Prognostic and Predictive Factors for Pancreatic Adenocarcinoma

Česká verzia

Authors: P. Karásek ¹; M. Hermanová ²
Authors place of work: Klinika komplexní onkologické péče, Masarykův onkologický ústav, Brno ¹; I. patologicko-anatomický ústav, LF MU a FN u sv. Anny v Brně ²
Published in the journal: Klin Onkol 2016; 29(5): 336-341
Category: Reviews
doi: https://doi.org/http://dx.doi.org/10.14735/amko2016336

Summary

Background:
Pancreatic ductal adenocarcinoma is a highly aggressive disease with 5-year overall survival not exceeding 5%. In the Czech Republic, the incidence of this tumor has been increasing; according to recent statistics, the Czech Republic is already number one worldwide in the occurrence of this malignancy. Delayed diagnosis due to asymptomatic course of the disease in the early stages is characteristic for this disease.

Aim:
The objective of this article is to give an overview of the most important factors, which according to current knowledge of pancreatic adenocarcinoma have a prognostic and predictive potential. This work describes both traditional prognostic factors, such as tumor resectability, its extent and localization, application of adjuvant chemotherapy, microscopically positive resection margin, presence of metastases in lymph nodes, histological grade, vascular and perineural invasion. Further, the paper lists a number of different biological markers that could contribute to early detection of cancer, better prognosis and optimization of treatment, for example hENT1 (human equilibrative nucleoside transporter-1), SPARC (secreted protein acidic and rich in cysteine), AGR2, Bcl-2, VEGF, Ki-67, COX-2 and more. Also, genetic mutations and significance of microRNA are discussed.

Conclusion:
Despite great efforts that have been devoted to the research of biological markers, so far the only clinically accepted and used marker is CA 19-9. Its use is primarily in patients already diagnosed with adenocarcinoma of the pancreas. A lot of attention has recently been focused on other potential biomarkers, their application in clinical practice would however still require further research.

Key words:
carcinoma pancreatic ductal − biological tumor markers − prognosis − prognostic factors

The authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
16. 2. 2016

Accepted:
17. 2. 2016

Zdroje

1. GLOBOCAN. European age-standardised rates calculated by the statistical information team at cancer research [online]. UK: 2012. Using data from GLOBOCAN 2012, IARC [cited 2015 Octo 1]. Available at: http: //globocan.iarc.fr.

2. Uzis.cz. Národní onkologický registr, 010_20140101 [online]. ČR: UZIS, 2015 [citováno 1. října 2015]. Dostupné z: www.uzis.cz/registry-nzis/nor.

3. Gillen S, Schuster T, Meyer Zum Büschenfelde C et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and metaanalysis of response and resection percentages. PLoS Med 2010; 7 (4): e1000267. doi: 10.1371/journal.pmed.1000267.

4. Kuhlmann KF, de Castro SM, Wesseling JG et al. Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 2004; 40 (4): 549–558.

5. Van den Broeck A, Sergeant G, Ectors N et al. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma. Eur J Surg Oncol 2009; 35 (6): 600–604. doi: 10.1016/j.ejso.2008.12.006.

6. Shimada K, Sakamoto Y, Sano T et al. Prognostic factors after distal pancreatectomy with extended lymphadenectomy for invasive pancreatic adenocarcinoma of the body and tail. Surgery 2006; 139 (3): 288–295.

7. Herman JM, Swartz MJ, Hsu CC et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol 2008; 26 (21): 3503–3510. doi: 10.1200/JCO.2007.15. 8469.

8. Oettle H, Post S, Neuhaus P et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 2007; 297 (3): 267–277.

9. Neoptolemos JP, Dunn JA, Stocken DD et al. European Study Group for Pancreatic Cancer Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001; 358 (9293): 1576–1585.

10. Neoptolemos JP, Stocken DD, Bassi 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 (10): 1073–1081. doi: 10.1001/jama.2010.1275.

11. Oettle H, Neuhaus P, Hochhaus A et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013; 310 (14): 1473–1481. doi: 10.1001/jama.2013.279201.

12. Neoptolemos JP, Stocken DD, Dunn JA et al. 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. European Study Group for Pancreatic Cancer. Ann Surg 2001; 234 (6): 758–768.

13. Verbeke CS, Leitch D, Menon KV et al. Redefining the R1resection in pancreatic cancer. Br J Surg 2006; 93 (10): 1232–1237.

14. Verbeke CS, Gladhaug IP. Resection margin involvement and tumour origin in pancreatic head cancer. Br J Surg 2012; 99 (8): 1036–1049. doi: 10.1002/bjs.8734.

15. Esposito I, Kleeff J, Bergmann F et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 2008; 15 (6): 1651–1660. doi: 10.1245/s10434-008-9839-8.

16. Gebauer F, Tachezy M, Vashist YK et al. Resection margin clearance in pancreatic cancer after implementation of the Leeds Pathology Protocol (LEEPP): clinically relevant or just academic? World J Surg 2015; 39 (2): 493–499. doi: 10.1007/s00268-014-2808-4.

17. House MG, Gönen M, Jarnagin WR et al. Prognostic significance of pathologic nodal status in patients with resected pancreatic cancer. J Gastrointest Surg 2007; 11 (11): 1549–1555.

18. Pawlik TM, Gleisner AL, Cameron JL et al. Prognostic relevance of lymph node ratio following pancreaticoduodenectomy for pancreatic cancer. Surgery 2007; 141 (5): 610–618.

19. Lüttges J, Schemm S, Vogel I et al. The grade of pancreatic ductal carcinoma is an independent prognostic factor and is superior to the immunohistochemical assessment of proliferation. J Pathol 2000; 191 (2): 154–161.

20. Nakao A, Harada A, Nonami T et al. Clinical significance of carcinoma invasion of the extrapancreatic nerve plexus in pancreatic cancer. Pancreas 1996; 12 (4): 357–361.

21. Reni M, Cereda S, Balzano G et al. Carbohydrate antigen 19-9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer 2009; 115 (12): 2630–2639. doi: 10.1002/cncr.24302.

22. Bunger S, Laubert T, Roblick UJ et al. Serum biomarkers for improved diagnostic of pancreatic cancer: a current overview. J Cancer Res Clin Oncol 2011; 137 (3): 375–389. doi: 10.1007/s00432-010-0965-x.

23. Mackey JR, Mani RS, Selner M et al. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res 1988; 58 (19): 4349–4357.

24. Greenhalf W, Ghaneh P, Neoptolemos JP et al. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Natl Cancer Inst 2014; 106 (1): djt347. doi: 10.1093/jnci/djt347.

25. Poplin E, Wasan H, Rolfe L 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. J Clin Oncol 2013; 31 (35): 4453–4461. doi: 10.1200/JCO.2013.51.0826.

26. Hidalgo M, Cascinu S, Kleeff J et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015; 15 (1): 8–18. doi: 10.1016/j.pan.2014.10.001.

27. Guweidhi A, Kleeff J, Adwan H et al. Osteonectin influences growth and invasion of pancreatic cancer cells. Ann Surg 2005; 242 (2): 224–234.

28. Sinn M, Sinn, BV, Striefler JK et al. SPARC expression in resected pancreatic cancer patients treated with gemcitabine: results from the CONKO-001 study. Ann Oncol 2014; 25 (5): 1025–1032. doi: 10.1093/annonc/mdu084.

29. Von Hoff DD, Ramanathan RK, Borad MJ et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 2011; 29 (34): 4548–4554. doi: 10.1200/ JCO.2011.36.5742.

30. Hidalgo M, Plaza C, Illei P et al. SPARC analysis in the phase III MPACT trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) vs Gem alone for patients with metastatic pancreatic cancer (PC). Ann Oncol 2013; 25 (Suppl 2): ii105–ii117.

31. Klimstra DS, Longnecker DS. K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 1994; 145 (6): 1547–1550.

32. Löhr M, Klöppel G, Maisonneuve P et al. Frequency of Kras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 2005; 7 (1): 17–23.

33. Van Cutsem E, van de Velde H, Karasek P et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22 (8): 1430–1438.

34. Huang H, Daniluk J, Liu Y et al. Oncogenic K-Ras requires activation for enhanced activity. Oncogene 2014; 33 (4): 532–535. doi: 10.1038/onc.2012.619.

35. Biankin AV, Waddell N, Kassahn KS et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491 (7424): 399–405. doi: 10.1038/nature11547.

36. Iacobuzio-Donahue CA, Fu B, Yachida S et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009; 27 (11): 1806–1813. doi: 10.1200/JCO.2008.17.7188.

37. Tsuji T, Satoyoshi R, Aiba N et al. Agr2 mediates paracrine effects on stromal fibroblasts that promote invasion by gastric signet-ring carcinoma cells. Cancer Res 2015; 75 (2): 356–366. doi: 10.1158/0008-5472.CAN-14-1693.

38. Dumartin L, Whiteman HJ, Weeks ME et al. AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. Cancer Res 2011; 71 (22): 7091–7102. doi: 10.1158/0008-5472.CAN-11-1367.

39. Ramachandran V, Arumugam T, Wang H et al. Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival. Cancer Res 2008; 68 (19): 7811–7818. doi: 10.1158/0008-5472.CAN-08-1320.

40. Brychtova V, Hermanova M, Karasek P et al. Anterior gradient 2 and mucin 4 expression mirrors tumor cell differentiation in pancreatic adenocarcinomas, but aberrant anterior gradient 2 expression predicts worse patient outcome in poorly differentiated tumors. Pancreas 2014; 43 (1): 75–81. doi: 10.1097/MPA.0b013e3182a63bc3.

41. Nio Y, Dong M, Iguchi C et al. Expression of Bcl-2 and p53 protein in resectable invasive ductal carcinoma of the pancreas: effects on clinical outcome and efficacy of adjuvant chemotherapy. J Surg Oncol 2001; 76 (3): 188–196.

42. Dong M, Zhou JP, Zhang H et al. Clinicopathological significance of Bcl-2 and Bax protein expression in human pancreatic cancer. World J Gastroenterol 2005; 11 (18): 2744–2747.

43. Campani D, Esposito I, Boggi U et al. Bcl-2 expression in pankreas development and pancreatic cancer progression. J Pathol 2001; 194 (4): 444–450.

44. Bold RJ, Hess KR, Pearson AS et al. Prognostic factors in resectable pancreatic cancer: p53 and bcl-2. J Gastrointest Surg 1999; 3 (3): 263–277.

45. Seo Y, Baba H, Fukuda T et al. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 2000; 88 (10): 2239–2245.

46. Kuwahara K, Sasaki T, Kuwada Y et al. Expressions of angiogenic factors in pancreatic ductal carcinoma: a correlative study with clinicopathologic parameters and patient survival. Pancreas 2003; 26 (4): 344–349.

47. Ikeda N, Adachi M, Taki T et al. Prognostic significance of angiogenesis in human pancreatic cancer. Br J Cancer 1999; 9 (9–10): 1553–1563.

48. Sun HC, Qiu ZJ, Liu J et al. Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. Int J Oncol 2007; 30 (6): 1359–1367.

49. Ai KX, Lu LY, Huang XY et al. Prognostic significance of S100A4 and vascular endothelial growth factor expression in pancreatic cancer. World J Gastroenterol 2008; 14 (12): 1931–1935.

50. Linder S, Parrado C, Falkmer UG et al. Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma: a study of the monoclonal antibodies MIB-1 and DO-7 in formalin-fixed paraffin-embedded tumour material. Br J Cancer 1997; 76 (1): 54–59.

51. Karamitopoulou E, Zlobec I, Tornillo L et al. Differential cell cycle and proliferation marker expression in ductal pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia (PanIN). Pathology 2010; 42 (3): 229–234. doi: 10.3109/00313021003631379.

52. Yamamoto S, Tomita Y, Hoshida Y et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res 2004; 10 (8): 2846–2850.

53. Lebe B, Sağol O, Ulukuş C et al. The importance of cyclin D1 and Ki67 expression on the biological behavior of pancreatic adenocarcinomas. Pathol Res Pract 2004; 200 (5): 389–396.

54. Stanton KJ, Sidner RA, Miller GA et al. Analysis of Ki-67 antigen expression, DNA proliferative fraction, and survival in resected cancer of the pancreas. Am J Surg 2003; 186 (5): 486–492.

55. Sarela AI, Verbeke CS, Ramsdale J et al. Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, inpancreatic adenocarcinoma. Br J Cancer 2002; 86 (6): 886–892.

56. Sagol O, Yavuzsen T, Oztop I et al. The effect of apoptotic activity, survivin, Ki-67, and P-glycoprotein expression on prognosis in pancreatic carcinoma. Pancreas 2005; 30 (4): 343–348.

57. Oida Y, Yamazaki H, Tobita K et al. Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer. Oncol Rep 2006; 16 (3): 457–463.

58. Tabata T, Tsukamoto N, Fooladi AA et al. RNA interference targeting against S100A4 suppresses cell growth and motility and induces apoptosis in human pancreatic cancer cells. Biochem Biophys Res Commun 2009; 390 (4): 475–480. doi: 10.1016/j.bbrc.2009.09.096.

59. Tanabe T, Tohnai N. Cyclooxygenase isozymes and their gene structures and expression. Prostaglandins Other Lipid Mediat 2002; 68–69: 95–114.

60. Fosslien E. Biochemistry of cyclooxygenase (COX) -2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000; 37 (5): 431–502.

61. Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene 1999; 18 (55): 7908–7916.

62. Kokawa A, Kondo H, Gotoda T et al. Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors. Cancer 2001; 91 (2): 333–338.

63. Albazaz R, Verbeke CS, Rahman SH et al. Cyclooxygenase-2 expression associated with severity of PanIN lesions: a possible link between chronic pancreatitis and pancreatic cancer. Pancreatology 2005; 5 (4–5): 361–369.

64. Hermanova M, Trna J, Nenutil R et al. Expression of COX-2 is associated with accumulation of p53 in pancreatic cancer: analysis of COX-2 and p53 expression in premalignant and malignant ductal pancreatic lesions. Eur J Gastroenterol Hepatol 2008; 20 (8): 732–739. doi: 10.1097/MEG.0b013e3282f945fb.

65. Juuti A, Louhimo J, Nordling S et al. Cyclooxygenase-2 expression correlates with poor prognosis in pancreatic cancer. J Clin Pathol 2006; 59 (4): 382–386.

66. Dannenberg AJ, Altorki NK, Boyle JO et al. Cyclo-oxygenase 2: a pharmacological target for the prevention of cancer. Lancet Oncol 2001; 2 (9): 544–551.

67. Shi H, Xu JM, Hu NZ et al. Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma. World J Gastroenterol 2003; 9 (7): 1421–1426.

68. Hermanova M, Karasek P, Nenutil R et al. Clinicopathological correlations of cyclooxygenase-2, MDM2, and p53 expressions in surgically resectable pancreatic invasive ductal adenocarcinoma. Pancreas 2009; 38 (5): 565–571. doi: 10.1097/MPA.0b013e31819fef8b.

69. Osada H, Takahashi T. MicroRNAs in biological processes and carcinogenesis. Carcinogenesis 2007; 28 (1): 2–12.

70. Sun T, Kong X, Du Y et al. Aberrant microRNAs in pancreatic cancer: researches and clinical implications. Gastroenterol Res Pract 2014; 2014: ID 386561. doi: 10.1155/2014/386561.

71. Frampton AE, Krell J, Jamieson NB et al. MicroRNAs with prognostic significance in pancreatic ductal adenocarcinoma: a meta-analysis. Eur J Cancer 2015; 51 (11): 1389–1404. doi: 10.1016/j.ejca.2015.04.006.

72. Wang P, Zhuang L, Zhang J. The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL. Mol Oncol 2013; 7 (3): 334–345. doi: 10.1016/j.molonc.2012.10.011.

73. Abue M, Yokoyama M, Shibuya R. Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol 2015; 46 (2): 539–547. doi: 10.3892/ijo.2014.2743.