Treatment of pancreatic cancer: What can we really predict today?

Cancers

Volumn 3, Issue 1, 2011, Pages 675-699

  Bachet, Jean Baptiste ^a,b,c   Marechal, Raphael ^a   van Laethem, Jean Luc ^a  

^a ERASME HOSPITAL   (Belgium)

^b LABORATOIRE DES SCIENCES DU CLIMAT ET DE L ENVIRONNEMENT   (France)

^c ASSISTANCE PUBLIQUE HÔPITAUX DE PARIS   (France)

Author keywords

Biomarkers gemcitabine; Cancer personalized; Nucleoside; Pancreatic; Therapy predictive; Transporters CXCR4 SMAD4 hENT1

Indexed keywords

BIOLOGICAL MARKER; CHEMOKINE RECEPTOR CXCR4; CISPLATIN; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; EXCISION REPAIR CROSS COMPLEMENTING PROTEIN 1; FLUOROURACIL; GEMCITABINE; IRINOTECAN; OXALIPLATIN; PLATINUM DERIVATIVE; PROTEIN S 100A2; SMAD4 PROTEIN; THYMIDYLATE SYNTHASE; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG;

ADJUVANT CHEMOTHERAPY; ANTINEOPLASTIC ACTIVITY; CANCER CELL CULTURE; CANCER RECURRENCE; CANCER RESEARCH; CANCER SURVIVAL; CARCINOGENESIS; CHEMORADIOTHERAPY; CHROMOSOMAL INSTABILITY; CLINICAL TRIAL (TOPIC); COLORECTAL CANCER; COMBINATION CHEMOTHERAPY; DIARRHEA; DNA METHYLATION; DNA REPLICATION; DRUG EFFICACY; DRUG POTENTIATION; DRUG SENSITIVITY; EFGR GENE; EPIGENETICS; ERCC1 GENE; ESOPHAGUS CANCER; GENE MUTATION; GENE OVEREXPRESSION; GENETIC POLYMORPHISM; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; GSTM1 GENE; GSTP1 GENE; GSTT1 GENE; HISTONE ACETYLATION; HISTONE METHYLATION; HISTONE MODIFICATION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; METASTASIS; METASTASIS POTENTIAL; MICROSATELLITE INSTABILITY; MONOTHERAPY; NEUROTOXICITY; NEUTROPENIA; NONHUMAN; ONCOGENE; ONCOGENE K RAS; OUTCOME ASSESSMENT; OVERALL SURVIVAL; PALLIATIVE THERAPY; PANCREAS; PANCREAS ADENOCARCINOMA; PANCREATICODUODENECTOMY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PREDICTION; PROGNOSIS; QUALITATIVE ANALYSIS; QUANTITATIVE ANALYSIS; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; STOMACH CANCER; TREATMENT RESPONSE; UGT1A1 GENE;

EID: 79953704508     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers3010675     Document Type: Review

References (130)

1. Bouvier, A.M.; Remontet, L.; Jougla, E.; Launoy, G.; Grosclaude, P.; Buémi, A.; Tretarre, B.; Velten, M.; Dancourt, V.; Menegoz, F.; et al. Bercell Incidence of Gastrointestinal Cancers in France. Gastroenterol. Clin. Biol. 2004, 28, 877-881.
2. Coleman, M.P.; Gatta, G.; Verdecchia, A.; Estève, J.; Sant, M.; Storm, H.; Allemani, C.; Ciccolallo, L.; Santaquilani, M.; Berrino, F.; EUROCARE Working Group. EUROCARE-3 Summary: Cancer Survival in Europe at the End of the 20th Century. Ann. Oncol. 2003, 14, 128-149.
3. Carpelan-Holmström, M.; Nordling, S.; Pukkala, E.; Sankila, R.; Lüttges, J.; Klöppel, G.; Haglund, C. Does Anyone Survive Pancreatic Ductal Adenocarcinoma? A Nationwide Study re-Evaluating the Data of the Finnish Cancer Registry. Gut 2005, 54, 385-387.
4. Oettle, H.; Post, S.; Neuhaus, P.; Gellert, K.; Langrehr, J.; Ridwelski, K.; Schramm, H.; Fahlke, J.; Zuelke, C.; Burkart, C.; et al. Adjuvant Chemotherapy with Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer: A Randomized Controlled Trial. JAMA 2007, 297, 267-277.
5. Neuhaus, P.; Riess, H.; Post, S.; Gellert, K.; Ridwelski, K.; Schramm, H.; Zuelke, C.; Fahlke, J.; Langrehr, J.; Oettle, H.; et al. (CAO/AIO). CONKO-001: Final Results of the Randomized, Prospective, Multicenter Phase III Trial of Adjuvant Chemotherapy with Gemcitabine versus Observation in Patients with Resected Pancreatic Cancer (PC). J. Clin. Oncol. 2008, 26, 4504.
6. Neoptolemos, J.P.; Stocken, D.D.; Friess, H.; Bassi, C.; Dunn, J.A.; Hickey, H.; Beger, H.; Fernandez-Cruz, L.; Dervenis, C.; Lacaine, F.; et al. European Study Group for Pancreatic Cancer. A Randomized trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer. N. Engl. J. Med. 2004, 350, 1200-1210.
7. Neoptolemos, J.P.; Stocken, D.D.; Bassi, C.; Ghaneh, P.; Cunningham, D.; Goldstein, D.; Padbury, R.; Moore, M.J.; Gallinger, S.; Mariette, C.; et al. European Study Group for Pancreatic Cancer. Adjuvant Chemotherapy with Fluorouracil plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection: A Randomized Controlled Trial. JAMA. 2010, 304, 1073-1081.
8. Stocken, D.D.; Büchler, M.W.; Dervenis, C.; Bassi, C.; Jeekel, H.; Klinkenbijl, J.H.; Bakkevold, K.E.; Takada, T.; Amano, H.; Neoptolemos, J.P.; Pancreatic Cancer Meta-Analysis Group. Meta-Analysis of Randomised Adjuvant Therapy Trials for Pancreatic Cancer. Br. J. Cancer. 2005, 92, 1372-1381.
9. Chauffert, B.; Mornex, F.; Bonnetain, F.; Rougier, P.; Mariette, C.; Bouché, O.; Bosset, J.F.; Aparicio, T.; Mineur, L.; Azzedine, A.; et al. Phase III Trial Comparing Intensive Induction Chemoradiotherapy (60 Gy, Infusional 5-FU and Intermittent Cisplatin) Followed by Maintenance Gemcitabine with Gemcitabine alone for Locally Advanced Unresectable Pancreatic Cancer. Definitive Results of the 2000-01 FFCD/SFRO Study. Ann. Oncol. 2008, 19, 1592-1599.
10. Huguet, F.; André, T.; Hammel, P.; Artru, P.; Balosso, J.; Selle, F.; Deniaud-Alexandre, E.; Ruszniewski; P.; Touboul, E.; Labianca, R.; de Gramont, A.; Louvet, C. Impact of Chemoradiotherapy after Disease Control with Chemotherapy in Locally Advanced Pancreatic Adenocarci noma in G ERCOR Phase II and III Studies. J. Clin. Oncol. 2007, 25, 326-331.
11. Burris, H.A., 3rd.; Moore, M.J.; Andersen, J.; Green, M.R.; Rothenberg, M.L.; Modiano, M.R.; Cripps, M.C.; Portenoy, R.K.; Storniolo, A.M.; Tarassoff, P.; 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. 1997, 15, 2403-2413.
12. Heinemann, V.; Labianca, R.; Hinke, A.; Louvet, C. Increased Survival Using Platinum Analog Combined with Gemcitabine as Compared to Single-Agent Gemcitabine in Advanced Pancreatic Cancer: Pooled Analysis of two Randomized Trials, the GERCOR/GISCAD Intergroup Study and a German Multicenter study. Ann. Oncol. 2007, 18, 1652-1659.
13. Banu, E.; Banu, A.; Fodor, A.; Landi, B.; Rougier, P.; Chatellier, G.; Andrieu, J.M.; Oudard, S. Meta-Analysis of Randomised Trials Comparing Gemcitabine-Based Doublets versus Gemcitabine alone in Patients with Advanced and Metastatic Pancreatic Cancer. Drugs Aging 2007, 24, 865-879.
14. Cunningham, D.; Chau, I.; Stocken, D.D.; Valle, J.W.; Smith, D.; Steward, W.; Harper, P.G.; Dunn, J.; Tudur-Smith, C.; West, J.; et al. Phase III Randomized Comparison of Gemcitabine versus Gemcitabine plus Capecitabine in Patients with Advanced Pancreatic Cancer. J. Clin. Oncol. 2009, 27, 5513-5518.
15. Moore, M.J.; Goldstein, D.; Hamm, J.; Figer, A.; Hecht, J.R.; Gallinger, S.; Au, H.J.; Murawa, P.; Walde, D.; Wolff, R.A.; et al National Cancer Institute of Canada Clinical Trials Group. 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. 2007, 25, 1960-1966.
16. Conroy, T.; Desseigne, F.; Ychou, M.; Ducreux, M.; Bouche, O.; Guimbaud, R.; Becouarn, Y.; Montoto-Grillot, C.; Gourgou-Bourgade, S.; Adenis, A.; FNCLCC-FFCD PRODIGE Group. Randomized Phase III trial Comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and Oxaliplatin [O]) versus Gemcitabine (G) as First-Line Treatment for Metastatic Pancreatic Adenocarcinoma (M PA): Preplanned Interim Analysis Results of the PRODIGE 4/ACCORD 11 trial. J. Clin. Oncol. 2010, 28, 4010.
17. Brennan, M.F.; Kattan, M.W.; Klimstra, D.; Conlon, K. Prognostic Nomogram for Patients Undergoing Resection for Adenocarcinoma of the Pancreas. Ann. Surg. 2004, 240, 293-298.
18. Kuhlmann, K.F.; de Castro, S.M.; Wesseling, Gten, J.; Kate, F.J.; Offerhaus, G.J.; Busch, O.R.; van Gulik, T.M.; Obertop, H.; Gouma, D.J. Surgical Treatment of Pancreatic Adenocarcinoma; Actual Survival and Prognostic Factors in 343 Patients. Eur. J. Cancer. 2004, 40, 549-558.
19. Verbeke, C.S.; Leitch, D.; Menon, K.V.; McMahon, M.J.; Guillou, P.J.; Anthoney, A. Redefining the R1 Resection in Pancreatic Cancer. Br. J. Surg. 2006, 93, 1232-1237.
20. Esposito, I.; Kleeff, J.; Bergmann, F.; Reiser, C.; Herpel, E.; Friess, H.; Schirmacher, P.; Büchler, M.W. Most Pancreatic Cancer Resections are R1 Resections. Ann. Surg. Oncol. 2008, 15, 1651-1660.
21. Sobin, L.H. International Union Against Cancer: TNM Classification of Malignat Tumors, 5th ed.; Wiley-Liss: New York, NY, USA, 1997.
22. The Royal College of Pathologists. Standard and minimum datasets for reporting cancers. Minimum Dataset for the Histopathological Reporting of Pancreatic, Ampulla of Vater and Bile Duct Carcinoma; The Royal College of Pathologists: London, UK, 2002.
23. Jamieson, N.B.; Foulis, A.K.; Oien, K.A.; Going, J.J.; Glen, P.; Dickson, E.J.; Imrie, C.W.; McKay, C.J.; Carter, R. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann. Surg. 2010, 251, 1003-1010.
24. Neoptolemos, J.P.; Stocken, D.D.; Dunn, J.A.; Almond, J.; Beger, H.G.; Pederzoli, P.; Bassi, C.; Dervenis, C.; Fernandez-Cruz, L.; Lacaine, F.; Buckels, J.; et al. European Study Group for Pancreatic Cancer. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann. Surg. 2001, 234, 758-768.
25. Blobe, G.C.; Schiemann, W.P.; Lodish, H.F. Role of transforming growth factor β in human disease. N. Engl. J Med. 2000, 342, 1350-1358.
26. Jones, S.; Zhang, X.; Parsons, D.W.; Lin, J.C.; Leary, R.J.; Angenendt, P.; Mankoo, P.; Carter, H.; Kamiyama, H.; Jimeno, A.; et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008, 321, 1801-1806.
27. Friess, H.; Yamanaka, Y.; Büchler, M.; Berger, H.G.; Kobrin, M.S.; Baldwin, R.L.; Korc, M. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 1993, 53, 2704-2707.
28. Chen, R.; Yi, E.C.; Donohoe, S.; Pan, S.; Eng, J.; Cooke, K.; Crispin, D.A.; Lane, Z.; Goodlett, D.R.; Bronner, M.P.; Aebersold, R.; Brentnall, T.A. Pancreatic cancer proteome: The proteins that underlie invasion, metastasis, and immunologic escape. Gastroenterology 2005, 129, 1187-1197.
29. Nakamura, T.; Furukawa, Y.; Nakagawa, H.; Tsunoda, T.; Ohigashi, H.; Murata, K.; Ishikawa, O.; Ohgaki, K.; Kashimura, N.; Miyamoto, M.; et al. Genome-wide cDNA microarray analysis of gene expression profiles in pancreatic cancers using populations of tumor cells and normal ductal epithelial cells selected for purity by laser microdissection. Oncogene 2004, 23, 2385-2400.
30. Wagner, M.; Kleeff, J.; Friess, H.; Büchler, M.W.; Korc, M. Enhanced expression of the type II transforming growth factor-beta receptor is associated with decreased survival in human pancreatic cancer. Pancreas 1999, 19, 370-376.
31. Shi, Y.; Massague, J. Mechanisms of TGF-β signalling from cell membrane to the nucleus. Cell 2003, 113, 685-700.
32. Hahn, S.A.; Schutte, M.; Hoque, A.T.; Moskaluk, C.A.; da Costa, L.T.; Rozenblum, E.; Weinstein, C.L.; Fischer, A.; Yeo, C.J.; Hruban, R.H.; Kern, S.E. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996, 271, 350-353.
33. Wilentz, R.E.; Su, G.H.; Dai, J.L.; Sparks, A.B.; Argani, P.; Sohn, T.A.; Yeo, C.J.; Kern, S.E.; Hruban, R.H. Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: A new marker of DPC4 inactivation. Am. J. Pathol. 2000, 156, 37-43.
34. Tascilar, M.; Skinner, H.G.; Rosty, C.; Sohn, T.; Wilentz, R.E.; Offerhaus, G.J.; Adsay, V.; Abrams, R.A.; Cameron, J.L.; Kern, S.E.; Yeo, C.J.; Hruban, R.H.; Goggins, M. The SMAD4 protein and prognosis of pancreatic ductal adenocarci noma. Clin. Cancer Res. 2001, 7, 4115-4121.
35. Biankin, A.V.; Morey, A.L.; Lee, C.S.; Kench, J.G.; Biankin, S.A.; Hook, H.C.; Head, D.R.; Hugh, T.B.; Sutherland, R.L.; Henshall, S.M. DPC4/Smad4 expression and outcome in pancreatic ductal adenocarci noma. J. Clin. Oncol. 2002, 20, 4531-4542.
36. Blackford, A.; Serrano, O.K.; Wolfgang, C.L.; Parmigiani, G.; Jones, S.; Zhang, X.; Parsons, D.W.; Lin, J.C.; Leary, R.J.; Eshleman, J.R.; et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin. Cancer Res. 2009, 15, 4674-4679.
37. Bierie, B.; Moses, H.L. Tumour microenvironment: TGFbeta: The molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer. 2006, 6, 506-520.
38. Zavadil, J.; Böttinger, E.P. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 2005, 24, 5764-5774.
39. Bardeesy, N.; Cheng, K.H.; Berger, J.H.; Chu, G.C.; Pahler, J.; Olson, P.; Hezel, A.F.; Horner, J.; Lauwers, G.Y.; Hanahan, D.; DePinho, R.A. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes. 2006, 20, 3130-3146.
40. Giampieri, S.; Manning, C.; Hooper, S.; Jones, L.; Hill, C.S.; Sahai, E. Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat. Cell. Biol. 2009, 11, 1287-1296.
41. Iacobuzio-Donahue, C.A.; Fu, B.; Yachida, S.; Luo, M.; Abe, H.; Henderson, C.M.; Vilardell, F.; Wang, Z.; Keller, J.W.; Banerjee, P.; et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J. Clin. Oncol. 2009, 27, 1806-1813.
42. Biankin, A.V.; Kench, J.G.; Colvin, E.K.; Segara, D.; Scarlett, C.J.; Nguyen, N.Q.; Chang, D.K.; Morey, A.L.; Lee, C.S.; Pinese, M.; et al. NSW Pancreatic Cancer Network. Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer. Gastroenterology. 2009, 137, 558-568.
43. Salama, I.; Malone, P.S.; Mihaimeed, F.; Jones, J.L. A review of the S100 proteins in cancer. Eur. J. Surg. Oncol. 2008, 34, 357-364.
44. Proudfoot, A.E. Chemokine receptors: Multifaceted therapeutic targets. Nat. Rev. Immunol. 2002, 2, 106-115.
45. Teicher, B.A.; Fricker, S.P. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin. Cancer. Res. 2010, 16, 2927-2931.
46. Müller, A.; Homey, B.; Soto, H.; Ge, N.; Catron, D.; Buchanan, M.E.; McClanahan, T.; Murphy, E.; Yuan, W.; Wagner, S.N.; et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001, 410, 50-56.
47. Marchesi, F.; Monti, P.; Leone, B.E.; Zerbi, A.; Vecchi, A.; Piemonti, L.; Mantovani, A.; Allavena, P. Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4. Cancer. Res. 2004, 64, 8420-8427.
48. Saur, D.; Seidler, B.; Schneider, G.; Algül, H.; Beck, R.; Senekowitsch-Schmidtke, R.; Schwaiger, M.; Schmid, R.M. CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer. Gastroenterology 2005, 129, 1237-1250.
49. Koshiba, T.; Hosotani, R.; Miyamoto, Y.; Ida, J.; Tsuji, S.; Nakajima, S.; Kawaguchi, M.; Kobayashi, H.; Doi, R.; Hori, T.; Fujii, N.; Imamura, M. Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: A possible role for tumor progression. Clin. Cancer. Res. 2000, 6, 3530-3535.
50. Thomas, R.M.; Kim, J.; Revelo-Penafiel, M.P.; Angel, R.; Dawson, D.W.; Lowy, A.M. The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia. Gut 2008, 57, 1555-1560.
51. Maréchal, R.; Demetter, P.; Nagy, N.; Berton, A.; Decaestecker, C.; Polus, M.; Closset, J.; Devière, J.; Salmon, I.; Van Laethem, J.L. High expression of CX CR4 may predict poor survival in resected pancreatic adenocarcinoma. Br. J. Cancer 2009, 100, 1444-1451.
52. Bertran, E.; Caja, L.; Navarro, E.; Sancho, P.; Mainez, J.; Murillo, M.M.; Vinyals, A.; Fabra, A.; Fabregat, I. Role of CXCR4/SDF-1 alpha in the migratory phenotype of hepatoma cells that have undergone epithelial-mesenchymal transition in response to the transforming growth factor-beta. Cell. Signal. 2009, 21, 1595-1606.
53. Moriyama, T.; Ohuchida, K.; Mizumoto, K.; Cui, L.; Ikenaga, N.; Sato, N.; Tanaka, M. Enhanced cell migration and invasion of CD133+ pancreatic cancer cells cocultured with pancreatic stromal cells. Cancer 2010, 116, 3357-3368.
54. Baldwin, S.A.; Yao, S.Y.; Hyde, R.J.; Ng, A.M.; Foppolo, S.; Barnes, K.; Ritzel, M.W.; Cass, C.E.; Young, J.D. Functional characterization of novel human and mouse equilibrative nucleoside transporters (hENT3 and mENT3) located in intracellular membranes. J. Biol. Chem. 2005, 280, 15880-15887.
55. Barnes, K.; Dobrzynski, H.; Foppolo, S.; Beal, P.R.; Ismat, F.; Scullion, E.R.; Sun, L.; Tellez, J.; Ritzel, M.W.; Claycomb, W.C.; Cass, C.E.; Young, J.D.; Billeter-Clark, R.; Boyett, M.R.; Baldwin, S.A. Distribution and functional characterization of equilibrative nucleoside transporter-4, a novel cardiac adenosine transporter activated at acidic pH. Circ. Res. 2006, 99, 510-519.
56. Smith, K.M.; Slugoski, M.D.; Loewen, S.K.; Ng, A.M.; Yao, S.Y.; Chen, X.Z.; Karpinski, E.; Cass, C.E.; Baldwin, S.A.; Young, J.D. The broadly selective human Na+/nucleoside cotransporter (hCNT3) exhibits novel cation-coupled nucleoside transport characteristics. J. Biol. Chem. 2005, 280, 25436-25449.
57. Mackey, J.R.; Yao, S.Y.; Smith, K.M.; Karpinski, E.; Baldwin, S.A.; Cass, C.E.; Young, J.D. Gemcitabine transport in Xenophus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J. Natl. Cancer. Inst. 1999, 91, 1876-1881.
58. Ritzel, M.W.; Ng, A.M.; Yao, S.Y.; Graham, K.; Loewen, S.K.; Smith, K.M.; Hyde, R.J.; Karpinski, E.; Cass, C.E.; Baldwin, S.A.; Young, J.D. Recent molecular advances in studies of the concentrative nucleoside transporter (CNT): Identification and characterization of novel human and mouse proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides. Mol. Memb. Biol. 2001, 18, 65-72.
59. Mackey, J.R.; Mani, R.S.; Selner, M.; Mowles, D.; Young, J.D.; Belt, J.A.; Crawford, C.R.; Cass, C.E. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998, 58, 4349-4357.
60. Garcia-Manteiga, J.; Molina-Arcas, M.; Casado, F.J.; Mazo, A.; Pastor-Anglada, M. Nucleoside transporter profiles in human pancreatic cancer cells: Role of hCNT1 in 2',2'-difluorodeoxycitidine-induced cytotoxicity. Clin. Cancer Res. 2003, 9, 5000-5008.
61. Giovannetti, E.; Del Tacca, M.; Mey, V.; Funel, N.; Nannizzi, S.; Ricci, S.; Orlandini, C.; Boggi, U.; Campani, D.; Del Chiaro, M.; Iannopollo, M.; Bevilacqua, G.; Mosca, F.; Danesi, R. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemci tabi ne. Cancer Res. 2006, 66, 3928-3935.
62. Spratlin, J.; Sangha, R.; Glubrecht, D.; Dabbagh, L.; Young, J.D.; Dumontet, C.; Cass, C.; Lai, R.; Mackey, J.R. The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma. Clin. Cancer Res. 2004, 10, 6956-6961.
63. Farrell, J.J.; Elsaleh, H.; Garcia, M.; Lai, R.; Ammar, A.; Regine, W.F.; Abrams, R.; Benson, A.B.; Macdonald, J.; Cass, C.E.; Dicker, A.P.; Mackey, J.R. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology 2009, 136, 187-195.
64. Nakahira, S.; Nakamori, S.; Tsujie, M.; Takahashi, Y.; Okami, J.; Yoshioka, S.; Yamasaki, M.; Marubashi, S.; Takemasa, I.; Miyamoto, A.; et al. Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer. Int. J. Cancer 2007, 120, 1355-1363.
65. Itoi, T.; Sofuni, A.; Fukushima, N.; Itokawa, F.; Tsuchiya, T.; Kurihara, T.; Moriyasu, F.; Tsuchida, A.; Kasuya, K. Ribonucleotide reductase subunit M2 mRNA expression in pretreatment biopsies obtained from unresectable pancreatic carcinomas. J. Gastroenterol. 2007, 42, 389-394.
66. Sebastiani, V.; Ricci, F.; Rubio-Viqueira, B.; Kulesza, P.; Yeo, C.J.; Hidalgo, M.; Klein, A.; Laheru, D.; Iacobuzio-Donahue, C.A. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: Relationship to molecular mechanisms of gemcitabine resistance and survival. Clin. Cancer Res. 2006, 12, 2492-2497.
67. Maréchal, R.; Mackey, J.R.; Lai, R.; Demetter, P.; Peeters, M.; Polus, M.; Cass, C.E.; Salmon, I.; Devière, J.; Van Laethem, J.L. Deoxycitidine kinase is associated with prolonged survival after adjuvant gemcitabine for resected pancreatic adenocarcinoma. Cancer 2010, 116, 5200-5206.
68. Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat. Rev. Genet. 2007, 8, 286-298.
69. Suzuki, H.; Gabrielson, E.; Chen, W.; Anbazhagan, R.; van Engeland, M.; Weijenberg, M.P.; Herman, J.G.; Baylin, S.B. A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat. Genet. 2002, 31, 141-149.
70. Fitzgerald, M.; Oshiro, M.; Holtan, N.; Krager, K.; Cullen, J.J.; Futscher, B.W.; Domann, F.E. Human pancreatic carcinoma cells activate maspin expression through loss of epigenetic control. Neoplasia 2003, 5, 427-436.
71. Von Burstin, J.; Eser, S.; Paul, M.C.; Seidler, B.; Brandl, M.; Messer, M.; Von Werder, A.; Schmidt, A.; Mages, J.; Pagel, P.; et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 2009, 137, 361-371.
72. Wei, Y.; Xia, W.; Zhang, Z.; Liu, J.; Wang, H.; Adsay, NV.; Albarracin, C.; Yu, D.; Abbruzzese, J.L.; Mills, G.B.; Bast, R.C. Jr.; Hortobagyi, G.N.; Hung, M.C. Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers. Mol. Carcinog. 2008, 47, 701-706.
73. Manuyakorn, A.; Paulus, R.; Farrell, J.; Dawson, N.A.; Tze, S.; Cheung-Lau, G.; Hines, O.J.; Reber, H.; Seligson, D.B.; Horvath, S.; et al. Histone modification patterns predict prognosis and treatment response in resectable pancreatic adenocarcinoma: Results from RTOG 9704. J. Clin. Oncol. 2010, 28, 1358-1365.
74. Regine, W.F.; Winter, K.A.; Abrams, R.A.; Safran, H.; Hoffman, J.P.; Konski, A.; Benson, A.B.; Macdonald, J.S.; Kudrimoti, M.R.; Fromm, M.L.; et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial. JAMA 2008, 299, 1019-1026.
75. Lee, J.H.; Park, J.H.; Jung, Y.; Kim, J.H.; Jong, H.S.; Kim, T.Y.; Bang, Y.J. Histone deacetylase inhibitor enhances 5-f luorouracil cytotoxicity by down-regulating thymidylate synthase in human cancer cells. Mol. Cancer Ther. 2006, 5, 3085-3095.
76. Fazzone, W.; Wilson, P.M.; Labonte, M.J.; Lenz, H.J.; Ladner, R.D. Histone deacetylase inhibitors suppress thymidylate synthase gene expression and synergize with the fluoropyrimidines in colon cancer cells. Int. J. Cancer 2009, 125, 463-473.
77. Danenberg, P.V.; Heidelberger, C.; Mulkins, M.A.; Peterson, A.R. The incorporation of 5-fluoro-2'-deoxyuridine into DNA of mammalian tumor cells. Biochem. Biophys. Res. Commun. 1981 102, 654-658.
78. Berger, S.H.; Jenh, C.H.; Johnson, L.F.; Berger, F.G. Thymidylate synthase overproduction and gene amplification in fluorodeoxyuridine-resistant human cells. Mol. Pharmacol. 1985, 28, 461-467.
79. Popat, S.; Matakidou, A.; Houlston, R.S. Thymidylate synthase expression and prognosis in colorectal cancer: A systematic review and meta-analysis. J. Clin. Oncol. 2004, 22, 529-536.
80. Marsh, S.; McKay, J.A.; Cassidy, J.; McLeod, H.L. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int. J. Oncol. 2001, 19, 383-386.
81. Kawakami, K.; Salonga, D.; Park, J.M.; Danenberg, K.D.; Uetake, H.; Brabender, J.; Omura, K.; Watanabe, G.; Danenberg, P.V. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin. Cancer Res. 2001, 7, 4096-4101.
82. Mandola, M.V.; Stoehlmacher, J.; Zhang, W.; Groshen, S.; Yu, M.C.; Iqbal, S.; Lenz, H.J.; Ladner, R.D. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004, 14, 319-327.
83. Mandola, M.V.; Stoehlmacher, J.; Muller-Weeks, S.; Cesarone, G.; Yu, M.C.; Lenz, H.J.; Ladner R.D. A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res. 2003, 63, 2898-2904.
84. Lurje, G.; Zhang, W.; Yang, D.; Groshen, S.; Hendifar, A.E.; Husain, H.; Nagashima, F.; Chang, H.M.; Fazzone, W.; Ladner, R.D.; et al. Thymidylate synthase haplotype is associated with tumor recurrence in stage II and stage III colon cancer. Pharmacogenet. Genomics 2008, 18, 161-168.
85. Boige, V.; Mendiboure, J.; Pignon, J.P.; Loriot, M.A.; Castaing, M.; Barrois, M.; Malka, D.; Trégouët, D.A.; Bouché, O.; Le Corre, D.; et al. Pharmacogenetic assessment of toxicity and outcome in patients with metastatic colorectal cancer treated with LV5FU2, FOLFOX, and FOL FIRI: FFCD 2000-05. J. Clin. Oncol. 2010, 28, 2556-2564.
86. Grady, W.M.; Carethers, J.M. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 2008, 135, 1079-1099.
87. Cunningham, J.M.; Christensen, E.R.; Tester, D.J.; Kim, C.Y.; Roche, P.C.; Burgart, L.J.; Thibodeau, S.N. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998, 58, 3455-3460.
88. Bachet, J.B.; Laurent-Puig, P.; de Gramont, A.; André, T. Microsatellite status and adjuvant chemotherapy in patients with stage II colon cancer. Curr. Colorectal Cancer Rep. 2010, 6, 148-157.
89. Umar, A.; Boland, C.R.; Terdiman, J.P.; Syngal, S.; de la Chapelle, A.; Rüschoff, J.; Fishel, R.; Lindor, N.M.; Burgart, L.J.; Hamelin, R.; et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl. Cancer Inst. 2004, 96, 261-268.
90. Yamamoto, H.; Itoh, F.; Nakamura, H.; Fukushima, H.; Sasaki, S.; Perucho, M.; Imai, K. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res. 2001, 61, 3139-3144.
91. Nakata, B.; Wang, Y.Q.; Yashiro, M.; Nishioka, N.; Tanaka, H.; Ohira, M.; Ishikawa, T.; Nishino, H.; Hirakawa, K. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin. Cancer Res. 2002, 8, 2536-2540.
92. Ouyang, H.; Furukawa, T.; Abe, T.; Kato, Y.; Horii, A. The BAX gene, the promoter of apoptosis, is mutated in genetically unstable cancers of the colorectum, stomach, and endometrium. Clin. Cancer Res. 1998, 4, 1071-1074.
93. Van Cutsem, E.; Vervenne, W.L.; Bennouna, J.; Humblet, Y.; Gill, S.; Van Laethem, J.L.; Verslype, C.; Scheithauer, W.; Shang, A.; Cosaert, J.; et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J. Clin. Oncol. 2009, 27, 2231-2237.
94. Shaw, R.J.; Cantley, L.C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 2006, 441, 424-430.
95. Almoguera, C.; Shibata, D.; Forrester, K.; Martin, J.; Arnheim, N.; Perucho, M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988, 53, 549-554.
96. Caldas, C.; Kern, S.E. K-ras mutation and pancreatic adenocarcinoma. Int. J. Pancreatol. 1995, 18, 1-6.
97. da Cunha Santos, G.; Dhani, N.; Tu, D.; Chin, K.; Ludkovski, O.; Kamel-Reid, S.; Squire, J.; Parulekar, W.; Moore, M.J.; Tsao, M.S. Molecular predictors of outcome in a phase 3 study of gemcitabine and erloti nib therapy in patients with advanced pancreatic cancer: National Cancer I nsti tute of Canada Clinical Trials Group Study PA.3. Cancer 2010, 116, 559-607.
98. Lee, J.; Jang, K.T.; Ki, C.S.; Lim, T.; Park, Y.S.; Lim, H.Y.; Choi, D.W.; Kang, W.K.; Park, K.; Park, J.O. Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer 2007, 109, 1561-1569.
99. Lièvre, A.; Bachet, J.B.; Boige, V.; Cayre, A.; Le Corre, D.; Buc, E.; Ychou, M.; Bouché, O.; Landi, B.; Louvet, C.; et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008, 26, 374-379.
100. Karapetis, C.S.; Khambata-Ford, S.; Jonker, D.J.; O'Callaghan, C.J.; Tu, D.; Tebbutt, N.C.; Simes, R.J.; Chalchal, H.; Shapiro, J.D.; Robitaille, S.; et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 2008, 359, 1757-1765.
101. Laurent-Puig, P.; Cayre, A.; Manceau, G.; Buc, E.; Bachet, J.B.; Lecomte, T.; Rougier, P.; Lievre, A.; Landi, B.; Boige, V.; et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J. Clin. Oncol. 2009, 27, 5924-5930.
102. Eberhard, D.A.; Johnson, B.E.; Amler, L.C.; Goddard, A.D.; Heldens, S.L.; Herbst, R.S.; Ince, W.L.; Jänne, P.A.; Januario, T.; Johnson, D.H.; et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 2005, 23, 5900-5909.
103. Zhu, C.Q.; da Cunha Santos, G.; Ding, K.; Sakurada, A.; Cutz, J.C.; Liu, N.; Zhang, T.; Marrano, P.; Whitehead, M.; Squire, J.A.; et al. National Cancer Institute of Canada Clinical Trials Group Study BR.21. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J. Clin. Oncol. 2008, 26, 4268-4275.
104. Martin, L.P.; Hamilton, T.C.; Schilder, R.J. Platinum resistance: The role of DNA repair pathways. Clin. Cancer Res. 2008, 14, 1291-1295.
105. Arnould, S.; Hennebelle, I.; Canal, P.; Bugat, R.; Guichard, S. Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines. Eur. J. Cancer. 2003, 39, 112-119.
106. Welsh, C.; Day, R.; McGurk, C.; Masters, J.R.; Wood, R.D.; Köberle, B. Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int. J. Cancer. 2004, 110, 352-361.
107. Yang, L.Y.; Li, L.; Jiang, H.; Shen, Y.; Plunkett, W. Expression of ERCC1 antisense RNA abrogates gemicitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cells defective in mismatch repair but proficient in nucleotide excision repair. Clin. Cancer Res. 2000, 6, 773-781.
108. Joshi, M.B.; Shirota, Y.; Danenberg, K.D.; Conlon, D.H.; Salonga, D.S.; Herndon, J.E., 2nd.; Danenberg, P.V.; Harpole, D.H., Jr. High gene expression of TS1, GSTP1, and ERCC1 are risk factors for survival in patients treated with trimodality therapy for esophageal cancer. Clin. Cancer Res. 2005, 11, 2215-2221.
109. Shirota, Y.; Stoehlmacher, J.; Brabender, J.; Xiong, Y.P.; Uetake, H.; Danenberg, K.D.; Groshen, S.; Tsao-Wei, D.D.; Danenberg, P.V.; Lenz, H.J. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J. Clin. Oncol. 2001, 19, 4298-4304.
110. Metzger, R.; Leichman, C.G.; Danenberg, K.D.; Danenberg, P.V.; Lenz, H.J.; Hayashi, K.; Groshen, S.; Salonga, D.; Cohen, H.; Laine, L.; et al. ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J. Clin. Oncol. 1998, 16, 309-316.
111. Olaussen, K.A.; Dunant, A.; Fouret, P.; Brambilla, E.; André, F.; Haddad, V.; Taranchon, E.; Filipits, M.; Pirker, R.; Popper, H.H.; et al. IALT Bio Investigators. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N. Engl. J. Med. 2006, 355, 983-991.
112. Viguier, J.; Boige, V.; Miquel, C.; Pocard, M.; Giraudeau, B.; Sabourin, J.C.; Ducreux, M.; Sarasin, A.; Praz, F. ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer. Clin. Cancer Res. 2005, 11, 6212-6217.
113. Stoehlmacher, J.; Park, D.J.; Zhang, W.; Yang, D.; Groshen, S.; Zahedy, S.; Lenz, H.J. A multivariate analysis of genomic polymorphisms: Prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br. J. Cancer 2004, 91, 344-354.
114. McLeod, H.L.; Sargent, D.J.; Marsh, S.; Green, E.M.; King, C.R.; Fuchs, C.S.; Ramanathan, R.K.; Williamson, S.K.; Findlay, B.P.; Thibodeau, S.N.; et al. Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: Results from North A merican Gastrointestinal I ntergroup Trial N 9741. J. Clin. Oncol. 2010, 28, 3227-3233.
115. McIlwain, C.C.; Townsend, D.M.; Tew, K.D. Glutathione S-transf erase polymorphisms: Cancer incidence and therapy. Oncogene 2006, 25, 1639-1648.
116. Goekkurt, E.; Al-Batran, S.E.; Hartmann, J.T.; Mogck, U.; Schuch, G.; Kramer, M.; Jaeger, E.; Bokemeyer, C.; Ehninger, G.; Stoehlmacher, J. Pharmacogenetic analyses of a phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil and leucovorin plus either oxaliplatin or cisplatin: A study of the arbeitsgemeinschaft internistische onkologie. J. Clin. Oncol. 2009, 27, 2863-2873.
117. Iyer, L.; Hall, D.; Das, S.; Mortell, M.A.; Ramírez, J.; Kim, S.; Di Rienzo, A.; Ratain, M.J. Phenotype-genotype correlation of in vitro SN-38 (active metabolite of irinotecan) and bilirubin glucuronidation in human liver tissue with UGT1A1 promoter polymorphism. Clin. Pharmacol. Ther. 1999, 65, 576-582.
118. Hoskins, J.M.; Goldberg, R.M.; Qu, P.; Ibrahim, J.G.; McLeod, H.L. UGT1A1*28 genotype and irinotecan-induced neutropenia: Dose matters. J. Natl. Cancer. Inst. 2007, 99, 1290-1295.
119. Takeda, S.; Shimazoe, T.; Sato, K.; Sugimoto, Y.; Tsuruo, T.; Kono, A. Differential expression of DNA topoisomerase I gene between CPT-11 acquired-and native-resistant human pancreatic tumor cell lines: Detected by RNA/PCR-based quantitation assay. Biochem. Biophys. Res. Commun. 1992, 184, 618-625.
120. Taïeb, J.; Lecomte, T.; Aparicio, T.; Asnacios, A.; Mansourbakht, T.; Artru, P.; Fallik, D.; Spano, J.P.; Landi, B.; Lledo, G.; Desrame, J. FOLFIRI.3, a new regimen combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: Results of an Association des Gastro-Enterologues Oncologues (Gastroenterologist Oncologist Association) multi center phase II study. Ann. Oncol. 2007, 18, 498-503.
121. Wagener, D.J.; Verdonk, H.E.; Dirix, L.Y.; Catimel, G.; Siegenthaler, P.; Buitenhuis, M.; Mathieu-Boué, A.; Verweij, J. Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. Ann. Oncol. 1995, 6, 129-132.
122. Ulrich-Pur, H.; Raderer, M.; Verena Kornek, G.; Schüll, B.; Schmid, K.; Haider, K.; Kwasny, W.; Depisch, D.; Schneeweiss, B.; Lang, F.; Scheithauer, W. Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br. J. Cancer 2003, 88, 1180-1184.
123. Ashida, R.; Nakata, B.; Shigekawa, M.; Mizuno, N.; Sawaki, A.; Hirakawa, K.; Arakawa, T.; Yamao, K. Gemcitabine sensitivity-related mRNA expression in endoscopic ultrasound-guided fine-needle aspi ration biopsy of unresectable pancreatic cancer. J. Exp. Clin. Cancer Res. 2009, 28, 83.
124. Li, A.; Omura, N.; Hong, S.M.; Vincent, A.; Walter, K.; Griffith, M.; Borges, M.; Goggins, M. Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res. 2010, 70, 5226-5237.
125. Paproski, R.J.; Young, J.D.; Cass, C.E. Predicting gemcitabine transport and toxicity in human pancreatic cancer cell lines with the positron emission tomography tracer 3'-deoxy-3'-fluorothymidine. Biochem. Pharmacol. 2010, 79, 587-595.
126. Popat, S.; Hubner, R.; Houlston, R.S. Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 2005, 23, 609-618.
127. Sargent, D.J.; Marsoni, S.; Monges, G.; Thibodeau, S.N.; Labianca, R.; Hamilton, S.R.; French, A.J.; Kabat, B.; Foster, N.R.; Torri, V.; et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J. Clin. Oncol. 2010, 28, 3219-3226.
128. Elsaleh, H.; Joseph, D.; Grieu, F.; Zeps, N.; Spry, N.; Iacopetta, B. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000, 355, 1745-1750.
129. Mandrekar, S.J.; Sargent, D.J. Clinical trial designs for predictive biomarker validation: Theoretical considerations and practical challenges. J. Clin. Oncol. 2009, 27, 4027-4034.
130. Philip, P.A.; Mooney, M.; Jaffe, D.; Eckhardt, G.; Moore, M.; Meropol, N.; Emens, L.; O'Reilly, E.; Korc, M.; Ellis, L.; et al. Tepper, J. Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. J. Clin. Oncol. 2009, 27, 5660-5669.