New developments in pathogenesis, diagnosis, therapy and prevention of gastric cancer Matthias Ebert II. Medizinische Klinik Klinikum rechts der Isar TU München
Gastric Cancer Pathogenesis Diagnosis Treatment Prevention
World Cancer Report 2006: Gastric Cancer 4 th most common cancer 870.000 new cases p.a. 650.000 deaths p.a. Mortality : 2 nd place 60% of gastric cancer in developing world
Gastric Cancer: Correa Modell Mucosa H. pylori Chron. Gastritis Atrophy Intestinale Metaplasia Dysplasia Cancer
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
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
Correa Modell of Gastric Carcinogenesis Houghton and Wang, Gastroenterology 2005
Suerbaum, NEJM 2002
Gastric Cancer
H. pylori and Gastric Cancer Uemura, NEJM 2001
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
ph and Hp Hp-Gastritis Acid secretion Disease Antrum dominant high Duodenal ulcer Pangastritis moderate Gastric ulcer Corpus dominant low Gastric ulcer Gastric cancer
H. pylori and Gastric Cancer IL-1β: TNF α IL-1 β Strong acid inhibitor proinflammatory cytokine IL-10 (... type)
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
Risk for gastric cancer based on combination of bacterial and host-dependent risk-genotypes Figueiredo et al, J. Nat. Cancer Inst. 2002; 94: 1680
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
Pathogenesis of Gastric Cancer Epithelial Cell Stem Cell Chron. Gastritis Atrophy Intest. Metaplasia Dysplasia Cancer Cancer
Gastric Cancer: Stem cells Stem Cell Identification of stem cells? Genetic and molecular changes? Cancer Karam, Anat Rec 1993
Stem Cell Model X-gal Beta-galactosidase Houghton et al., Science 2004 Y
Gastric Cancer: Stem cells Beta-Galactosidase Pancytokeratin Gastric Cancer: A cancer stem cell disease induced by H. pylori? Houghton et al., Science 2004
Stem Cell Model ph Th1 IFN-µ
Gastric Cancer Pathogenesis Diagnosis Treatment Prevention
Molecular Diagnosis Prognosis Diagnosis Genomics -/+ - Transcriptomics + - Proteomics Epigenetics?
Gastric Cancer Patient SELDI TOF MS Serum
Normal SAX2 5000 10000 15000 20000 Tumor 5000 10000 15000 20000
5000 10000 15000 20000 2610 11537 12470 * normal * cancer 5000 10000 15000 20000
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) M1 36 87.8 41 89.1 M2 33 80.5 43 93.5 M3 36 87.8 37 80.4 M4 35 85.4 38 82.6 M5 31 75.6 39 84.8 M6 21 51.2 43 93.5 M7 16 39.0 46 100.0 M8 29 70.7 33 71.7 M9 18 43.9 45 97.8 M10 35 85.4 35 76.1 M11 21 51.2 41 89.1 M12 19 46.3 40 86.9 M13 25 60.9 40 86.9
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
Trees Mass number 1 2 3 4 5 Decision trees 28 of 71 masses were randomly selected and 50 decision trees were generated Decison trees Frequency [n(%)] 1 2610 12471 5650 1510-2 3654 1510 2610 - - 3 3654 1510 5650 - - 4 3654 2610 5650 4198-5 3654 3503 1510 5650-6 3946 1510 17409 4158-7 3946 1510 2049 6879-8 3946 1510 3503 8938-9 3946 1510 3503 8938 1510 10 3946 1510 4359 4103-11 3946 1510 5492 8233-12 3946 15958 3654 - - 13 3946 2049 8791 - - 14 3946 3503 12471 - - 15 3946 3503 12471 4478-16 3946 3503 1510 6879 7966 17 3946 3503 15958 - - 18 3946 3503 15958 2022-19 3946 3503 15958 6449-20 3946 3503 2610 9435-21 3946 3503 6879 - - 22 3946 3503 6879 4198-23 3946 4198 12471 - - 24 3946 4198 12471 - - 25 3946 4198 15958 - - 26 3946 4198 18137 6449-27 3946 4198 18137 6449-28 3946 4198 3503 15958-29 3946 4198 6879 15958-30 3946 4198 8791 - - 31 3946 5650 18137 - - 32 3946 5650 4478 - - 33 3946 7966 12471 - - 34 5492 1510 12663 - - 35 5492 1510 2610 3654 3946 36 5492 1510 8791 4478-37 5492 4103 2049 - - 38 12471 2049 2610 3946-39 12471 2610 11537 3503-40 12471 2610 1510 - - 41 12471 6449 1510 - - 42 12471 2610 7966 3946-43 12471 3654 1510 - - 44 12471 3946 1510 - - 45 12471 4478 1510 6647 11537 46 12471 4478 6647 1510-47 12471 5492 11537 2049-48 12471 6647 2610 3946-49 12471 6647 7966 3946-50 12471 7966 6647 6647 3654 0 0 20 (40) 25 (50) 5 (10)
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 85.4 91.8 89.9 100 100 90 single tree 3946 Da + 3503 Da + 15,958 Da 92.7 94.1 89.9 90.9 92.8 86.7 tree ensemble 50 decision trees, 28 masses 100 100 89.9 100 100 96.7 all gastric cancers and normal controls were classified correctly (training set). Ebert et al., J Proteome Res 2004, 2005
Cancer Proteomics: Critical Issues Sensitivity Cancer-Specificity Reproducibility Patient populations Peak identification Assay Development Ebert et al., J Proteome Res 2006
Cancer Proteomics: Specificity & Sensitivity mm -3 10 12 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
MALDI Imaging Chaurand et al., Am J Pathol 2004
MALDI Imaging: Gastric Cancer Mucosa Tumor Inflammation and single cancer cells
Mucosa A B Tumor C D Neoplasia Inflammation
MALDI Imaging: Gastric Cancer submucosa mucosa Tumor 1 Tumor 2 Tumor Blood
Epigenetic control of gene expression Glozak, Oncogene 2007
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
Gastric Cancer Pathogenesis Diagnosis Treatment Prevention
Gastric Cancer: : TNM 5-year survival rate: 12-28%
Siewert, Ann Surg 1998
LN-Dissection in gastric cancer D1 = LN 1-6 D2 = LN 7-11 +/- splenectomy/resection of pancreas Hartgrink et al., J Clin Oncol 2004
Comparison of D1 versus D2 resection in gastric cancer Hartgrink et al., J Clin Oncol 2004
Comparison of D1 versus D2 resection in gastric cancer N2 tumors Hartgrink et al., J Clin Oncol 2004
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
Röcken, Ebert, Clin Cancer Res 2005
Röcken, Ebert. CEBP 2007
Predictive marker for nodal involvement? Predict extent of lymph node dissection?
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
Magic Trial Cunningham D et al. N Engl J Med 2006;355:11-20
Magic Trial: Tumor location Cunningham et al., NEJM 2006
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 94012-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 111 113 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
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 94012-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
Gastric Cancer: : REAL-2 Cunningham, ASCO 2006 Cunningham ASCO 2006
Gastric Cancer: : REAL-2 Cunningham, ASCO 2006 Cunningham ASCO 2006
Gastric Cancer: : REAL-2 Cunningham, ASCO 2006 Cunningham ASCO 2006
Gastric Cancer Pathogenesis Diagnosis Treatment Prevention
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 24+26 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 226 + 245 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 120 + 111 GERD, HP 2 yrs Antrum and corpus Histology improved Unchanged Mera 2005 A 795 Hp 12 yrs Antrum and corpus Histology improved improved
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
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
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...
Thank you for your attention..however, prevention, early diagnosis and cure remain challenging..