Review Article

Investigational Biomarkers for Pancreatic Adenocarcinoma: Where Do We Stand?

Authors: Jashodeep Datta, MD, Charles M. Vollmer, MD

Abstract

Although the outcomes for pancreatic ductal adenocarcinoma (PDAC) remain disappointing, there has been considerable improvement in the 5-year survival rate of patients with resectable disease. As such, an R0 surgical resection (microscopic tumor clearance) offers patients with PDAC the greatest survival benefit. Carbohydrate antigen 19-9, the only US Food and Drug Administration-approved biomarker for PDAC, is a poor screening tool and is most informative after PDAC resection. Consequently, there has been a tremendous initiative to discover novel biomarkers that may aid in detecting the disease earlier, improving prognosis, and predicting response to available chemotherapy. The number of implicated biomarkers in PDAC is indeed staggering, with >2500 proposed candidates presented in the recent literature. A vast majority of these biomarkers, however, remain in the investigational phase. This review categorizes the most promising biomarkers-those closest to potential clinical application-into diagnostic and prognostic/predictive groups. The greatest challenge likely lies in the search for an effective diagnostic biomarker that can accurately discriminate between malignant and benign disease, and thereby facilitate earlier identification of those patients with PDAC who may benefit most from surgical resection.

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References

1. Lewis R, Drebin JA, Callery MP, et al. A contemporary analysis of survival for resected pancreatic ductal adenocarcinoma.HPB (Oxford)2013;15:49-60.
 
2. Harsha HC, Kandasamy K, Ranganathan P, et al. A compendium of potential biomarkers of pancreatic cancer. PLoS Med 2009;6:e1000046.
 
3. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69:89-95.
 
4. Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19-9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol 2012;3:105-119.
 
5. Locker GY, Hamilton S, Harris J, et al. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol 2006;24:5313-5327.
 
6. Berger AC, Garcia M Jr, Hoffman JP, et al. Postresection CA 19-9 predicts overall survival in patients with pancreatic cancer treated with adjuvant chemoradiation: a prospective validation by RTOG 9704. J Clin Oncol 2008;26:5918-5922.
 
7. Humphris JL, Chang DK, Johns AL, et al. The prognostic and predictive value of serumCA19.9 in pancreatic cancer. Ann Oncol2012;23:1713-1722.
 
8. Reni M, Cereda S, Balzano G, et al. Carbohydrate antigen 19-9 change during chemotherapy for advanced pancreatic adenocarcinoma. Cancer 2009;115:2630-2639.
 
9. Halm U, Schumann T, Schiefke I, et al. Decrease of CA 19-9 during chemotherapy with gemcitabine predicts survival time in patients with advanced pancreatic cancer. Br J Cancer 2000;82:1013-1016.
 
10. Goonetilleke KS, Siriwardena AK. Systematic review of carbohydrate antigen (CA 19-9) as a biochemical marker in the diagnosis of pancreatic cancer. Eur J Surg Oncol 2007;33:266-270.
 
11. Duraker N, Hot S, Polat Y, et al. CEA, CA 19-9, and CA 125 in the differential diagnosis of benign and malignant pancreatic diseases with or without jaundice. J Surg Oncol 2007;95:142-47.
 
12. Waldman SA, Hyslop T, Schulz S, et al. Association of GUCY2C expression in lymph nodes with time to recurrence and disease-free survival in pN0 colorectal cancer. JAMA 2009;301:745-752.
 
13. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004;351:2817-2826.
 
14. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2716.
 
15. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:408-1417.
 
16. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status vas a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003;349:247-257.
 
17. Fong ZV, Winter JM. Biomarkers in pancreatic cancer: diagnostic, prognostic, and predictive. Cancer J 2012;18:530-538.
 
18. Koopmann J, Buckhaults P, Brown DA, et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 2004;10:2386:2392.
 
19. Koopmann J, Fedarko NS, Jain A, et al. Evaluation of osteopontin as biomarker for pancreatic adenocarcinoma. Cancer Epidemiol Biomarkers Prev 2004;13:487-491.
 
20. Ozkan H, Kaya M, Cengiz A. Comparison of tumor marker CA 242 with CA 19-9 and carcinoembryonic antigen (CEA) in pancreatic cancer. Hepatogastroenterology 2003;50:1669-1674.
 
21. Dabritz J, Preston R, Hanfler J, et al. Follow-up study of K-ras mutations in the plasma of patients with pancreatic cancer: correlation with clinical features and carbohydrate antigen 19-9. Pancreas 2009;38:534-541.
 
22. Sturm PD, Hruban RH, Ramsoekh TB, et al. The potential diagnostic use of K-ras codon 12 and p53 alterations in brush cytology from the pancreatic head region. J Pathol 1998;186:247-253.
 
23. Brand RE, Nolen BM, Zeh HJ, et al. Serum biomarker panels for the detection of pancreatic cancer. Clin Cancer Res 2011;17:805-816.
 
24. Ohuchida K, Mizumoto K, Egami T, et al. S100P is an early developmental marker of pancreatic carcinogenesis.Clin Cancer Res 2006;12:5411-5416.
 
25. OuYang D, Xu J, Huang H, et al. Metabolomic profiling of serum from human pancreatic cancer patients using 1H NMR spectroscopy and principal component analysis. Appl Biochem Biotechnol 2011;165:148-154.
 
26. Liu R, Chen X, Du Y, et al. Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer. Clin Chem 2012;58:610-618.
 
27. Bausch D, Thomas S, Mino-Kenudson M, et al. Plectin-1 as a novel biomarker for pancreatic cancer. Clin Cancer Res 2011;17:302-309.
 
28. Corcoran RB, Contino G, Deshpande V, et al. STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 2011;71:1-10.
 
29. Gold DV, Karanjawala Z, Modrak DE, et al. PAM4-reactive MUC1 is a biomarker for early pancreatic adenocarcinoma. Clin Cancer Res 2007;13:7380-7387.
 
30. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008;321:1801-1806.
 
31. Khaled YS, Elkord E, Ammori BJ. Macrophage inhibitory cytokine-1: a review of its pleiotropic actions in cancer. Cancer Biomark 2012;11:183-190.
 
32. Poruk KE, Firpo MA, Scaife CL, et al. Serum osteopontin and tissue inhibitor of metalloproteinase 1 as diagnostic and prognostic biomarkers for pancreatic adenocarcinoma. Pancreas 2013;42:193-197.
 
33. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988;53:549-554.
 
34. Singh P, Srinivasan R, Wig JD. Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. Pancreas 2011;40:644-652.
 
35. Hustinx SR, Leoni LM, Yeo CJ, et al. Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol 2005;18:959-963.
 
36. van Heek T, Rader AE, Offerhaus GJ, et al. K-ras, p53, and DPC4 (MAD4) alterations in fine-needle aspirates of the pancreas: a molecular panel correlates with and supplements cytologic diagnosis. Am J Clin Pathol 2002;117:755-765.
 
37. Gronborg M, Bunkenborg J, Kristiansen TZ, et al. Comprehensive proteomic analysis of human pancreatic juice. J Proteome Res 2004;3:1042-1055.
 
38. Wingren C, Sandstrom A, Segersvard R, et al. Identification of serum biomarker signatures associated with pancreatic cancer. Cancer Res 2012;72:2481-2490.
 
39. Kell DB. Metabolomic biomarkers: search, discovery and validation. Expert Rev Mol Diagn 2007;7:329-333.
 
40. LaConti JJ, Shivapurkar N, Preet A, et al. Tissue and serum microRNAs in the Kras(G12D) transgenic animal model and in patients with pancreatic cancer. PLoS One 2011;6:e20687.
 
41. He X, Zheng Z, Li J, et al. DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. Carcinogenesis 2012;33:555-562.
 
42. Crane CH, Varadhachary GR, Yordy JS, et al. Phase II trial of cetuximab, gemcitabine, and oxaliplatin followed by chemoradiation with cetuximab for locally advanced (T4) pancreatic adenocarcinoma: correlation of Smad4(Dpc4) immunostaining with pattern of disease progression. J Clin Oncol 2011;29:3037-3043.
 
43. Winter JM, Tang LH, Klimstra DS, et al. Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression. Ann Surg 2013;258:331-335.
 
44. Stratford JK, Bentrem DJ, Anderson JM, et al. A six-gene signature predicts survival of patients with localized pancreatic ductal adenocarcinoma. PLoS Med 2010;7:e1000307.
 
45. Uchikura K, Takao S, Nakajo A, et al. Intraoperative molecular detection of circulating tumor cells by reverse transcription-polymerase chain reaction in patients with biliary-pancreatic cancer is associated with hematogenous metastasis. Ann Surg Oncol 2002;9:364-370.
 
46. Perez-Torras S, Garcıa-Manteiga J, Mercade´ E, et al. Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT1) enhances gemcitabine response in human pancreatic cancer. Biochem Pharmacol 2008;76:322-329.
 
47. Akita H, Zheng Z, Takeda Y, et al. Significance of RRM1 and ERCC1 expression in resectable pancreatic adenocarcinoma. Oncogene 2009;28:2903-2909.
 
48. Richards NG, Rittenhouse DW, Freydin B, et al. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg 2010;252:499-506.
 
49. Mantoni TS, Schendel RR, Rodel F, et al. Stromal SPARC expression and patient survival after chemoradiation for non-resectable pancreatic adenocarcinoma. Cancer Biol Ther 2008;7:1806-1815.
 
50. Donahue TR, Tran LM, Hill R, et al. Integrative survival-based molecular profiling of human pancreatic cancer.Clin Cancer Res 2012;18:1352-1363.
 
51. Winter JM, Tang LH, Klimstra DS, et al. A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers. PLoS One 2012;7:e40157.
 
52. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation. Cell 2012;148:349-361.
 
53. Khoja L, Backen A, Sloane R, et al. A pilot study to explore circulating tumour cells in pancreatic cancer as a novel biomarker. Br J Cancer 2012;106:508-517.
 
54. Alberts SR. K-ras inhibitors and pancreatic cancer. In: Lowy AM, Leach SD, Philip PA, eds. Pancreatic Cancer: M.D. Anderson Solid Tumor Oncology Series. New York: Springer; 2008:601-607.
 
55. Gallmeier E, Kern SE. Targeting Fanconi anemia/BRCA2 pathway defects in cancer: the significance of preclinical pharmacogenomic models. Clin Cancer Res 2007;13:4-10.