New developments in pathogenesis, gastric cancer. Matthias Ebert. II. Medizinische Klinik Klinikum rechts der Isar TU München

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1 New developments in pathogenesis, diagnosis, therapy and prevention of gastric cancer Matthias Ebert II. Medizinische Klinik Klinikum rechts der Isar TU München

2 Gastric Cancer Pathogenesis Diagnosis Treatment Prevention

3 World Cancer Report 2006: Gastric Cancer 4 th most common cancer new cases p.a deaths p.a. Mortality : 2 nd place 60% of gastric cancer in developing world

4 Gastric Cancer: Correa Modell Mucosa H. pylori Chron. Gastritis Atrophy Intestinale Metaplasia Dysplasia Cancer

5 H. pylori and Gastric Cancer Population based control study Gastric Ca Controls n = 279 n = 238 H. pylori (IgG Ab) 72 % 55 % OR 2,2 [1,4-3,6] Immunoblot (CagA+) 91 % 56 % OR 21 [8,3-53,4] 71 % of Non-Cardia-Cancer due to H. pylori infection Ekstrom et al., Gastroenterology 2001

6 H. pylori and Gastric Cancer 1246 individuals with H. pylori infection, 280 w/o H. pylori infection, Follow-up 7.8 years (1-10.6) Uemura, NEJM 2001

7 Correa Modell of Gastric Carcinogenesis Houghton and Wang, Gastroenterology 2005

8 Suerbaum, NEJM 2002

9 Gastric Cancer

10 H. pylori and Gastric Cancer Uemura, NEJM 2001

11 antrum dominant gastritis acid Topography of gastritis and acid secretion Duodenal Ulcer Host (e.g. parietal cell number, IL 1ß) Environment (e.g. nicotine) Virulence (e.g. CagA, VacA) Pangastritis or Corpus dominant gastritis acid Gastric ulcer Gastric cancer

12 ph and Hp Hp-Gastritis Acid secretion Disease Antrum dominant high Duodenal ulcer Pangastritis moderate Gastric ulcer Corpus dominant low Gastric ulcer Gastric cancer

13 H. pylori and Gastric Cancer IL-1β: TNF α IL-1 β Strong acid inhibitor proinflammatory cytokine IL-10 (... type)

14 H. pylori and Gastric Cancer IL-1 β and IL-1 RN polymorphisms High mucosal IL-1 β production Hypochlorhydria Atrophy Cancer Hwang et al, Gastroenterology 2002, 123: 1793

15 Risk for gastric cancer based on combination of bacterial and host-dependent risk-genotypes Figueiredo et al, J. Nat. Cancer Inst. 2002; 94: 1680

16 Normal Chronic active gastritis Atrophic gastritis H. pylori and gastric cancer IL-1 β IL-1 RN IL-10 TNF α ACID CONTROL Intestinal metaplasia TRANSFORMATION p53 MSI E-Cadherin p16 Dysplasia Cancer

17 Pathogenesis of Gastric Cancer Epithelial Cell Stem Cell Chron. Gastritis Atrophy Intest. Metaplasia Dysplasia Cancer Cancer

18 Gastric Cancer: Stem cells Stem Cell Identification of stem cells? Genetic and molecular changes? Cancer Karam, Anat Rec 1993

19 Stem Cell Model X-gal Beta-galactosidase Houghton et al., Science 2004 Y

20 Gastric Cancer: Stem cells Beta-Galactosidase Pancytokeratin Gastric Cancer: A cancer stem cell disease induced by H. pylori? Houghton et al., Science 2004

21 Stem Cell Model ph Th1 IFN-µ

22 Gastric Cancer Pathogenesis Diagnosis Treatment Prevention

23 Molecular Diagnosis Prognosis Diagnosis Genomics -/+ - Transcriptomics + - Proteomics Epigenetics?

24 Gastric Cancer Patient SELDI TOF MS Serum

25 Normal SAX Tumor

26 * normal * cancer

27 Bioinformatics: Peak detection with Ciphergen ProteinChip Software CART decision tree approach Design of decision tress Cancer Cases Normal Cases Sensitivity Specificity Mass identified identified (%) (%) (n=41) (n=46) M M M M M M M M M M M M M

28 Train Set M1 n=87 normal: n=46 tumor: n=41 M6 n=41 normal: 5 tumor: 36 M10 n=46 normal: 41 tumor: 5 Terminal Node n=37 normal: 1 tumor: 36 Terminal Node n=4 normal: 4 tumor: 0 Terminal Node n=42 normal: 41 tumor: 1 Terminal Node n=4 normal: 0 tumor: 4 TUMOR NORMAL NORMAL TUMOR

29 Trees Mass number Decision trees 28 of 71 masses were randomly selected and 50 decision trees were generated Decison trees Frequency [n(%)] (40) 25 (50) 5 (10)

30 SELDI: classifier ensemble Classifier Characterization Training set 1. Test set 2. Test set 3. Test set Group 1 Group 2 Group 1 Group 2 Group 3 Group 4 n=41 n=49 n=9 n=11 n=28 n=30 sensitivity specificity sensitivity specificity sensitivity specificity single mass 3946 Da single tree 3946 Da Da + 15,958 Da tree ensemble 50 decision trees, 28 masses all gastric cancers and normal controls were classified correctly (training set). Ebert et al., J Proteome Res 2004, 2005

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32 Cancer Proteomics: Critical Issues Sensitivity Cancer-Specificity Reproducibility Patient populations Peak identification Assay Development Ebert et al., J Proteome Res 2006

33 Cancer Proteomics: Specificity & Sensitivity mm Albumin Ig Major Serum proteins µm -6 nm -9 Transferrin Alk. Phospatase NSE Disease markers pm -12 PSA fm -15 TNF am -18 Hanash, 2005

34 MALDI Imaging Chaurand et al., Am J Pathol 2004

35 MALDI Imaging: Gastric Cancer Mucosa Tumor Inflammation and single cancer cells

36 Mucosa A B Tumor C D Neoplasia Inflammation

37 MALDI Imaging: Gastric Cancer submucosa mucosa Tumor 1 Tumor 2 Tumor Blood

38 Epigenetic control of gene expression Glozak, Oncogene 2007

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40 n=49, p=0.010 n=123, p=0.001 HDAC2 negative HDAC2 negative HDAC2 positive A HDAC2 positive B n=49, p=0.045 n=123, p=0.002 HDAC all negative HDAC all negative HDAC part. pos. HDAC all pos. C HDAC part. pos. HDAC all pos. D

41 Gastric Cancer Pathogenesis Diagnosis Treatment Prevention

42 Gastric Cancer: : TNM 5-year survival rate: 12-28%

43 Siewert, Ann Surg 1998

44 LN-Dissection in gastric cancer D1 = LN 1-6 D2 = LN /- splenectomy/resection of pancreas Hartgrink et al., J Clin Oncol 2004

45 Comparison of D1 versus D2 resection in gastric cancer Hartgrink et al., J Clin Oncol 2004

46 Comparison of D1 versus D2 resection in gastric cancer N2 tumors Hartgrink et al., J Clin Oncol 2004

47 ACE polymorphisms in Gastric Cancer Angiotensinogen II ID DD Figure 1 M N1 N2N3N4N5T1T2T3 T4T5 490 bp 190 bp Renin Angiotensin I Figure 2 ACE Proliferation Angiotensin II Migration Angiogenesis AT-receptors Metastasis ECM

48 Röcken, Ebert, Clin Cancer Res 2005

49 Röcken, Ebert. CEBP 2007

50 Predictive marker for nodal involvement? Predict extent of lymph node dissection?

51 Magic Trial resectable esophageal/gastric cancer AEGII/III stage II, III and IV, no distant metastasis Randomisation 3xECF/OP/3xECF vs. OP (250 patients per group) Epirubicin 50 mg/m2, Cisplatin 60 mg/m2, 5FU 200 mg/m2 (21 d) Cunningham D et al. N Engl J Med 2006;355:11-20

52 Magic Trial Cunningham D et al. N Engl J Med 2006;355:11-20

53 Magic Trial: Tumor location Cunningham et al., NEJM 2006

54 Neoadjuvant Chemotherapy Follow Up Study Phase III preliminary results of preoperative fluorouracil (F) and cisplatin (P) versus surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC FFCD 9703 trial - resectable cancers of the stomach, cardia and lower esophagus R A N D O M I S A T I O N Surgery Chemotherapy 2-3 cycles Cisplatin (100 mg/m 2 )/ 5-FU (800 mg/m 2 d1-d5 infusion) every 28 d Followed by surgery Boige et al. ASCO 2007, # 4510

55 Neoadjuvant Chemotherapy Follow Up Study Phase III preliminary results of preoperative fluorouracil (F) and cisplatin (P) versus surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC FFCD 9703 trial -R0 rate 87% vs. 74% - 3 year DFS 40% vs. 25% - 5 year OS 38 % vs. 24% Boige et al. ASCO 2007, # 4510

56 Gastric Cancer: : REAL-2 Cunningham, ASCO 2006 Cunningham ASCO 2006

57 Gastric Cancer: : REAL-2 Cunningham, ASCO 2006 Cunningham ASCO 2006

58 Gastric Cancer: : REAL-2 Cunningham, ASCO 2006 Cunningham ASCO 2006

59 Gastric Cancer Pathogenesis Diagnosis Treatment Prevention

60 Prevention of gastric cancer: H. pylori eradication Eradication trials: Design only RCT Author Year Evid. N Patients Follow-up Marker Atrophy IM Schenk 2000 A Reflux esophagitis 12 months Antrum and corpus Histology improved Unchanged Correa 2000 A 631 Hp positive patients with atrophy 6 yrs Antrum and corpus Histology improved improved Sung 2000 B Hp Dyspepsia 12 months Antrum and corpus Histology Unchanged Unchanged Zhou 2003 A 552 Hp Infection 5 yrs Antrum and corpus Histology Unchanged improved Kuipers 2003 A GERD, HP 2 yrs Antrum and corpus Histology improved Unchanged Mera 2005 A 795 Hp 12 yrs Antrum and corpus Histology improved improved

61 Prevention of gastric cancer: H. pylori eradication Prospective randomised trial Hp, n=1630 Eradication (n=817) Placebo (n=813) 7 cancers 11 cancers p=0.33 Wong et al., JAMA 2004

62 Prevention of gastric cancer: H. pylori eradication Prospective randomised trial: Only patients w/o preneoplastic lesions Eradication Hp, n=988 Placebo No atrophy No IM No Dysplasia 0 cancers 6 cancers p=0.02 Wong et al., JAMA 2004

63 Gastric cancer: : Update 2007 Pathogenesis: Hp-Host Genotype, Stem cells Diagnosis: Proteomics, Epigenetics...Validation Treatment: Neoadjuvant therapy, LN..prognosis Prevention: Eradicate early enough...recent progress will improve outcome of GC patients...

64 Thank you for your attention..however, prevention, early diagnosis and cure remain challenging..