Barrett’s Esophagus and Esophageal Carcinoma: Can Biomarkers Guide Clinical Practice?

  • Vani J. A. Konda
  • Rhonda F. SouzaEmail author
GI Oncology (R Bresalier, Section Editor)
Part of the following topical collections:
  1. Topical Collection on GI Oncology


Purpose of Review

Despite gastrointestinal societal recommendations for endoscopic screening and surveillance of Barrett’s esophagus, the rates of esophageal adenocarcinoma continue to rise. Furthermore, this current practice is costly to patients and the medical system without clear evidence of reduction in cancer mortality. The use of biomarkers to guide screening, surveillance, and treatment strategies might alleviate some of these issues.

Recent Findings

Incredible advances in biomarker identification, biomarker assays, and minimally-invasive modalities to acquire biomarkers have shown promising results.


We will highlight recently published, key studies demonstrating where we are with using biomarkers for screening and surveillance in clinical practice, and what is on the horizon regarding novel non-invasive and minimally invasive methods to acquire biomarkers. Proof-of principle studies using in silico models demonstrate that biomarker-guided screening, surveillance, and therapeutic intervention strategies can be cost-effective and can reduce cancer deaths in patients with Barrett’s esophagus.


Screening Surveillance Gastroesophageal reflux disease Endoscopic Imaging Tissue 



Vani J.A. Konda, M.D. has served as a consultant for and received research support from Pentax/C2 therapeutics and has past received research support from Olympus. Rhonda F. Souza, M.D. has served as a consultant and receives research support from Ironwood Pharmaceuticals.

Funding Information

This work was supported by the National Institutes of Health (R01 DK103598, R01 DK063621, R21 DK111369 to R.F.S.)

Compliance with Ethical Standards

Conflict of Interest

Rhonda Souza reports grants from National Institutes of Health and research support as a consultant from Ironwood Pharmaceuticals, outside the submitted work.

Vani Konda reports grants from Olympus, honoraria for teaching events from Mauna Kea Technologies, and grants from Pentax/C2 Therapeutics, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Spechler SJ, Souza RF. Barrett’s esophagus. N Engl J Med. 2014;371(9):836–45. Scholar
  2. 2.
    Thrift AP. Barrett’s esophagus and esophageal adenocarcinoma: how common are they really? Dig Dis Sci. 2018;63(8):1988–96. Scholar
  3. 3.
    Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):1084–91. Scholar
  4. 4.
    Shaheen NJ, Falk GW, Iyer PG, Gerson LB. ACG clinical guideline: diagnosis and management of Barrett’s esophagus. Am J Gastroenterol. 2016;111(1):30–50; quiz 1. Scholar
  5. 5.
    Fitzgerald RC, di Pietro M, Ragunath K, Ang Y, Kang JY, Watson P, et al. British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut. 2014;63(1):7–42. Scholar
  6. 6.
    El-Serag HB, Naik AD, Duan Z, Shakhatreh M, Helm A, Pathak A, et al. Surveillance endoscopy is associated with improved outcomes of oesophageal adenocarcinoma detected in patients with Barrett’s oesophagus. Gut. 2016;65(8):1252–60. Scholar
  7. 7.
    Corley DA, Mehtani K, Quesenberry C, Zhao W, de Boer J, Weiss NS. Impact of endoscopic surveillance on mortality from Barrett's esophagus-associated esophageal adenocarcinoma. Gastroenterology. 2013;145(2):312–9.e1. Scholar
  8. 8.
    Dulai GS, Guha S, Kahn KL, Gornbein J, Weinstein WM. Preoperative prevalence of Barrett's esophagus in esophageal adenocarcinoma: a systematic review. Gastroenterology. 2002;122(1):26–33.CrossRefGoogle Scholar
  9. 9.
    Hvid-Jensen F, Pedersen L, Drewes AM, Sorensen HT, Funch-Jensen P. Incidence of adenocarcinoma among patients with Barrett's esophagus. N Engl J Med. 2011;365(15):1375–83. Scholar
  10. 10.
    Pohl H, Sirovich B, Welch HG. Esophageal adenocarcinoma incidence: are we reaching the peak? Cancer Epidemiol Biomarkers Prev. 2010;19(6):1468–70. Scholar
  11. 11.
    Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol. 2012;23(12):3155–62. Scholar
  12. 12.
    Shaheen NJ, Sharma P, Overholt BF, Wolfsen HC, Sampliner RE, Wang KK, et al. Radiofrequency ablation in Barrett’s esophagus with dysplasia. N Engl J Med. 2009;360(22):2277–88. Scholar
  13. 13.
    Phoa KN, van Vilsteren FG, Weusten BL, Bisschops R, Schoon EJ, Ragunath K, et al. Radiofrequency ablation vs endoscopic surveillance for patients with Barrett esophagus and low-grade dysplasia: a randomized clinical trial. JAMA. 2014;311(12):1209–17. Scholar
  14. 14.
    Ell C, Pech O, May A. Radiofrequency ablation in Barrett’s esophagus. N Engl J Med. 2009;361(10):1021; author reply 2–2. Scholar
  15. 15.
    Eluri S, Brugge WR, Daglilar ES, Jackson SA, Styn MA, Callenberg KM, et al. The presence of genetic mutations at key loci predicts progression to esophageal adenocarcinoma in Barrett’s esophagus. Am J Gastroenterol. 2015;110(6):828–34. Scholar
  16. 16.
    Critchley-Thorne RJ, Davison JM, Prichard JW, Reese LM, Zhang Y, Repa K, et al. A tissue systems pathology test detects abnormalities associated with prevalent high-grade dysplasia and esophageal Cancer in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev. 2017;26(2):240–8. Scholar
  17. 17.
    Ek WE, Levine DM, D’Amato M, Pedersen NL, Magnusson PK, Bresso F, et al. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett's esophagus, and gastroesophageal reflux. J Natl Cancer Inst. 2013;105(22):1711–8. Scholar
  18. 18.
    Buas MF, He Q, Johnson LG, Onstad L, Levine DM, Thrift AP, et al. Germline variation in inflammation-related pathways and risk of Barrett’s oesophagus and oesophageal adenocarcinoma. Gut. 2017;66(10):1739–47. Scholar
  19. 19.
    Su Z, Gay LJ, Strange A, Palles C, Band G, Whiteman DC, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat Genet. 2012;44(10):1131–6. Scholar
  20. 20.
    Palles C, Chegwidden L, Li X, Findlay JM, Farnham G, Castro Giner F, et al. Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett’s esophagus. Gastroenterology. 2015;148(2):367–78. Scholar
  21. 21.
    Levine DM, Ek WE, Zhang R, Liu X, Onstad L, Sather C, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat Genet. 2013;45(12):1487–93. Scholar
  22. 22.
    Dai JY, de Dieu TJ, Buas MF, Onstad LE, Levine DM, Risch HA, et al. A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett's esophagus. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015;24(11):1739–47. Scholar
  23. 23.
    • Kunzmann AT, Canadas Garre M, Thrift AP, McMenamin UC, Johnston BT, Cardwell CR, et al. Information on genetic variants does not increase identification of individuals at risk of esophageal adenocarcinoma compared to clinical risk factors. Gastroenterology. 2018. Assessment of genetic susceptibility markers combined with known clinical risk factors to predict risk of esophageal adenocarcinoma development.
  24. 24.
    Bus P, Kestens C, Ten Kate FJ, Peters W, Drenth JP, Roodhart JM, et al. Profiling of circulating microRNAs in patients with Barrett’s esophagus and esophageal adenocarcinoma. J Gastroenterol. 2016;51(6):560–70. Scholar
  25. 25.
    Davelaar AL, Calpe S, Lau L, Timmer MR, Visser M, Ten Kate FJ, et al. Aberrant TP53 detected by combining immunohistochemistry and DNA-FISH improves Barrett’s esophagus progression prediction: a prospective follow-up study. Genes Chromosomes Cancer. 2015;54(2):82–90. Scholar
  26. 26.
    •• Stachler MD, Camarda ND, Deitrick C, Kim A, Agoston AT, Odze RD, et al. Detection of mutations in Barrett’s esophagus before progression to high-grade dysplasia or adenocarcinoma. Gastroenterology. 2018;155(1):156–67. Case-control study demonstrating that abnormalities in p53 dectected by IHC in patients with non-dysplastic Barrett’s esophagus can predict neoplastic progression. This study also demonstrated a strong, but not perfect, correlation between p53 mutations dected by gene sequencing and p53 overexpression by IHC.CrossRefPubMedGoogle Scholar
  27. 27.
    Souza RF, Spechler SJ. Concepts in the prevention of adenocarcinoma of the distal esophagus and proximal stomach. CA Cancer J Clin. 2005;55(6):334–51.CrossRefGoogle Scholar
  28. 28.
    Spechler SJ, Sharma P, Souza RF, Inadomi JM, Shaheen NJ. American Gastroenterological Association technical review on the management of Barrett’s esophagus. Gastroenterology. 2011;140(3):e18–52; quiz e13. Scholar
  29. 29.
    •• Choi WT, Tsai JH, Rabinovitch PS, Small T, Huang D, Mattis AN, et al. Diagnosis and risk stratification of Barrett’s dysplasia by flow cytometric DNA analysis of paraffin-embedded tissue. Gut. 2018;67(7):1229–38. DNA content abnormalities were tested in paraffin-embedded tissues of Barrett’s patients with high grade, low grade or indefinite for dysplasia and negative for dysplasia. DNA content abnormality correlated with increasing levels of dysplasia and could identify patients with indefinite or negative for dysplasia who are at high risk for subsequent progression to high grade dysplasia or cancer.CrossRefPubMedGoogle Scholar
  30. 30.
    Prichard JW, Davison JM, Campbell BB, Repa KA, Reese LM, Nguyen XM, et al. TissueCypher(): a systems biology approach to anatomic pathology. J Pathol Inform. 2015;6:48. Scholar
  31. 31.
    Critchley-Thorne RJ, Duits LC, Prichard JW, Davison JM, Jobe BA, Campbell BB, et al. A tissue systems pathology assay for high-risk Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev. 2016;25(6):958–68. Scholar
  32. 32.
    •• Januszewicz W, Tan WK, Lehovsky K, Debiram-Beecham I, Nuckcheddy T, Moist S, et al. Safety and acceptability of a nonendoscopic esophageal sampling device - cytosponge: a systematic review of multicenter data. Clin Gastroenterol Hepatol. 2018. This multicenter experience reports the safety and acceptability using the string on a sponge test for sampling of esophageal cells without endoscopy.
  33. 33.
    Kadri SR, Lao-Sirieix P, O’Donovan M, Debiram I, Das M, Blazeby JM, et al. Acceptability and accuracy of a non-endoscopic screening test for Barrett’s oesophagus in primary care: cohort study. BMJ. 2010;341:c4372. Scholar
  34. 34.
    Ross-Innes CS, Debiram-Beecham I, O'Donovan M, Walker E, Varghese S, Lao-Sirieix P, et al. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett’s esophagus: a multi-center case-control study. PLoS Med. 2015;12(1):e1001780. Scholar
  35. 35.
    Iyer PG, Taylor WR, Johnson ML, Lansing RL, Maixner KA, Yab TC, et al. Highly discriminant methylated DNA markers for the non-endoscopic detection of Barrett’s esophagus. Am J Gastroenterol. 2018;113(8):1156–66. Scholar
  36. 36.
    Ross-Innes CS, Chettouh H, Achilleos A, Galeano-Dalmau N, Debiram-Beecham I, MacRae S, et al. Risk stratification of Barrett's oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study. Lancet Gastroenterol Hepatol. 2017;2(1):23–31. Scholar
  37. 37.
    Richardson C, Colavita P, Dunst C, Bagnato J, Billing P, Birkenhagen K, et al. Real-time diagnosis of Barrett’s esophagus: a prospective, multicenter study comparing confocal laser endomicroscopy with conventional histology for the identification of intestinal metaplasia in new users. Surg Endosc. 2018.
  38. 38.
    Wallace M, Lauwers GY, Chen Y, Dekker E, Fockens P, Sharma P, et al. Miami classification for probe-based confocal laser endomicroscopy. Endoscopy. 2011;43(10):882–91. Scholar
  39. 39.
    •• Gaddam S, Mathur SC, Singh M, Arora J, Wani SB, Gupta N, et al. Novel probe-based confocal laser endomicroscopy criteria and interobserver agreement for the detection of dysplasia in Barrett’s esophagus. Am J Gastroenterol. 2011;106(11):1961–9. Key criteria for confocal laser endomicroscopy to distinguish between dysplastic and non-dysplastic tissue in Barrett’s esophagus.CrossRefPubMedGoogle Scholar
  40. 40.
    Sharma P, Meining AR, Coron E, Lightdale CJ, Wolfsen HC, Bansal A, et al. Real-time increased detection of neoplastic tissue in Barrett’s esophagus with probe-based confocal laser endomicroscopy: final results of an international multicenter, prospective, randomized, controlled trial. Gastrointest Endosc. 2011;74(3):465–72. Scholar
  41. 41.
    Sturm MB, Joshi BP, Lu S, Piraka C, Khondee S, Elmunzer BJ, et al. Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: first-in-human results. Sci Transl Med. 2013;5(184):184ra61. Scholar
  42. 42.
    • Sauk J, Coron E, Kava L, Suter M, Gora M, Gallagher K, et al. Interobserver agreement for the detection of Barrett’s esophagus with optical frequency domain imaging. Dig Dis Sci. 2013;58(8):2261–5. Study using volumetrc laser endomicrosopy demonstrating excellent interobserver variability to distinguish between squamous, gastric cardia, and Barrett’s esophagus.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Gora MJ, Simmons LH, Queneherve L, Grant CN, Carruth RW, Lu W, et al. Tethered capsule endomicroscopy: from bench to bedside at a primary care practice. J Biomed Opt. 2016;21(10):104001. Scholar
  44. 44.
    Evans JA, Poneros JM, Bouma BE, Bressner J, Halpern EF, Shishkov M, et al. Optical coherence tomography to identify intramucosal carcinoma and high-grade dysplasia in Barrett’s esophagus. Clin Gastroenterol Hepatol. 2006;4(1):38–43.CrossRefGoogle Scholar
  45. 45.
    Leggett CL, Gorospe EC, Chan DK, Muppa P, Owens V, Smyrk TC, et al. Comparative diagnostic performance of volumetric laser endomicroscopy and confocal laser endomicroscopy in the detection of dysplasia associated with Barrett’s esophagus. Gastrointest Endosc. 2016;83(5):880–8.e2. Scholar
  46. 46.
    Swager AF, Tearney GJ, Leggett CL, van Oijen MGH, Meijer SL, Weusten BL, et al. Identification of volumetric laser endomicroscopy features predictive for early neoplasia in Barrett’s esophagus using high-quality histological correlation. Gastrointestinal endoscopy. 2017;85(5):918–26.e7. Scholar
  47. 47.
    Lee HC, Ahsen OO, Liang K, Wang Z, Figueiredo M, Giacomelli MG, et al. Endoscopic optical coherence tomography angiography microvascular features associated with dysplasia in Barrett’s esophagus (with video). Gastrointestinal endoscopy. 2017;86(3):476–84.e3. Scholar
  48. 48.
    Kumar S, Huang J, Abbassi-Ghadi N, Mackenzie HA, Veselkov KA, Hoare JM, et al. Mass spectrometric analysis of exhaled breath for the identification of volatile organic compound biomarkers in esophageal and gastric adenocarcinoma. Ann Surg. 2015;262(6):981–90. Scholar
  49. 49.
    Chan DK, Zakko L, Visrodia KH, Leggett CL, Lutzke LS, Clemens MA, et al. Breath testing for Barrett’s esophagus using exhaled volatile organic compound profiling with an electronic nose device. Gastroenterology. 2017;152(1):24–6. Scholar
  50. 50.
    • Spechler SJ, Katzka DA, Fitzgerald RC. New screening techniques in Barrett’s esophagus: great ideas or great practice? Gastroenterology. 2018;154(6):1594–601. Commentary on approaches to screening for Barrett’s esophagus, whether they are ready for rountine clinical practice, and the hurdles that still need to be overcome before they are put into clincal practice.CrossRefPubMedGoogle Scholar
  51. 51.
    • Heberle CR, Omidvari AH, Ali A, Kroep S, Kong CY, Inadomi JM, et al. Cost effectiveness of screening patients with gastroesophageal reflux disease for Barrett's esophagus with a minimally invasive cell sampling device. Clin Gastroenterol Hepatol. 2017;15(9):1397–404.e7. Computer modeling study demonstrating that using a biomarker-based sponge on a string screening-surveillance-therapeutic strategy has the potential not only to decrease deaths from esophageal adenocarcinoma but also the associated costs when this strategy is used compared with no screening or conventional endoscopic screening.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Das A, Wells C, Kim HJ, Fleischer DE, Crowell MD, Sharma VK. An economic analysis of endoscopic ablative therapy for management of nondysplastic Barrett's esophagus. Endoscopy. 2009;41(5):400–8. Scholar
  53. 53.
    • Das A, Callenberg KM, Styn MA, Jackson SA. Endoscopic ablation is a cost-effective cancer preventative therapy in patients with Barrett’s esophagus who have elevated genomic instability. Endosc Int Open. 2016;4(5):E549–59. Computer modeling study demonstrating that biomarker-guided RFA for patients with non-dysplastic Barrett’s esophagus yielded the highest number of quality of life years at the lowest cost and the fewest cancers being diagnosed over the lifetime of the cohort compared with no surveillance, current American College of Gastroenterology recommended surveillance, and RFA of all patients with non-dysplastic Barrett’s esophagus.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Medicine and the Center for Esophageal DiseasesBaylor University Medical CenterDallasUSA
  2. 2.The Center for Esophageal ResearchBaylor Scott and White Research Institute, Baylor University Medical CenterDallasUSA

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