Transcript Surveillance and Diagnosis of Gastroesophageal Carcinoma

Surveillance and Diagnosis of
Gastroesophageal Carcinoma
David Watkins, MB BS, MRCP
Consultant Medical Oncologist
Gastrointestinal Cancer Unit
Royal Marsden Hospital
London and Surrey, United Kingdom
This program is supported by an educational donation from
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Program Faculty
Program Director:
Faculty:
Manish A. Shah, MD
David Watkins, MB BS, MRCP
Director, Gastrointestinal Oncology
Weill Cornell Medical College
NewYork-Presbyterian Hospital
New York, New York
Consultant Medical Oncologist
Gastrointestinal Cancer Unit
Royal Marsden Hospital
London and Surrey, United
Kingdom
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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.
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World Cancer Incidence
Stomach
8%
Stomach
16%
Stomach
7%
Stomach
8%
Esophagus
8%
Esophagus
7%
Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer.
2010;127:2893-2917.
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World Cancer Incidence
Stomach
~68,800
Stomach
~595,300
Stomach
~15,600
Stomach
~14,100
Esophagus
~7100
Esophagus
~15,500
Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer.
2010;127:2893-2917.
Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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World Cancer Incidence
Stomach
8%
Squamous cell
esophagus
Stomach
16%
Stomach
7%
Stomach
8%
Esophagus
8%
Esophagus
7%
Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer.
2010;127:2893-2917.
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Esophageal Cancer
Age-Standardized Incidence and Mortality:
Males
Southern Africa
Eastern Asia
Eastern Africa
World
Northern Europe
South-Central Asia
Western Europe
South America
Northern America
Central and Eastern Europe
Australia/New Zealand
Incidence
Mortality
Stomach Cancer
0
10
20
30
Rate per 100,000
40
Eastern Asia
Central and Eastern Europe
World
South America
Southern Europe
Central America
Western Asia
Caribbean
Southeastern Asia
Western Europe
Northern Europe
Incidence
Mortality
0
Cancer Research UK.
50
10
20
30
Rate per 100,000
40
50
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Age-Standardized Mortality Trends: Males
90
80
Stomach Cancer
11
Japan
UK
USA
10
Esophageal Cancer
Japan
UK
USA
9
70
60
50
40
30
Rate per 100,000
Rate per 100,000
8
7
6
5
4
3
20
10
0
1950 1960 1970 1980 1990 2000
Yr
World Health Organization. Mortality database.
2
1
0
1950 1960 1970 1980 1990 2000
Yr
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Age-Standardized Mortality Trends: Males
All Cancers
11
200
10
180
9
160
8
Rate per 100,000
Rate per 100,000
220
140
120
100
80
60
40
Japan
UK
USA
20
0
1950 1960 1970 1980 1990 2000
Yr
World Health Organization. Mortality database.
Esophageal Cancer
7
6
5
4
3
2
Japan
UK
USA
1
0
1950 1960 1970 1980 1990 2000
Yr
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Age-Standardized Mortality Trends:
Esophageal Cancer
55
Squamous Regions
11
Kazakhstan
Turkmenistan
Uzbekistan
50
45
10
9
35
30
25
20
7
6
5
4
15
3
10
2
5
1
0
1981
Japan
UK
USA
8
Rate per 100,000
Rate per 100,000
40
Esophageal Cancer
1991
2001
Yr
World Health Organization. Mortality database.
0
1950 1960 1970 1980 1990 2000
Yr
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Risk Factors for Gastroesophageal Cancer
Diet, alcohol, hot drinks,
tobacco smoking
Acid reflux, obesity,
smoking, diet
Esophagus
Gastroesophageal junction
Liver
Cardiac
sphincter
H. pylori, atrophic gastritis, diet
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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;120:16071619. 3. AGA, et al. Gastroeneterology. 2011;140:1084-1091.
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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.
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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.
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Data on H. pylori Eradication Studies
 Multicenter, prospective cohort
study 2000-2007 (Japan)[1]
 Randomized placebo-controlled
study 1994-2002 (China)[2]
– 4133 patients with H. pylorisensitive peptic ulcers elected
to undergo H. pylori eradication
or standard antacid therapy
– 1630 healthy H. pylori carriers
randomized to H. pylori
eradication vs placebo
– 56 gastric cancer cases with
mean follow-up of 5.6 yrs
– No significant incidence
difference with vs without
eradication treatment in
overall population (P = .33)
– Overall no significant difference
in incidence with vs without
eradication therapy
– Incidence ratio: 0.58
(95% CI: 0.28-1.19)
– 18 gastric cancer cases
– 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.
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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
Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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Trends in Obesity
80
USA
England
Spain
Austria
Australia
France
Korea
Canada
Italy
Proportion Overweight (%)
70
60
50
40
30
20
10
0
1970
1980
1990
2000
Yr
Wang YC, et al. Lancet. 2011;378:815-825.
2010
2020
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Aspirin as Primary Prevention
1.8
Randomised trail data
Significant effect (P < .05)
Trend (P < .1)
No effect (P > .1)
Case-control studies (odds ratio)
1.6
Renal
1.4
Endometrial
1.2
Bladder
1.0
0.8
Pancreatic
Ovarian
Lymphoma
Prostate Melanoma
Breast
Gastric
Lung
Leukemia Colorectal
0.6
Biliary Esphageal
(no cohort data)
0.4
0.4
0.6
0.8
1.0
1.2
Cohorts (risk ratio)
Algra AM, et al. Lancet Oncol. 2012;13:518-527.
1.4
1.6
1.8
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Aspirin as Primary Prevention – AspECT
Study
 A phase III, randomized study of aspirin and esomeprazole
chemoprevention in Barrett's metaplasia
2500 Patients –
Recruitment completed
Esomeprazole
Clinicaltrials.gov. NCT00357682.
Randomize
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Transition From Normal Mucosa to
Barrett’s Esophagus
Damage to
squamous
epithelium
Mutagenic
effects
Facilitating
molecular
events
 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.
Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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Transition From Barrett’s Esophagus
to Invasive Cancer
Genomic
instability[1]
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.
Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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Transition From Barrett’s Esophagus
to Invasive Cancer
Individual 1
A
89%
A
69%
A
51%
B
11%
B
31%
C
49%
21 cM
G
91%
D
100%
A
68%
35 cM
E
100%
F
100%
C
32%
33 cM
Incidence of esophageal
adenocarcinoma
Shannon index = 1.60
Divergence = 0.21
H
9%
I
100%
I
100%
I
100%
I
100%
H
100%
J
100%
P < .001
0.8
Genetic divergence,
upper quartile
0.4
0.2
Lower 3 quartiles
0.0
0
22 cM
Individual 3
1 2 3 4 5 6
Yrs of follow-up
7
Maley CC, et al. Nature Genetics. 2006;38:468-473.
K
100%
L
100%
K
100%
24 cM
28 cM
Shannon index = 1.15
Divergence = 0.05
1.0
0.6
Individual 4
Incidence of esophageal
adenocarcinoma
Biopsies:
Individual 2
A
100%
21 cM
30 cM
Shannon index = 0.64
Divergence = 0.27
M
100%
M
100%
M
100%
M
100%
M
100%
Shannon index = 0
Divergence = 0
1.0
P = .044
0.8
0.6
Segment length,
upper quartile
0.4
0.2
Lower 3 quartiles
0.0
0
1 2 3 4 5 6
Yrs of follow-up
7
140
120
100
0
Beroukhim R, et al.
Nature. 2010;463:899-905.
Myeloproliferative Disorder
Myxoid Liposarcoma
Acute Lymphoblastic Leukemia
Synovial Sarcoma
Medulloblastoma
Neuroblastoma
Renal
GIST
Hepatocellular
Non-Hodgkin’s Lymphoma
Colorectal
Glioma
Mesothelioma
All Cancers
Thyroid
Melanoma
Prostate
Leiomyosarcoma
NSCL
Ovarian
SCL
Breast
Gastric
Esophageal Squamous
Esophageal Adenocarcinoma
Pleomorphic Liposarcoma
Malignant Fibrous Histiocytoma
Dedifferentiated Liposarcoma
SCNAs
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Tumor Heterogeneity
Average Number of SCNAs per Tumor Type
Amplifications
Deletions
80
60
40
20
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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.
Gastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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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.
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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.
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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
Deng N, et al. Gut. 2012;61:673-684.
FGFR2
KRAS
ERBB2
= 72/193 (37.3%)
EGFR
MET
RTK/RAS absent
 Data suggest that ≥ 37%
of gastric cancer cases
may be responsive to
RTK/RAS-targeted therapy
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Implications of Genetic Heterogeneity
Solid tumors often show
heterogeneity
Subpopulations with differing
molecular characteristics
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
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Implications of Genetic Heterogeneity
Targeted therapy
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
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Implications of Genetic Heterogeneity
Targeted therapy
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
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Implications of Genetic Heterogeneity
Targeted therapy
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
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Acquired Resistance to Targeted
Therapies
Acquired resistance
targeted therapy
Clonal selection of resistant
subpopulation
Need for biopsies at the time of
disease progression
Evidence of relevance in
NSCLC
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
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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
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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
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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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