Skip to main content

Serum Biomarkers in Gastric Cancer

  • Chapter
  • First Online:
Book cover Gastric Cancer In The Precision Medicine Era

Part of the book series: Current Clinical Pathology ((CCPATH))

  • 625 Accesses

Abstract

Serum tumor markers are blood-based biomarkers that are potentially useful in cancer detection, surveillance following curative surgery, prediction of drug response or resistance, and monitoring therapy in advance setting.

International guidelines do not accept tumor markers in the process of gastric cancer (GC) diagnosis. Their usefulness in GC can be mainly acknowledged in monitoring the effectiveness of antineoplastic therapy and the surveillance period and in identifying patients at risk for GC. The majority of the commonly used tumor biomarkers are neither specific nor sensitive; moreover, the issue of the almost complete lack of prospectively validated data remains.

The four most frequently used tumor biomarkers in GC follow-up are carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), carbohydrate antigen 125 (CA 125), and carbohydrate antigen 72-4 (CA 72-4). In particular, the value of pretreatment serum CEA also represents an independent prognostic factor; CA 19-9 value is often used for the diagnosis of GC; CA 72-4 is considered the major marker for GC, mainly for detecting advanced stages; and elevated serum CA 125 levels are associated with a variety of benign and malignant causes of pelvic mass, including peritoneal metastasis of GC.

Specific gastric biomarkers, i.e., pepsinogen (PG) I, PGII, gastrin-17 (G-17), and anti-Helicobacter pylori (HP) antibodies, are being used to identify patients at risk for development of GC, particularly combined in a panel test (GastroPanel) which provides comprehensive information on both the structure and the function of the entire stomach mucosa.

In the era of precision medicine, liquid biopsy may represent a prognostic or predictive biomarker and a noninvasive tool for monitoring disease in terms of evaluation of response to systemic therapy as well as in monitoring clonal evolution. It could also be useful for screening and earlier detection, but patients with early stage disease often harbor a plasma concentration of mutant template molecules which is beyond the limit of detection of the most diffuse technologies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 99.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 129.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AG:

Atrophic gastritis

AUC:

Area under the curve

CA 19-9:

Carbohydrate antigen 19-9

CA 72-4:

Carbohydrate antigen 72-4

CA 125:

Carbohydrate antigen 125

CEA:

Carcinoembryonic antigen

cfDNA:

Cell-free DNA

CI:

Confidence interval

CTCs:

Circulating tumor cells

DSS:

Disease-specific survival

DFS:

Disease-free survival

G-17:

Gastrin-17

GC:

Gastric cancer

HP:

Helicobacter pylori

HR:

Hazard ratio

IgG:

Immunoglobulin G

IM:

Intestinal metaplasia

NCA:

Nonspecific cross-reacting antigen

OR:

Odds ratio

OS:

Overall survival

PG:

Pepsinogen

TAG-72:

Tumor-associated glycoprotein 72

References

  1. McShane LM, et al. Reporting recommendations for tumor marker prognostic studies. J Clin Oncol. 2005;23:9067–72.

    Article  PubMed  Google Scholar 

  2. Sun Z, Zhang N. Clinical evaluation of CEA, CA19-9, CA72-4 and CA125 in gastric cancer patients with neoadjuvant chemotherapy. World J Surg Oncol. 2014;12:397.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sturgeon CM, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem. 2010;56:e1–48.

    Article  CAS  PubMed  Google Scholar 

  4. Smyth EC, et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v38–49.

    Article  CAS  PubMed  Google Scholar 

  5. SyrjäNen K. A panel of serum biomarkers (GastroPanel®) in non-invasive diagnosis of atrophic gastritis. Systematic review and meta-analysis. Anticancer Res. 2016;36:5133–44.

    Article  PubMed  Google Scholar 

  6. Zagari RM, et al. Systematic review with meta-analysis: diagnostic performance of the combination of pepsinogen, gastrin-17 and anti-Helicobacter pylori antibodies serum assays for the diagnosis of atrophic gastritis. Aliment Pharmacol Ther. 2017;46:657–67.

    Article  CAS  PubMed  Google Scholar 

  7. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965;122:467–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Benchimol S, et al. Carcinoembryonic antigen, a human tumor marker, functions as an intercellular adhesion molecule. Cell. 1989;57:327–34.

    Article  CAS  PubMed  Google Scholar 

  9. Hammarström S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 1999;9:67–81.

    Article  PubMed  Google Scholar 

  10. Öbrink B. CEA adhesion molecules: multifunctional proteins with signal-regulatory properties. Curr Opin Cell Biol. 1997;9:616–26.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Burtis CA, Ashwood ER, Bruns DE. Tietz textbook of clinical chemistry and molecular diagnostics – E-book. St. Louis: Elsevier Health Sciences; 2012.

    Google Scholar 

  12. Sell S. Serological cancer markers. New York: Springer Science & Business Media; 2012.

    Google Scholar 

  13. Cascinu S, Labianca R. La Medicina Oncologica: Diagnosi, Terapia e gestione clinica. Milano: Edra Masson; 2015.

    Google Scholar 

  14. Deng K, et al. The prognostic significance of pretreatment serum CEA levels in gastric cancer: a meta-analysis including 14651 patients. PLoS One. 2015;10(4):e0124151.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Shimada H, Noie T, Ohashi M, Oba K, Takahashi Y. Clinical significance of serum tumor markers for gastric cancer: a systematic review of literature by the Task Force of the Japanese Gastric Cancer Association. Gastric Cancer. 2014;17:26–33.

    Article  CAS  PubMed  Google Scholar 

  16. Takahashi Y, et al. The usefulness of CEA and/or CA19-9 in monitoring for recurrence in gastric cancer patients: a prospective clinical study. Gastric Cancer. 2003;6:142–5.

    Article  PubMed  Google Scholar 

  17. Wang T, et al. Carbohydrate antigen 19-9-positive gastric adenocarcinoma: autopsy findings and review of the literature. Case Rep Gastroenterol. 2017;11:545–53.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Koprowski H, et al. Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic Cell Genet. 1979;5:957–71.

    Article  CAS  PubMed  Google Scholar 

  19. Hotakainen K, Tanner P, Alfthan H, Haglund C, Stenman U-H. Comparison of three immunoassays for CA 19-9. Clin Chim Acta. 2009;400:123–7.

    Article  CAS  PubMed  Google Scholar 

  20. Song Y, et al. Clinicopathologic and prognostic value of serum carbohydrate antigen 19-9 in gastric cancer: a meta-analysis. Dis Markers. 2015;2015:549843. https://doi.org/10.1155/2015/549843.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fernandes LL, et al. CA72-4 antigen levels in serum and peritoneal washing in gastric cancer: correlation with morphological aspects of neoplasia. Arq Gastroenterol. 2007;44:235–9.

    Article  PubMed  Google Scholar 

  22. Căinap C, et al. Classic tumor markers in gastric cancer. Current standards and limitations. Clujul Med. 2015;88:111–5.

    PubMed  PubMed Central  Google Scholar 

  23. Emoto S, et al. Clinical significance of CA125 and CA72-4 in gastric cancer with peritoneal dissemination. Gastric Cancer. 2012;15:154–61.

    Article  CAS  PubMed  Google Scholar 

  24. Sharma S. Tumor markers in clinical practice: general principles and guidelines. Indian J Med Paediatr Oncol. 2009;30:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen X-Z, et al. Correlation between serum CA724 and gastric cancer: multiple analyses based on Chinese population. Mol Biol Rep. 2012;39:9031–9.

    Article  CAS  PubMed  Google Scholar 

  26. Abbas M, et al. The relevance of gastric cancer biomarkers in prognosis and pre- and post- chemotherapy in clinical practice. Biomed Pharmacother. 2017;95:1082–90.

    Article  CAS  PubMed  Google Scholar 

  27. Aloe S, et al. Prognostic value of serum and tumor tissue CA 72-4 content in gastric cancer. Int J Biol Markers. 2008;18:21–7.

    Article  Google Scholar 

  28. Bast RC, et al. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest. 1981;68:1331–7.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yin BWT, Lloyd KO. Molecular cloning of the CA125 ovarian cancer antigen: identification as a new mucin, MUC16. J Biol Chem. 2001;276:27371–5.

    Article  CAS  PubMed  Google Scholar 

  30. Sturgeon CM, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem. 2008;54:e11–79.

    Article  CAS  PubMed  Google Scholar 

  31. Diamandis EP. Tumor markers: physiology, pathobiology, technology, and clinical applications. Washington, DC: American Association for Clinical Chemistry; 2002.

    Google Scholar 

  32. Kabawat SE, et al. Tissue distribution of a coelomic-epithelium-related antigen recognized by the monoclonal antibody OC125. Int J Gynecol Pathol. 1983;2:275–85.

    Article  CAS  PubMed  Google Scholar 

  33. Hwang GI, et al. Predictive value of preoperative serum CEA, CA19-9 and CA125 levels for peritoneal metastasis in patients with gastric carcinoma. Cancer Res Treat. 2004;36:178–81.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nakata B, et al. Serum CA 125 level as a predictor of peritoneal dissemination in patients with gastric carcinoma. Cancer. 1998;83:2488–92.

    Article  CAS  PubMed  Google Scholar 

  35. Samloff IM. Immunologic studies of human group I pepsinogens. J Immunol. 1971;1950(106):962–8.

    Google Scholar 

  36. Nasrollahzadeh D, et al. Accuracy and cut-off values of pepsinogens I, II and gastrin 17 for diagnosis of gastric fundic atrophy: influence of gastritis. PLoS One. 2011;6:e26957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Samloff IM, Varis K, Ihamaki T, Siurala M, Rotter JI. Relationships among serum pepsinogen I, serum pepsinogen II, and gastric mucosal histology. A study in relatives of patients with pernicious anemia. Gastroenterology. 1982;83:204–9.

    CAS  PubMed  Google Scholar 

  38. Slpponen P, Kekki M, Haapakoski J, Ihamäki T, Siurala M. Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data. Int J Cancer. 1985;35:173–7.

    Article  Google Scholar 

  39. Dinis-Ribeiro M, et al. Meta-analysis on the validity of pepsinogen test for gastric carcinoma, dysplasia or chronic atrophic gastritis screening. J Med Screen. 2004;11:141–7.

    Article  CAS  PubMed  Google Scholar 

  40. Huang Y, et al. Significance of serum pepsinogens as a biomarker for gastric cancer and atrophic gastritis screening: a systematic review and meta-analysis. PLoS One. 2015;10:e0142080.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Miki K. Gastric cancer screening by combined assay for serum anti-Helicobacter pylori IgG antibody and serum pepsinogen levels – ‘ABC method’. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:405–14.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lomba-Viana R, et al. Serum pepsinogen test for early detection of gastric cancer in a European Country. Eur J Gastroenterol Hepatol. 2012;24:37–41.

    Article  PubMed  Google Scholar 

  43. Farias CB, et al. Stimulation of proliferation of U138-MG glioblastoma cells by gastrin-releasing peptide in combination with agents that enhance cAMP signaling. Oncology. 2008;75:27–31.

    Article  CAS  PubMed  Google Scholar 

  44. Sawada M, Dickinson CJ. The G cell. Annu Rev Physiol. 1997;59:273–98.

    Article  CAS  PubMed  Google Scholar 

  45. Dockray GJ, Varro A, Dimaline R, Wang T. The gastrins: their production and biological activities. Annu Rev Physiol. 2001;63:119–39.

    Article  CAS  PubMed  Google Scholar 

  46. The EUROGAST Study Group. An international association between Helicobacter pylori infection and gastric cancer. Lancet. 1993;341:1359–63.

    Article  Google Scholar 

  47. Yamada T. Helicobacter pylori in peptic ulcer disease. JAMA J Am Med Assoc. 1994;272:65.

    Article  Google Scholar 

  48. Hallissey MT, Dunn JA, Fielding JW. Evaluation of pepsinogen A and gastrin-17 as markers of gastric cancer and high-risk pathologic conditions. Scand J Gastroenterol. 1994;29:1129–34.

    Article  CAS  PubMed  Google Scholar 

  49. Sun L, et al. A comprehensive evaluation of fasting serum gastrin-17 as a predictor of diseased stomach in Chinese population. Scand J Gastroenterol. 2014;49:1164–72.

    Article  CAS  PubMed  Google Scholar 

  50. Wang X, et al. The diagnostic value of gastrin-17 detection in atrophic gastritis: a meta-analysis. Medicine (Baltimore). 2016;95:e3599.

    Article  CAS  Google Scholar 

  51. Correa P. Chronic gastritis: a clinico-pathological classification. Am J Gastroenterol. 1988;83:504–9.

    CAS  PubMed  Google Scholar 

  52. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process – First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;52:6735–40.

    CAS  PubMed  Google Scholar 

  53. de Vries AC, Haringsma J, Kuipers EJ. The detection surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection. Helicobacter. 2007;12(1):1–15.

    Article  PubMed  Google Scholar 

  54. Agréus L, et al. Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol. 2012;47:136–47.

    Article  PubMed  PubMed Central  Google Scholar 

  55. De Re V, et al. Pepsinogens to distinguish patients with gastric intestinal metaplasia and Helicobacter pylori infection among populations at risk for gastric cancer. Clin Transl Gastroenterol. 2016;7:e183.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Syrjänen KJ, Sipponen P, Härkönen M, Peetsalu A, Korpela S. Accuracy of the GastroPanel test in the detection of atrophic gastritis. Eur J Gastroenterol Hepatol. 2015;27:102–4.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kurilovich S, et al. Stomach-specific Biomarkers (GastroPanel) can predict the development of gastric cancer in a Caucasian population: a longitudinal nested case-control study in Siberia. Anticancer Res. 2016;36:247–53.

    CAS  PubMed  Google Scholar 

  58. Perakis S, Speicher MR. Emerging concepts in liquid biopsies. BMC Med. 2017;15(1):75.

    Google Scholar 

  59. Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov. 2014;4:650–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bettegowda C, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra24.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Butler TM, Spellman PT, Gray J. Circulating-tumor DNA as an early detection and diagnostic tool. Curr Opin Genet Dev. 2017;42:14–21.

    Article  CAS  PubMed  Google Scholar 

  62. Nordgård O, Tjensvoll K, Gilje B, Søreide K. Circulating tumour cells and DNA as liquid biopsies in gastrointestinal cancer. Br J Surg. 2018;105:e110–20.

    Article  PubMed  Google Scholar 

  63. Bardelli A, Pantel K. Liquid Biopsies, What We Do Not Know (Yet). Cancer Cell. 2017;31:172–9.

    Article  CAS  PubMed  Google Scholar 

  64. Cohen JD, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018;359(6378):926–30. https://doi.org/10.1126/science.aar3247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fabio Puglisi .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Steffan, A., Cervo, S., Fanotto, V., Puglisi, F. (2019). Serum Biomarkers in Gastric Cancer. In: Canzonieri, V., Giordano, A. (eds) Gastric Cancer In The Precision Medicine Era. Current Clinical Pathology. Humana, Cham. https://doi.org/10.1007/978-3-030-04861-7_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-04861-7_6

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-04860-0

  • Online ISBN: 978-3-030-04861-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics