publisher · View at Google Scholar · View at Scopus
  43. V. Heinemann, D. Quietzsch, F. Gieseler et al., “Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer,” Journal of Clinical Oncology, vol. 24, no. 24, pp. 3946–3952, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. G. Colucci, F. Giuliani, V. Gebbia et al., “Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologico dell'Italia Meridionale,” Cancer, vol. 94, no. 4, pp. 902–910, 2002. View at Publisher · View at Google Scholar · View at Scopus
  45. A. Sonnenblick, L. Kadouri, L. Appelbaum et al., “Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy,” Cancer Biology & Therapy, vol. 12, no. 3, pp. 165–168, 2011. View at Publisher · View at Google Scholar · View at Scopus
  46. M. A. Lowery, D. P. Kelsen, Z. K. Stadler et al., “An emerging entity: pancreatic adenocarcinoma associated with a known brca mutation: clinical descriptors, treatment implications, and future directions,” The Oncologist, vol. 16, no. 10, pp. 1397–1402, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. T. Golan, Z. S. Kanji, R. Epelbaum et al., “Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers,” British Journal of Cancer, vol. 111, no. 6, pp. 1132–1138, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. D. R. Fogelman, R. A. Wolff, S. Kopetz et al., “Evidence for the efficacy of iniparib, a PARP-1 inhibitor, in BRCA2-associated pancreatic cancer,” Anticancer Reseach, vol. 31, no. 4, pp. 1417–1420, 2011. View at Google Scholar · View at Scopus
  49. B. Kaufman, R. Shapira-Frommer, R. K. Schmutzler et al., “Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation,” Journal of Clinical Oncology, vol. 33, no. 3, pp. 244–250, 2015. View at Publisher · View at Google Scholar · View at Scopus
  50. S. M. Domchek, A. E. Hendifar, R. R. McWilliams et al., “RUCAPANC: An open-label, phase 2 trial of the PARP inhibitor rucaparib in patients (pts) with pancreatic cancer (PC) and a known deleterious germline or somatic BRCA mutation,” Journal of Clinical Oncology, vol. 34, no. 15, 2016. View at Google Scholar
  51. M. A. Tempero, M. P. Malafa, M. Al-Hawary et al., “Pancreatic adenocarcinoma, version 2.2017: Clinical practice guidelines in Oncology,” JNCCN — Journal of the National Comprehensive Cancer Network, vol. 15, no. 8, pp. 1028–1061, 2017. View at Publisher · View at Google Scholar · View at Scopus
  52. J. L. Lindner, S. Loibl, C. Denkert et al., “Expression of secreted protein acidic and rich in cysteine (SPARC) in breast cancer and response to neoadjuvant chemotherapy,” Annals of Oncology, vol. 26, no. 1, pp. 95–100, 2015. View at Publisher · View at Google Scholar · View at Scopus
  53. M. Hidalgo, C. Plaza, M. Musteanu et al., “SPARC expression did not predict efficacy of nab-paclitaxel plus gemcitabine or gemcitabine alone for metastatic pancreatic cancer in an exploratory analysis of the phase III MPACT trial,” Clinical Cancer Research, vol. 21, no. 21, pp. 4811–4818, 2015. View at Publisher · View at Google Scholar · View at Scopus
  54. B. Mohelnikova-Duchonova, V. Brynychova, V. Hlavac et al., “The association between the expression of solute carrier transporters and the prognosis of pancreatic cancer,” Cancer Chemotherapy and Pharmacology, vol. 72, no. 3, pp. 669–682, 2013. View at Publisher · View at Google Scholar · View at Scopus
  55. R. Mori, T. Ishikawa, Y. Ichikawa et al., “Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells,” Oncology Reports, vol. 17, no. 5, pp. 1201–1205, 2007. View at Google Scholar · View at Scopus
  56. M. Tsujie, S. Nakamori, S. Nakahira et al., “Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer,” Anticancer Reseach, vol. 27, no. 4 B, pp. 2241–2249, 2007. View at Google Scholar · View at Scopus
  57. R. Maréchal, J.-B. Bachet, J. R. MacKey et al., “Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma,” Gastroenterology, vol. 143, no. 3, pp. 664–e6, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. N. Nakagawa, Y. Murakami, K. Uemura et al., “Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection,” Surgery, vol. 153, no. 4, pp. 565–575, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. J. J. Farrell, H. Elsaleh, M. Garcia et al., “Human Equilibrative Nucleoside Transporter 1 Levels Predict Response to Gemcitabine in Patients With Pancreatic Cancer,” Gastroenterology, vol. 136, no. 1, pp. 187–195, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. J. P. Neoptolemos, W. Greenhalf, P. Ghaneh et al., “HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5FU on the ESPAC trials,” Journal of Clinical Oncology, vol. 31, no. 15, 2013. View at Google Scholar
  61. E. Giovannetti, M. Del Tacca, V. Mey et al., “Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine,” Cancer Research, vol. 66, no. 7, pp. 3928–3935, 2006. View at Publisher · View at Google Scholar · View at Scopus
  62. E. Poplin, H. Wasan, L. Rolfe et al., “Randomized, multicenter, phase ii study of co-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity,” Journal of Clinical Oncology, vol. 31, no. 35, pp. 4453–4461, 2013. View at Publisher · View at Google Scholar · View at Scopus
  63. R. Maréchal, J. R. Mackey, R. Lai et al., “Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapyin resected pancreatic adenocarcinoma,” Clinical Cancer Research, vol. 15, no. 8, pp. 2913–2919, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. K. E. Poruk, D. Z. Gay, K. Brown et al., “The clinical utility of CA 19-9 in pancreatic Adenocarcinoma: Diagnostic and prognostic updates,” Current Molecular Medicine, vol. 13, no. 3, pp. 340–351, 2013. View at Publisher · View at Google Scholar · View at Scopus
  65. G. Y. Locker, S. Hamilton, J. Harris et al., “ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer,” Journal of Clinical Oncology, vol. 24, no. 33, pp. 5313–5327, 2006. View at Publisher · View at Google Scholar · View at Scopus
  66. J.-E. Kim, K. T. Lee, J. K. Lee, S. W. Paik, J. C. Rhee, and K. W. Choi, “Clinical usefulness of carbohydrate antigen 19-9 as a screening test for pancreatic cancer in an asymptomatic population,” Journal of Gastroenterology and Hepatology, vol. 19, no. 2, pp. 182–186, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. C. R. Ferrone, D. M. Finkelstein, S. P. Thayer, A. Muzikansky, C. Fernandez-Del Castillo, and A. L. Warshaw, “Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma,” Journal of Clinical Oncology, vol. 24, no. 18, pp. 2897–2902, 2006. View at Publisher · View at Google Scholar · View at Scopus
  68. S. K. Maithel, S. Maloney, C. Winston et al., “Preoperative CA 19-9 and the yield of staging laparoscopy in patients with radiographically resectable pancreatic adenocarcinoma,” Annals of Surgical Oncology, vol. 15, no. 12, pp. 3512–3520, 2008. View at Publisher · View at Google Scholar · View at Scopus
  69. W. Hartwig, O. Strobel, U. Hinz et al., “CA19-9 in potentially resectable pancreatic cancer: Perspective to adjust surgical and perioperative therapy,” Annals of Surgical Oncology, vol. 20, no. 7, pp. 2188–2196, 2013. View at Publisher · View at Google Scholar · View at Scopus
  70. R. C. Montgomery, J. P. Hoffman, L. B. Riley, A. Rogatko, J. A. Ridge, and B. L. Eisenberg, “Prediction of recurrence and survival by post-resection CA 19-9 values in patients with adenocarcinoma of the pancreas,” Annals of Surgical Oncology, vol. 4, no. 7, pp. 551–556, 1997. View at Publisher · View at Google Scholar · View at Scopus
  71. M. F. Brennan, M. W. Kattan, D. Klimstra, and K. Conlon, “Prognostic nomogram for patients undergoing resection for adenocarcinoma of the pancreas,” Annals of Surgery, vol. 240, no. 2, pp. 293–298, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. J. M. Winter, J. L. Cameron, K. A. Campbell et al., “1423 Pancreaticoduodenectomies for pancreatic cancer: a single-institution experience,” Journal of Gastrointestinal Surgery, vol. 10, no. 9, pp. 1199–1211, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. J. E. Lim, M. W. Chien, and C. C. Earle, “Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients,” Annals of Surgery, vol. 237, no. 1, pp. 74–85, 2003. View at Publisher · View at Google Scholar · View at Scopus
  74. T. A. Sohn, C. J. Yeo, J. L. Cameron et al., “Resected adenocarcinoma of the pancreas—616 patients: results, outcomes, and prognostic indicators,” Journal of Gastrointestinal Surgery, vol. 4, no. 6, pp. 567–579, 2000. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Sperti, M. Gruppo, M. Valmasoni et al., “Para-aortic node involvement is not an independent predictor of survival after resection for pancreatic cancer,” World Journal of Gastroenterology, vol. 23, no. 24, pp. 4399–4406, 2017. View at Publisher · View at Google Scholar · View at Scopus
  76. M. J. Kang, J.-Y. Jang, Y. R. Chang, W. Kwon, W. Jung, and S.-W. Kim, “Revisiting the concept of lymph node metastases of pancreatic head cancer: Number of metastatic lymph nodes and lymph node ratio according to N stage,” Annals of Surgical Oncology, vol. 21, no. 5, pp. 1545–1551, 2014. View at Publisher · View at Google Scholar · View at Scopus
  77. J. S. Tomlinson, S. Jain, D. J. Bentrem et al., “Accuracy of staging node-negative pancreas cancer a potential quality measure,” JAMA Surgery, vol. 142, no. 8, pp. 767–773, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. S. Paiella, M. Sandini, L. Gianotti, G. Butturini, R. Salvia, and C. Bassi, “The prognostic impact of para-aortic lymph node metastasis in pancreatic cancer: A systematic review and meta-analysis,” European Journal of Surgical Oncology, vol. 42, no. 5, pp. 616–624, 2016. View at Publisher · View at Google Scholar · View at Scopus
  79. K. Y. Bilimoria, D. J. Bentrem, C. Y. Ko et al., “Validation of the 6th edition AJCC pancreatic cancer staging system: Report from the National Cancer Database,” Cancer, vol. 110, no. 4, pp. 738–744, 2007. View at Publisher · View at Google Scholar · View at Scopus
  80. C. J. Yeo, J. L. Cameron, T. A. Sohn et al., “Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes,” Annals of Surgery, vol. 226, no. 3, pp. 248–260, 1997. View at Publisher · View at Google Scholar · View at Scopus
  81. I. T. Konstantinidis, A. L. Warshaw, J. N. Allen et al., “Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a “true” R0 resection?” Annals of Surgery, vol. 257, no. 4, pp. 731–736, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. D. K. Chang, A. L. Johns, and N. D. Merrett, “Margin clearence and outcome in resected pancreatic cancer,” Journal of Clinical Oncology, vol. 27, no. 17, pp. 2855–2862, 2009. View at Publisher · View at Google Scholar
  83. M. Kulis and M. Esteller, “DNA methylation and cancer,” Advances in Genetics, vol. 70, pp. 27–56, 2010. View at Publisher · View at Google Scholar · View at Scopus
  84. S. D. Henriksen, P. H. Madsen, A. C. Larsen et al., “Promoter hypermethylation in plasma-derived cell-free DNA as a prognostic marker for pancreatic adenocarcinoma staging,” International Journal of Cancer, 2017. View at Publisher · View at Google Scholar · View at Scopus
  85. S. D. Henriksen, P. H. Madsen, H. Krarup, and O. Thorlacius-Ussing, “DNA hypermethylation as a blood-based marker for pancreatic cancer: A literature review,” Pancreas, vol. 44, no. 7, pp. 1036–1045, 2015. View at Publisher · View at Google Scholar · View at Scopus
  86. S. D. Henriksen, P. H. Madsen, A. C. Larsen et al., “Cell-free DNA promoter hypermethylation in plasma as a diagnostic marker for pancreatic adenocarcinoma,” Clinical Epigenetics, vol. 8, no. 1, article no. 117, 2016. View at Publisher · View at Google Scholar · View at Scopus
  87. S. Yokoyama, M. Higashi, S. Kitamoto et al., “Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas,” Oncotarget, vol. 7, no. 27, pp. 42553–42565, 2016. View at Google Scholar
  88. T. Golan, T. Sella, E. M. O'Reilly et al., “Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer,” British Journal of Cancer, vol. 116, no. 6, pp. 694–702, 2017. View at Publisher · View at Google Scholar · View at Scopus
  89. Y. Zhu, K. Zhai, J. Ke et al., “BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population,” Oncotarget , vol. 8, no. 22, 2017. View at Publisher · View at Google Scholar
  90. E. Yang, J. K. Hyun, H. K. Kwi, H. Rhee, K. K. Nam, and H. Kim, “Frequent inactivation of SPARC by promoter hypermethylation in colon cancers,” International Journal of Cancer, vol. 121, no. 3, pp. 567–575, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. C. Jones, A. Mackay, A. Grigoriadis et al., “Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer,” Cancer Research, vol. 64, no. 9, pp. 3037–3045, 2004. View at Publisher · View at Google Scholar · View at Scopus
  92. C.-S. Wang, K.-H. Lin, S.-L. Chen, Y.-F. Chan, and S. Hsueh, “Overexpression of SPARC gene in human gastric carcinoma and its clinic-pathologic significance,” British Journal of Cancer, vol. 91, no. 11, pp. 1924–1930, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. D. Massi, A. Franchi, L. Borgognoni, U. M. Reali, and M. Santucci, “Osteonectin expression correlates with clinical outcome in thin cutaneous malignant melanomas,” Human Pathology, vol. 30, no. 3, pp. 339–344, 1999. View at Publisher · View at Google Scholar · View at Scopus
  94. J. R. Infante, H. Matsubayashi, N. Sato et al., “Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma,” Journal of Clinical Oncology, vol. 25, no. 3, pp. 319–325, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. K. Miyoshi, N. Sato, K. Ohuchida, K. Mizumoto, and M. Tanaka, “SPARC mRNA expression as a prognostic marker for pancreatic adenocarcinoma patients,” Anticancer Reseach, vol. 30, no. 3, pp. 867–872, 2010. View at Google Scholar · View at Scopus
  96. Y. Zhang, J. Yang, H. Li, Y. Wu, H. Zhang, and W. Chen, “Tumor markers CA19-9, CA242 and CEA in the diagnosis of pancreatic cancer: A meta-analysis,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 7, pp. 11683–11691, 2015. View at Google Scholar · View at Scopus
  97. R. E. Brand, B. M. Nolen, H. J. Zeh et al., “Serum biomarker panels for the detection of pancreatic cancer,” Clinical Cancer Research, vol. 17, no. 4, pp. 805–816, 2011. View at Publisher · View at Google Scholar · View at Scopus
  98. J. Kim, Y. S. Lee, I. K. Hwang et al., “Postoperative carcinoembryonic antigen as a complementary tumor marker of carbohydrate antigen 19-9 in pancreatic ductal adenocarcinoma,” Journal of Korean Medical Science, vol. 30, no. 3, pp. 259–263, 2015. View at Publisher · View at Google Scholar
  99. H. S. Park, H. S. Lee, J. S. Park et al., “Prognostic scoring index for patients with metastatic pancreatic adenocarcinoma,” Cancer Research and Treatment, vol. 48, no. 4, pp. 1253–1263, 2016. View at Publisher · View at Google Scholar · View at Scopus