Barrett

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• Barretts surveillance
• Is there a case?
• Peter D. Siersema

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Wang et al. Am J Gastroenterol 2008 103788-97
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Barretts surveillance PRO

• Detection of adenocarcinoma at an earlier stage,
  .... Corley DA, et al.
  Gastroenterology 2002 122 633-40
• Cooper GS, et al. Cancer 2002 95 32-8
• Kearney DJ, et al. Gastrointest Endosc 2003
  57 823-9
• Fountoulakis, et al. Br J Surg 2004 91
  997-1003

surveillance-detected not
surveillance-detected
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Flow CYtometry in BARret esophagus (CYBAR study)
a prospective cohort study

• M.Sikkema1, M.Kerkhof1, E.W. Steyerberg2, H. van
  Dekken3, A.J. van Vuuren1, H.Geldof4, H. van der
  Valk5, R.J. Ouwendijk6, R. Giard7, W.
  Lesterhuis8, R. Heinhuis9, E.C. Klinkenberg10,
  G.A.Meijer11, F. ter Borg12, J.W. Arends13, J.J.
  Kolkman14, J. van Baarlen15, R.A. de Vries16,
  A.Mulder17, A. van Tilburg18, G.J.A.Offerhaus19,
  F.J.W. Ten Kate19, J.G. Kusters1, E.J. Kuipers1
  and P.D. Siersema1 for the CYBAR study group
• Depts. of Gastroenterology and Hepatology,
  ErasmusMC Rotterdam1, IJsselland Hospital Capelle
  a/d IJssel4, Ikazia Hospital Rotterdam6, Albert
  Schweizer Hospital Dordrecht8, VUMC Amsterdam10,
  Deventer Hospital Deventer12, Medisch Spectrum
  Twente Enschede14, Rijnstate Hospital Arnhem16,
  Sint Franciscus Gasthuis Rotterdam18Depts of
  Public Health2 and Pathology3, ErasmusMC
  Rotterdam PATHAN, Rotterdam5, Depts of
  Pathology, MCRZ Rotterdam7, Laboratory for
  Pathology Dordrecht9, VUMC Amsterdam11, Deventer
  Hospital Deventer13, Pathology Laboratory
  Enschede15, Rijnstate Hospital Arnhem17, UMC
  Utrecht19

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Barretts surveillance CYBAR study
N17 (71)
N703, FU 3 yrs, progression to HGD 14 or EAC
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Barretts surveillance PRO

• .. resulting in improved survival rates
  Corley DA, et al.
  Gastroenterology 2002 122 633-40
• Fountoulakis, et al. Br J Surg 2004 91
  997-1003

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Barretts surveillance PRO

• Barretts patients report less discomfort, pain
  and overall burden than patients with
  non-specific GI symptoms or esophageal
  cancer Kruijshaar, et al. Qual Life Res 2007
  161309-18

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Barretts surveillance PRO

• Surveillance at 2-year intervals would cost
  19,000 per live saved
• Armstrong. Best Pract Res Clin Gastroenterol
  2008 22 721-39

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Barretts surveillance PRO

• Surveillance at 2-year intervals would cost
  19,000 per live saved
• Armstrong. Best Pract Res Clin Gastroenterol
  2008 22 721-39
• More and less invasive treatment strategies are
  available for HGD and early adenocarcinoma
  (T1m1-3, sm1)

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Barretts surveillance PRO

• Surveillance at 2-year intervals would cost
  19,000 per live saved
• Armstrong. Best Pract Res Clin Gastroenterol
  2008 22 721-39
• More and less invasive treatment strategies are
  available for HGD and early adenocarcinoma
  (T1m1-3, sm1)
• As current guidelines recommend a surveillance
  strategy, legal aspects need to be considered

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Is surveillance of Barretts esophagus with
endoscopy indeed without discussion?
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Barretts surveillance CONTRA

• Intra- and interobserver variability in grading
  dysplasia is great Kerkhof et al. Histopathology
  2007 50 920-7
• Barretts esophagus is an unlikely cause of death
  (only 4 (6) of 105 patients after a mean FU of
  12.7 yrs.)
• Hage et al. Scand J Gastroenterol 2004 39
  1175-9
• The majority of cost-effectiveness acceptability
  curves show that surveillance is unlikely to be
  cost-effective
• Garside et al. Health Technol Assess 200711
  iii-iv, ix-221

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Barretts surveillance

• Imaging modalities to aid in detecting dysplasia
• NBI, FICE, Autofluorescence, Chromoendoscopy
• Confocal endomicroscopy, Endocytoscopy
• Chemoprevention to prevent progression towards
  malignancy in BE (ASPECT study)
• Biomarkers to detect the subgroup of patients
  with an increased risk of developing malignancy
  in BE

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Biomarkers in Barretts esophagus

• Biomarker Type of change Potential Use
• PCNA increased expression with proliferation
  / -
• Ki67 increased expression with proliferation
• p53 IHC (abnormal protein expression)
• LOH (frequent LOH at 17p13) / -
• p16 LOH at 9p21, early lesion -
• Cyclin D1 increased expression -
• ß-catenin increased nuclear expression -
• decreased membranous expression
• DNA ploidy aneuploidy with progression
• COX-2 increased expression -

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Flow cytometry
Diploid
(normal)
G1
G2/M
S
Aneuploid
Tetraploid
G1
G1
(abnormal)
(abnormal)
S
G2/M
S
G2/M
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Risk per surveillance arm
703 patients with BE 2 cm
Baseline ND n 604
Baseline LGD n 99
FC normal n471
FC abnormal n78
FC normal n84
FC abnormal n15
2 yr cum risk of progression 1.9 1.3 11.9 20
Log Rank p0.19 p0.19 p0.50 p0.50

one progression observed in pts without FC
analysis 1/52 1.9
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Other biomarkers
Retrospective study
BE without progression towards HGD/EAC
BE with progression towards HGD/EAC
n 27
n 28
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Biomarkers
Biopsies
Histology (HE)
IHC

• p53-staining
• Ki67-staining

p53
Ki67
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Results
HGD/EAC
Fraction LGD
HGD/EAC -
-15 -10 -5 0 Years before HGD/EAC
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Results
HGD/EAC
Fraction LGD
Fraction Ki67 expression
HGD/EAC -
-15 -10 -5 0 Years before HGD/EAC
-15 -10 -5 0 Years before HGD/EAC
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Results
Fraction LGD
Fraction Ki67 expression
-15 -10 -5 0 Years before HGD/EAC
-15 -10 -5 0 Years before HGD/EAC
HGD/EAC
Fraction p53 expression
HGD/EAC -
-15 -10 -5 0 Years before HGD/EAC
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Barretts surveillance Is there a case?

• YES, but this should
• not only be based on histology,
• but also include a panel of easy to use
  biomarkers,
• that is able to select the small group of
  Barretts patients at risk of progressing to
  malignancy

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