Barrett’s surveillance: Barrett’s surveillance:

Is there a case?Is there a case?

Peter D. SiersemaPeter D. Siersema

Wang et al. Am J Gastroenterol 2008: 103:788-97Wang et al. Am J Gastroenterol 2008: 103:788-97

Barrett’s surveillance: PROBarrett’s surveillance: PRO

• Detection of adenocarcinoma at an earlier stage, ....Detection of adenocarcinoma at an earlier stage, ....

Corley DA, et al.Corley DA, et al. Gastroenterology 2002; 122: 633- Gastroenterology 2002; 122: 633-

4040Cooper GS, et al. Cooper GS, et al. Cancer 2002; 95: 32-8Cancer 2002; 95: 32-8Kearney DJ, et al. Gastrointest Endosc 2003; 57: Kearney DJ, et al. Gastrointest Endosc 2003; 57:

823-9823-9Fountoulakis, et al. Br J Surg 2004; 91: 997-1003Fountoulakis, et al. Br J Surg 2004; 91: 997-1003

surveillance-detectedsurveillance-detected

not surveillance-detectednot surveillance-detected

Flow CYtometry in BARret esophagus Flow CYtometry in BARret esophagus (CYBAR study): a prospective cohort study(CYBAR study): a prospective cohort study

M.SikkemaM.Sikkema11, M.Kerkhof, M.Kerkhof11, E.W. Steyerberg, E.W. Steyerberg22, H. van Dekken, H. van Dekken33, A.J. van Vuuren, A.J. van Vuuren11, H.Geldof, H.Geldof44, H. van der Valk, H. van der Valk55, , R.J. OuwendijkR.J. Ouwendijk66, R. Giard, R. Giard77, W. Lesterhuis, W. Lesterhuis88, R. Heinhuis, R. Heinhuis99, E.C. Klinkenberg, E.C. Klinkenberg1010, G.A.Meijer, G.A.Meijer1111, F. ter Borg, F. ter Borg1212, ,

J.W. ArendsJ.W. Arends1313, J.J. Kolkman, J.J. Kolkman1414, J. van Baarlen, J. van Baarlen1515, R.A. de Vries, R.A. de Vries1616, A.Mulder, A.Mulder1717, A. van Tilburg, A. van Tilburg1818, , G.J.A.OfferhausG.J.A.Offerhaus1919, F.J.W. Ten Kate, F.J.W. Ten Kate1919, J.G. Kusters, J.G. Kusters11, E.J. Kuipers, E.J. Kuipers11 and P.D. Siersema and P.D. Siersema11 for the CYBAR study for the CYBAR study

groupgroup

Depts. of Gastroenterology and Hepatology, ErasmusMC RotterdamDepts. of Gastroenterology and Hepatology, ErasmusMC Rotterdam11, IJsselland Hospital Capelle a/d , IJsselland Hospital Capelle a/d IJsselIJssel44, Ikazia Hospital Rotterdam, Ikazia Hospital Rotterdam66, Albert Schweizer Hospital Dordrecht, Albert Schweizer Hospital Dordrecht88, VUMC Amsterdam, VUMC Amsterdam1010, Deventer , Deventer Hospital DeventerHospital Deventer1212, Medisch Spectrum Twente Enschede, Medisch Spectrum Twente Enschede1414, Rijnstate Hospital Arnhem, Rijnstate Hospital Arnhem1616, Sint Franciscus , Sint Franciscus

Gasthuis RotterdamGasthuis Rotterdam1818Depts of Public HealthDepts of Public Health22 and Pathology and Pathology33, ErasmusMC Rotterdam; PATHAN, , ErasmusMC Rotterdam; PATHAN, RotterdamRotterdam55, Depts of Pathology, MCRZ Rotterdam, Depts of Pathology, MCRZ Rotterdam77, Laboratory for Pathology Dordrecht, Laboratory for Pathology Dordrecht99, VUMC , VUMC

AmsterdamAmsterdam1111, Deventer Hospital Deventer, Deventer Hospital Deventer1313, Pathology Laboratory Enschede, Pathology Laboratory Enschede1515, Rijnstate Hospital Arnhem, Rijnstate Hospital Arnhem1717, , UMC UtrechtUMC Utrecht1919

Barrett’s surveillance: Barrett’s surveillance: CYBAR studyCYBAR study

0

2

4

6

8

10

12

14

HGD T1m T1sm T2 T3 T4

N=703, FU: 3 yrs, progression to HGD: 14 or EAC: 10N=703, FU: 3 yrs, progression to HGD: 14 or EAC: 10

N=17 (71%)N=17 (71%)

• …….. resulting in improved survival rates.. resulting in improved survival rates

Corley DA, et al.Corley DA, et al. Gastroenterology 2002; 122: 633- Gastroenterology 2002; 122: 633-

4040Fountoulakis, et al. Br J Surg 2004; 91: 997-1003Fountoulakis, et al. Br J Surg 2004; 91: 997-1003

Barrett’s surveillance: PROBarrett’s surveillance: PRO

• Barrett’s patients report less discomfort, pain and Barrett’s patients report less discomfort, pain and overall burden than patients with non-specific GI overall burden than patients with non-specific GI symptoms or esophageal cancersymptoms or esophageal cancer

Kruijshaar,Kruijshaar, et al. et al. Qual Life Res 2007; Qual Life Res 2007;

16:1309-1816:1309-18

Barrett’s surveillance: PROBarrett’s surveillance: PRO

• Surveillance at 2-year intervals would cost Surveillance at 2-year intervals would cost

£19,000 per live saved£19,000 per live savedArmstrong. Best Pract Res Clin

Gastroenterol 2008; 22: 721-39

Barrett’s surveillance: PROBarrett’s surveillance: PRO

• Surveillance at 2-year intervals would cost Surveillance at 2-year intervals would cost

£19,000 per live saved£19,000 per live savedArmstrong. Best Pract Res Clin Armstrong. Best Pract Res Clin

Gastroenterol 2008; 22: 721-39Gastroenterol 2008; 22: 721-39

• More and less invasive treatment strategies are More and less invasive treatment strategies are

available for HGD and early adenocarcinoma available for HGD and early adenocarcinoma

(T1(T1m1-3, sm1m1-3, sm1))

Barrett’s surveillance: PROBarrett’s surveillance: PRO

• Surveillance at 2-year intervals would cost Surveillance at 2-year intervals would cost £19,000 per £19,000 per

live savedlive savedArmstrong. Best Pract Res Clin Gastroenterol Armstrong. Best Pract Res Clin Gastroenterol

2008; 22: 721-392008; 22: 721-39

• More and less invasive treatment strategies are More and less invasive treatment strategies are

available for HGD and early adenocarcinoma (T1available for HGD and early adenocarcinoma (T1m1-3, sm1m1-3, sm1))

• As current guidelines recommend a surveillance As current guidelines recommend a surveillance

strategy, legal aspects need to be consideredstrategy, legal aspects need to be considered

Barrett’s surveillance: PROBarrett’s surveillance: PRO

Is surveillance of Barrett’s esophagus Is surveillance of Barrett’s esophagus

with endoscopy indeed with endoscopy indeed

without discussion?without discussion?

• ImagingImaging modalities to aid in detecting dysplasia modalities to aid in detecting dysplasia NBI, FICE, Autofluorescence, ChromoendoscopyNBI, FICE, Autofluorescence, Chromoendoscopy Confocal endomicroscopy, Confocal endomicroscopy, Endocytoscopy Endocytoscopy

• ChemopreventionChemoprevention to prevent progression towards to prevent progression towards malignancy in BE (ASPECT study) malignancy in BE (ASPECT study)

• BiomarkersBiomarkers to detect the subgroup of patients with to detect the subgroup of patients with an increased risk of developing malignancy in BEan increased risk of developing malignancy in BE

Barrett’s surveillanceBarrett’s surveillance

Biomarkers in Barrett’s esophagusBiomarkers in Barrett’s esophagusBiomarkerBiomarker Type of changeType of change Potential UsePotential Use

PCNAPCNA increased expression with proliferationincreased expression with proliferation + / -+ / -Ki67Ki67 increased expression with proliferationincreased expression with proliferation ++

p53p53 IHC (abnormal protein expression)IHC (abnormal protein expression) ++LOH (frequent LOH at 17p13)LOH (frequent LOH at 17p13) + / -+ / -

p16p16 LOH at 9p21, early lesionLOH at 9p21, early lesion --

Cyclin D1Cyclin D1 increased expressionincreased expression --

ββ-catenin-catenin increased nuclear expressionincreased nuclear expression --decreased membranous expressiondecreased membranous expression

DNA ploidyDNA ploidy aneuploidy with progressionaneuploidy with progression ++

COX-2COX-2 increased expressionincreased expression --

Kerkhof et al. Kerkhof et al. Cell Oncol 2007; 29: 507-17Cell Oncol 2007; 29: 507-17

Diploid

Aneuploid Tetraploid

G1

G1G1

S

S

S

G2/MG2/M

G2/M

(normal)

(abnormal) (abnormal)

Flow cytometryFlow cytometry

2 yr cum 2 yr cum risk of risk of progressiprogressionon

1.9%1.9% 1.3%1.3%

11.9%11.9% 20%20%

Log RankLog Rank p=0.19p=0.19 p=0.50p=0.50

703 patients with BE ≥ 2 cm

Baseline ND n = 604 Baseline LGD n = 99

FC normal n=471

FC abnormal n=78

FC normal n=84

FC abnormal n=15

Risk per surveillance armRisk per surveillance arm

one progression observed in pts without FC analysis: 1/52 = 1.9%

Retrospective study

BE with progression towards HGD/EAC

BE without progression towards HGD/EAC

n = 27 n = 28

Other biomarkersOther biomarkers

Biopsies

Histology (H&E)

IHC: • p53-staining

• Ki67-stainingp53

Ki67

BiomarkersBiomarkers

Fraction LGD

-15 -10 -5 0Years before HGD/EAC

HGD/EAC +HGD/EAC +

HGD/EAC -HGD/EAC -

ResultsResults

Fraction Ki67 expression

Fraction LGD

-15 -10 -5 0Years before HGD/EAC

-15 -10 -5 0Years before HGD/EAC

HGD/EAC +HGD/EAC +

HGD/EAC -HGD/EAC -

ResultsResults

Fraction Ki67 expression

Fraction LGD

Fraction p53 expression

-15 -10 -5 0Years before HGD/EAC

-15 -10 -5 0Years before HGD/EAC

-15 -10 -5 0Years before HGD/EAC

HGD/EAC +HGD/EAC +

HGD/EAC -HGD/EAC -

ResultsResults

Barrett’s surveillance: Barrett’s surveillance: Is there a case?Is there a case?

YESYES, but this should: , but this should:

not only be based on not only be based on histologyhistology, ,

but also include a panel of easy to use but also include a panel of easy to use

biomarkersbiomarkers, ,

that is able to select the small group of Barrett’s that is able to select the small group of Barrett’s

patients at risk of patients at risk of progressing to malignancyprogressing to malignancy