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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. About These Slides.

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Surveillance and Diagnosis of Gastroesophageal Carcinoma

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  1. Surveillance and Diagnosis ofGastroesophageal Carcinoma David Watkins, MB BS, MRCP Consultant Medical Oncologist Gastrointestinal Cancer UnitRoyal Marsden HospitalLondon and Surrey, United Kingdom This program is supported by an educational donation from

  2. About These Slides • Our thanks to the presenters who gave permission to include their original data • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Program Faculty Program Director: Manish A. Shah, MDDirector, Gastrointestinal Oncology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York Faculty: David Watkins, MB BS, MRCPConsultant Medical OncologistGastrointestinal Cancer Unit Royal Marsden Hospital London and Surrey, United Kingdom

  4. 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.

  5. World Cancer Incidence Stomach 8% Stomach 16% Stomach 7% Stomach 8% Esophagus 7% Esophagus 8% Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer. 2010;127:2893-2917.

  6. World Cancer Incidence Stomach ~68,800 Stomach ~595,300 Stomach ~15,600 Stomach ~14,100 Esophagus ~15,500 Esophagus ~7100 Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer. 2010;127:2893-2917.

  7. World Cancer Incidence Stomach 8% Squamous cell esophagus Stomach 16% Stomach 7% Stomach 8% Esophagus 7% Esophagus 8% Cancer Research UK. GLOBOCAN 2008 v. 1.2. Cancer incidence and mortality worldwide. Ferlay J, et al. Int J Cancer. 2010;127:2893-2917.

  8. Age-Standardized Incidence and Mortality: Males Southern Africa Eastern Asia Eastern Africa World Northern Europe Esophageal Cancer South-Central Asia Incidence Mortality Western Europe South America Northern America Central and Eastern Europe Australia/New Zealand 0 10 20 30 40 50 Rate per 100,000 Eastern Asia Central and Eastern Europe World South America Southern Europe Central America Stomach Cancer Incidence Mortality Western Asia Caribbean Southeastern Asia Western Europe Northern Europe 0 10 20 30 40 50 Cancer Research UK. Rate per 100,000

  9. Age-Standardized Mortality Trends: Males Stomach Cancer Esophageal Cancer 90 11 JapanUKUSA JapanUKUSA 10 80 9 70 8 60 7 50 6 Rate per 100,000 Rate per 100,000 5 40 4 30 3 20 2 10 1 0 0 1950 1960 1970 1980 1990 2000 1950 1960 1970 1980 1990 2000 Yr Yr World Health Organization. Mortality database.

  10. Age-Standardized Mortality Trends: Males All Cancers Esophageal Cancer 220 11 JapanUKUSA JapanUKUSA 200 10 180 9 160 8 140 7 120 6 Rate per 100,000 Rate per 100,000 100 5 80 4 60 3 40 2 20 1 0 0 1950 1960 1970 1980 1990 2000 1950 1960 1970 1980 1990 2000 Yr Yr World Health Organization. Mortality database.

  11. Age-Standardized Mortality Trends: Esophageal Cancer Squamous Regions Esophageal Cancer 55 11 KazakhstanTurkmenistanUzbekistan JapanUKUSA 50 10 45 9 40 8 35 7 30 6 Rate per 100,000 Rate per 100,000 25 5 20 4 15 3 10 2 5 1 0 0 1981 1991 2001 1950 1960 1970 1980 1990 2000 Yr Yr World Health Organization. Mortality database.

  12. Risk Factors for Gastroesophageal Cancer Diet, alcohol, hot drinks, tobacco smoking Acid reflux, obesity, smoking, diet Esophagus Gastroesophageal junction Cardiac sphincter H. pylori, atrophic gastritis, diet Liver

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. Trends in Obesity 80 USAEnglandSpainAustriaAustraliaFranceKoreaCanadaItaly 70 60 50 Proportion Overweight (%) 40 30 20 10 0 1970 1980 1990 2000 2010 2020 Yr Wang YC, et al. Lancet. 2011;378:815-825.

  19. Aspirin as Primary Prevention 1.8 Randomised trail dataSignificant effect (P < .05)Trend (P < .1)No effect (P > .1) 1.6 Renal 1.4 Endometrial 1.2 Bladder Case-control studies (odds ratio) Pancreatic 1.0 Ovarian Lymphoma Prostate Melanoma 0.8 Lung Breast Gastric Leukemia Colorectal 0.6 Esphageal Biliary(no cohort data) 0.4 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Cohorts (risk ratio) Algra AM, et al. Lancet Oncol. 2012;13:518-527.

  20. Aspirin as Primary Prevention – AspECT Study • A phase III, randomized study of aspirin and esomeprazole chemoprevention in Barrett's metaplasia 2500 Patients – Recruitment completed Randomize Esomeprazole Clinicaltrials.gov. NCT00357682.

  21. 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.

  22. 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.

  23. Transition From Barrett’s Esophagus to Invasive Cancer Individual 1 Individual 2 A100% 21 cM M100% M100% M100% M100% M100% A89% B11% G91% H9% 21 cM Individual 4 I100% I100% I100% I100% A69% B31% 22 cM A51% C49% Biopsies: D100% Individual 3 K100% 24 cM A68% C32% H100% E100% L100% F100% K100% 35 cM 33 cM 28 cM 30 cM J100% Shannon index = 1.60Divergence = 0.21 Shannon index = 1.15Divergence = 0.05 Shannon index = 0.64Divergence = 0.27 Shannon index = 0Divergence = 0 1.0 1.0 P < .001 P = .044 0.8 0.8 Genetic divergence, upper quartile 0.6 0.6 Incidence of esophagealadenocarcinoma Incidence of esophagealadenocarcinoma Segment length, upper quartile 0.4 0.4 0.2 0.2 Lower 3 quartiles Lower 3 quartiles 0.0 0.0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Yrs of follow-up Yrs of follow-up Maley CC, et al. Nature Genetics. 2006;38:468-473.

  24. Tumor Heterogeneity Average Number of SCNAs per Tumor Type 140 120 AmplificationsDeletions 100 80 SCNAs 60 40 20 0 Synovial Sarcoma Non-Hodgkin’s Lymphoma Melanoma Breast Gastric Myeloproliferative Disorder Neuroblastoma Renal Mesothelioma NSCL Ovarian Esophageal Adenocarcinoma Pleomorphic Liposarcoma Myxoid Liposarcoma Medulloblastoma GIST Hepatocellular Colorectal Glioma All Cancers Thyroid Prostate Leiomyosarcoma SCL Esophageal Squamous Dedifferentiated Liposarcoma Acute Lymphoblastic Leukemia Malignant Fibrous Histiocytoma Beroukhim R, et al. Nature. 2010;463:899-905.

  25. 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.

  26. 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.

  27. 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.

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

  29. 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.

  30. Implications of Genetic Heterogeneity Targeted therapy Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.

  31. Implications of Genetic Heterogeneity Targeted therapy Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.

  32. Implications of Genetic Heterogeneity Targeted therapy Turner NC, Reis-Filho JS. Lancet Oncol.2012;13:e178-85.

  33. Acquired Resistance to Targeted Therapies Acquired resistancetargeted 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.

  34. 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

  35. 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

  36. 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.

  37. Go Online for More CCO Coverage of Chicago 2012! Capsule Summariesof all the key data, plusCME-certified Slidesetsexploring the clinical implications of these findings Downloadable slides: for use as a study resource or in your noncommericial presentations clinicaloptions.com/oncology

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