david watkins, mb bs, mrcp consultant medical oncologist gastrointestinal cancer unit royal marsden...

David Watkins, MB BS, MRCPConsultant Medical OncologistGastrointestinal Cancer UnitRoyal Marsden HospitalLondon and Surrey, United Kingdom

Surveillance and Diagnosis of Gastroesophageal Carcinoma

This program is supported by an educational donation from

clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy

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Program Faculty

Program Director:Manish A. Shah, MDDirector, Gastrointestinal OncologyWeill Cornell Medical CollegeNewYork-Presbyterian HospitalNew York, New York

Faculty:David Watkins, MB BS, MRCPConsultant Medical OncologistGastrointestinal Cancer UnitRoyal Marsden HospitalLondon and Surrey, United Kingdom


Faculty Disclosures

Manish A. Shah, MD, has disclosed that he has received consulting fees and contracted research support from Genentech and sanofi-aventis.

David Watkins, MB BS, MRCP, has no significant financial relationships to disclose.


Stomach 8%

Stomach 8%

Esophagus8%

Esophagus8%

Esophagus7%

Esophagus7%

Stomach 7%

Stomach 7%

Stomach 16%

Stomach 16%

Stomach 8%

Stomach 8%

World Cancer Incidence

Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer. 2010;127:2893-2917.




Stomach ~14,100

Stomach ~14,100

Stomach ~68,800

Stomach ~68,800

Stomach ~595,300

Stomach ~595,300

Stomach ~15,600

Stomach ~15,600

Esophagus~15,500

Esophagus~15,500

Esophagus~7100

Esophagus~7100


Stomach 8%

Stomach 8%

Esophagus8%

Esophagus8%

Esophagus7%

Esophagus7%

Stomach 7%

Stomach 7%

Stomach 16%

Stomach 16%

Stomach 8%

Stomach 8%



Squamous cell esophagus


Rate per 100,000

Eso

ph

agea

l C

ance

r

IncidenceMortality

Sto

mac

h C

an

cer

Age-Standardized Incidence and Mortality: Males

0 10 20 30 40 50

Southern AfricaEastern Asia

Eastern AfricaWorld

Northern EuropeSouth-Central Asia

Western EuropeSouth America

Northern AmericaCentral and Eastern Europe

Australia/New Zealand

Rate per 100,000

IncidenceMortality

0 10 20 30 40 50

Eastern AsiaCentral and Eastern Europe

WorldSouth America

Southern EuropeCentral America

Western AsiaCaribbean

Southeastern AsiaWestern EuropeNorthern Europe

Cancer Research UK.


Stomach Cancer

World Health Organization. Mortality database.

Age-Standardized Mortality Trends: Males

JapanUKUSA

90

80

70

60

50

40

30

20

10

0

Rat

e p

er 1

00,0

00

1950 1960 1970 1980 1990 2000Yr

Esophageal CancerJapanUKUSA

11

10

7

6

5

4

3

2

1

0

Rat

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00,0

00

1950 1960 1970 1980 1990 2000Yr

9

8



Age-Standardized Mortality Trends: Males

All Cancers

JapanUKUSA

220

200

180

160

140

120

100

80

60

0

Rat

e p

er 1

00,0

00

1950 1960 1970 1980 1990 2000Yr

Esophageal Cancer

JapanUKUSA

11

10

7

6

5

4

3

2

1

0

Rat

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00,0

00

1950 1960 1970 1980 1990 2000Yr

9

8

40

20



Age-Standardized Mortality Trends: Esophageal Cancer

KazakhstanTurkmenistanUzbekistan

55

50

45

40

35

30

25

20

15

0

Rat

e p

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00,0

00

1981 1991 2001Yr

JapanUKUSA

11

10

7

6

5

4

3

2

1

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Rat

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00

1950 1960 1970 1980 1990 2000Yr

9

8

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Esophageal CancerSquamous Regions


H. pylori, atrophic gastritis, diet

Acid reflux, obesity, smoking, diet

Diet, alcohol, hot drinks, tobacco smoking

Risk Factors for Gastroesophageal Cancer

Esophagus

Gastroesophageal junction

Cardiac sphincterLiver


Barrett’s Esophagus

GERD: principle risk factor for Barrett’s esophagus[1]

Only 1% to 3% of patients will develop cancer[2]

Assessed endoscopically, histologically[3]

– Length of segment

– Grade of dysplasia

– Low grade: antireflux therapy (medical) recommended, followed by endoscopic surveillance every 6-12 mos

– High grade: antireflux therapy, followed by repeat endoscopic assessment and specialist review.

– Potential role for EMR, ablative therapy, surgery

1. Jemal A, et al. CA Cancer J Clin. 2011;61:69-90. 2. Schnell TG, et al. Gastroenterology. 2001;120:1607-1619. 3. AGA, et al. Gastroeneterology. 2011;140:1084-1091.


Screening and Surveillance for Barrett’s Esophagus BOSS: Barrett’s Esophagus Surveillance Study[1]

– Endoscopy with biopsy every 2 yrs for 10 yrs vs endoscopy as indicated[1]

1. Clinicaltrials.gov. NCT00987857. 2. Kadri SR, et al. BMJ.2010;341:c4372. 3. Lao-Sirieix P, et al. Gut. 2009;58:1451-1459. 4. Cancer Research UK.


Screening and Surveillance for Barrett’s Esophagus BOSS: Barrett’s Esophagus Surveillance Study[1]

– Endoscopy with biopsy every 2 yrs for 10 yrs vs endoscopy as indicated[1]

Identification of Barrett’s in the general population

– Cytosponge as a nonendoscopic procedure for the detection of Barrett’s esophagus in primary care[2]

– Microarray datasets were used to identify putative biomarkers present in Barrett’s esophagus but absent from normal mucosa[3]

– Trefoil factor 3 – marker of Barrett’s esophagus[3]

– Under evaluation in BEST2 study; 500-700 cases and 500-700 controls[4]

1. Clinicaltrials.gov. NCT00987857. 2. Kadri SR, et al. BMJ.2010;341:c4372. 3. Lao-Sirieix P, et al. Gut. 2009;58:1451-1459. 4. Cancer Research UK.


Data on H. pylori Eradication Studies

Multicenter, prospective cohort study 2000-2007 (Japan)[1]

– 4133 patients with H. pylori-sensitive peptic ulcers elected to undergo H. pylori eradication or standard antacid therapy

– 56 gastric cancer cases with mean follow-up of 5.6 yrs

– Overall no significant difference in incidence with vs without eradication therapy

– Incidence ratio: 0.58 (95% CI: 0.28-1.19)

Randomized placebo-controlled study 1994-2002 (China)[2]

– 1630 healthy H. pylori carriers randomized to H. pylori eradication vs placebo

– 18 gastric cancer cases

– No significant incidence difference with vs without eradication treatment in overall population (P = .33)

– In subgroup without precancerous lesions at entry (n = 988), eradication treatment was associated with significant reduction in gastric cancer incidence (P = .02)

1. Mabe K, et al. World J Gastroenterol. 2009;15:2490-2497. 2. Wong BC, et al. JAMA. 2004;291:187-194.


Dietary/Lifestyle Factors and Cancer Incidence Strong associations of stomach cancer with the intake of highly salted

foods including salted fish and pickled vegetables

A diet high in fresh fruit and vegetables seems to reduce the risk of esophageal cancer

Higher levels of selenium in the blood were shown to reduce the risk of esophageal cancer by almost 50%

Obesity roughly doubles the risk of adenocarcnima of the esophagus; accounts for approximately 20% of cases

Smoking tobacco and excess alcohol are some of the main risk factors for esophageal cancer in the Western parts of the world

Chewing tobacco or betel quid is also associated with an increased risk of cancer of the esophagus


Wang YC, et al. Lancet. 2011;378:815-825.

Trends in Obesity

80

70

60

50

40

30

20

10

0

Pro

po

rtio

n O

verw

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ht

(%)

1970 1980 1990 2000 2010 2020Yr

USAEnglandSpainAustriaAustraliaFranceKoreaCanadaItaly


Randomised trail dataSignificant effect (P < .05)Trend (P < .1)No effect (P > .1)

Algra AM, et al. Lancet Oncol. 2012;13:518-527.

Aspirin as Primary Prevention

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

Ca

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Cohorts (risk ratio)0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Renal

Endometrial

BladderPancreatic

LymphomaMelanoma

Lung

OvarianProstate

BreastGastric

Esphageal

ColorectalLeukemia

Biliary(no cohort data)


2500 Patients – Recruitment completed

Clinicaltrials.gov. NCT00357682.

Aspirin as Primary Prevention – AspECT Study A phase III, randomized study of aspirin and esomeprazole

chemoprevention in Barrett's metaplasia

Randomize

Esomeprazole


Transition From Normal Mucosa to Barrett’s Esophagus

Exposure of multipotential stem cells to acid results in abnormal differentiation

Potential involvement of stromal factors

Ongoing exposure to gastric acid Nitric oxide from dietary nitrates

Upregulation of COX2: increase invasion, proliferation Altered p16: deregulation of cell-cycle checkpoint Deregulation of p53: deregulation of genomic maintenance

Zhang HY, et al. Cancer Lett. 2009;275:170-177.


Transition From Barrett’s Esophagusto Invasive Cancer

P9 LOH P17 LOH DNA content abnormality

Characteristic genomic heterogeneity[2]

1. Zhang HY, et al. Cancer Lett. 2009;275:170-177. 2. Jankowski JA, et al. Am J Pathol. 1999; 154: 965-973.


A100%

Transition From Barrett’s Esophagus to Invasive Cancer

Maley CC, et al. Nature Genetics. 2006;38:468-473.

P < .0011.0

0.8

0.6

0.4

0.2

0.0

Inc

ide

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f e

so

ph

ag

ea

la

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0 1 2 3 5 64 7Yrs of follow-up

Genetic divergence, upper quartile

Lower 3 quartiles

P = .0441.0

0.8

0.6

0.4

0.2

0.0

Inc

ide

nc

e o

f e

so

ph

ag

ea

la

de

no

ca

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0 1 2 3 5 64 7Yrs of follow-up

Segment length, upper quartile

Lower 3 quartiles

Individual 1 Individual 2

Individual 3

Individual 4

Biopsies:

21 cM

35 cM 33 cM

21 cM

24 cM

28 cM 30 cM

22 cM

A89%

B11%

A69%

B31%

A51%

C49%

D100%

E100%

F100%

A68%

C32%

Shannon index = 1.60Divergence = 0.21



Shannon index = 0Divergence = 0

G91%

H9%

I100%

I100%

I100%

I100%

H100%

J100%

K100%

L100%

K100%

M100%

M100%

M100%

M100%

M100%


Tumor HeterogeneityAverage Number of SCNAs per Tumor Type

AmplificationsDeletions

SC

NA

s140

120

100

80

60

40

20

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Beroukhim R, et al. Nature. 2010;463:899-905.


Molecular Drivers and Therapeutic Targets

Chromosomal instability is the most common phenotype

High-level gene amplification is a late event

– Most frequently observed amplification events

– ERBB2

– CCNE1

– KRAS

– EGFR

– CCND1

– C-MYC

Miller CT, et al. Clin Cancer Res. 2003;9:4819-4825.


Molecular Drivers and Therapeutic Targets

Chromosomal instability is the most common phenotype High-level gene amplification is a late event

– Most frequently observed amplification events

– ERBB2 - proven

– CCNE1 - ? targetable

– KRAS - ? targetable

– EGFR – targetable - unproven

– CCND1 - ? targetable

– C-MYC - ? targetable

Identification of the proliferative drivers should result in active novel treatment options

Miller CT, et al. Clin Cancer Res. 2003;9:4819-4825.


Molecular Classification of Gastric Cancer Using cDNA Expression Analysis Gastric cancers treated uniformly, despite epidemiologic,

anatomic, and histopathologic distinctions between subtypes

Can subtypes be distinguished by gene expression analysis?

– Patients with localized gastric cancers (N = 36)

– cDNA expression analysis of endoscopic biopsy tissues by microarray

Proximal nondiffuse, diffuse, and distal nondiffuse gastric cancers can be distinguished by gene signatures

– Supervised classification: > 85% success in distinguishing subtypes

Shah MA, et al. Clin Cancer Res. 2011;17:2693-2701.


Deng N, et al. Gut. 2012;61:673-684.

Molecular Tumor Characterization and Classification Comprehensive genome

analysis of 233 gastric cancer samples and 98 matched nonmalignant gastric samples

22 recurrent alterations identified

– 13 amplifications; 9 deletions

– Included known targets and novel genes

– Mutual exclusivity of alterations identified

5 distinct gastric cancer subgroups defined by specific alterations

Data suggest that ≥ 37% of gastric cancer cases may be responsive to RTK/RAS-targeted therapy

= 72/193 (37.3%)FGFR2KRASERBB2

EGFRMETRTK/RAS absent


Solid tumors often show heterogeneity

Subpopulations with differing molecular characteristics

Implications of Genetic Heterogeneity

Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.


Implications of Genetic Heterogeneity

Targeted therapy



Acquired Resistance to Targeted Therapies

Clonal selection of resistant subpopulation

Need for biopsies at the time of disease progression

Evidence of relevance in NSCLC

Acquired resistancetargeted therapy



Novel Methods for Molecular Assessment

Analysis of circulating tumor cells

– Currently limited by technology (~ 50% of patients)

– New platforms in development

– Suitable for all biomarker analysis

– Potential to replace tissue biopsy

Analysis of circulating tumor DNA

– Tumor DNA mutational testing

– Potential for broader role?

Imaging biomarkers

– Radiolabeled targeted agents


Conclusions

Wide variation in global incidence

– Diet, life style, H. pylori

Falling incidence of gastric and squamous cancer

Barrett’s/esophageal carcinoma

– Rising incidence

– Screening strategies being studied

– Needs better markers to predict risk of progression

Knowledge of the molecular drivers will lead to new therapies


NCI’s 24 Provocative Questions

How does obesity contribute to cancer risk?

What environmental factors change the risk of various cancers when people move from 1 geographic region to another?

Why don't more people alter behaviors known to increase the risk of cancers?

Given the evidence that some drugs commonly and chronically used for other indications, such as an anti-inflammatory drug, can protect against cancer incidence and mortality, can we determine the mechanism by which any of these drugs work?

Are there definable properties of a nonmalignant lesion that predict the likelihood of progression to invasive or metastatic disease?

National Cancer Institute Provocative Questions Project.

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david watkins, mb bs, mrcp consultant medical oncologist gastrointestinal cancer unit royal marsden...

Documents

new directions

int j cancer

new yorkfaculty

comoncology carcinoma

ferlay j

targeted therapystomach

targeted therapyabout

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