david watkins, mb bs, mrcp consultant medical oncologist gastrointestinal cancer unit royal marsden...
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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
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clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
Squamous cell esophagus
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
e p
er 1
00,0
00
1950 1960 1970 1980 1990 2000Yr
9
8
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
World Health Organization. Mortality database.
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
e p
er 1
00,0
00
1950 1960 1970 1980 1990 2000Yr
9
8
40
20
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
World Health Organization. Mortality database.
Age-Standardized Mortality Trends: Esophageal Cancer
KazakhstanTurkmenistanUzbekistan
55
50
45
40
35
30
25
20
15
0
Rat
e p
er 1
00,0
00
1981 1991 2001Yr
JapanUKUSA
11
10
7
6
5
4
3
2
1
0
Rat
e p
er 1
00,0
00
1950 1960 1970 1980 1990 2000Yr
9
8
10
5
Esophageal CancerSquamous Regions
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
eig
ht
(%)
1970 1980 1990 2000 2010 2020Yr
USAEnglandSpainAustriaAustraliaFranceKoreaCanadaItaly
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
se
-co
ntr
ol
stu
die
s (
od
ds
ra
tio
)
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)
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
nc
e o
f e
so
ph
ag
ea
la
de
no
ca
rcin
om
a
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
rcin
om
a
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 = 1.15Divergence = 0.05
Shannon index = 0.64Divergence = 0.27
Shannon index = 0Divergence = 0
G91%
H9%
I100%
I100%
I100%
I100%
H100%
J100%
K100%
L100%
K100%
M100%
M100%
M100%
M100%
M100%
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
Tumor HeterogeneityAverage Number of SCNAs per Tumor Type
AmplificationsDeletions
SC
NA
s140
120
100
80
60
40
20
0
My
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life
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Ac
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Beroukhim R, et al. Nature. 2010;463:899-905.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
Implications of Genetic Heterogeneity
Targeted therapy
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
Implications of Genetic Heterogeneity
Targeted therapy
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
Implications of Genetic Heterogeneity
Targeted therapy
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically 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
Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted 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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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
clinicaloptions.com/oncologyGastroesophageal Carcinoma: New Directions in Mechanistically Targeted Therapy
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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