Lalan S. Wilfong

1. Lalan S. Wilfong GI malignancies May 28, 2009

2. Colon Cancer • 800,000 new cases per year globaly • 11% of cancer mortality in the US • Lifetime risk of 0.5-2.0% of developing colon cancer • Risk factors • Age, Western countries, high-fat diets • Obesity, Genetics, Inflammatory Bowel Disease

3. Genetic Causes • Familial Adenomatous Polyposis • Hereditary Nonpolyposis Colorectal Cancer • Hamartomatous Polyposis Syndromes • Familial Colorectal Cancer

4. Familial Adenomatous Polyposis • 1% of all colorectal cancer • Hallmark is hundreds to thousands of colon polyps • 100% develop colon cancer • Extracolonic features: • Hypertrophy of retinal epithelium • Mandibular osteomas • Epidermal cysts • Desmoid tumors • Adrenal cortical adenomas • Gene is APC on 5q21

5. 3% of colorectal cancer Usually occurs in right colon Accelerated progression of polyps to cancer Can have extracolonic tumors Risk: 80% for colon cancer 40% for endometrial With skin tumors called Muir-Torre syndrome Autosomal dominant with 80% penetrance Defect in mismatch repair genes Can test for Microsatellite instability in tumors HNPCC

6. Diagnosis of HNPCC

7. Diagnosis of HNPCC

8. What Happens? • Mismatch Repair genetic defect • Encode enzymes that repair errors during DNA replication • Main genes MLH1, MSH2, MSH6 and PMS2 • Microsatellite instability • Microsatellites are repetitive DNA sequences found throughout the genome • Loss of MMR results in repetitive coding and noncoding regions of genes including genes involved in tumor initiation and progression

9. Putative Role of Mutations in Mismatch-Repair Genes Lynch, H. T. et al. N Engl J Med 2003;348:919-932

10. Strategy for Risk Reduction • Colonoscopy every 1-3 years beginning age 20-25 or 10 years before earliest relative • Prophylactic colectomy • Chemoprevention? • Transvaginal ultrasound or endometrial aspiration annually • Prophylactic hysterectomy • If stomach cancer in family, EGD every 1-2 years • If urinary tract cancer, sono or urine cytology every 1-2 years

11. Slow progression from adenoma to cancer make screening appropriate Best approach is unknown DRE Fecal occult blood Sigmoidoscopy Barium enema Colonoscopy Average Risk FOBT Flex sig every 5 yrs Colon every 10 yrs Stop at age 75-85 Increased Risk Colon starting 10 years before youngest affected member 3 or more polyps, colon in 3 years 1-2 polyps (<1cm) colon in 5 yrs Screening for Population

12. Chemoprevention • Medications to prevent cancer before cancer begins • Since colon cancer has stepwise progression from adenoma to invasive disease, if we can block one of the steps we can stop cancer

13. Colon Carcinogenesis and the Effects of Chemopreventive Agents Janne, P. A. et al. N Engl J Med 2000;342:1960-1968

14. I II III IV Stage • T • 1: invades submucosa • 2: invades muscularis propria • 3: through muscularis propria • 4: invades other organs • N • 0: no lymph nodes • 1: 1-3 lymph nodes • 2: 4 or more lymph nodes • M: • 0: no mets • 1: with mets

19. Treatment • Stage I – surgery • Stage II – surgery unclear role of chemotherapy • Stage III – surgery followed by adjuvant chemotherapy • Stage IV – palliative chemotherapy • Rectal Cancer – surgery, radiation and chemotherapy

20. Disease-free survival after adjuvant chemotherapy for colorectal cancer using Fluorouracil and Leucovorin (FL) or FL + Oxaliplatin Andre, T. et al. NEJM 2004; 350:2343-2351

21. Trends in the Median Survival of Patients with Advanced Colorectal Cancer Meyerhardt, J. A. et al. NEJM 2005; 352:476-487 Adapted from Grothey et al

23. Targeted Therapies • Avastin • VEGF inhibitor • Blocks blood vessel formation • All cells need O2 and therefore blood • Erbitux/Vectibix • EGFR inhibitor • Overexpression in many cancer cell lines • Important ligand for growth factors

24. Angiogenesis • Cells cannot survive ifthey lack oxygenand nutrients • Oxygencan diffuse from capillaries to a distance of only 150 to 200µm • when cells are farther away from a blood supplytheydie. • Thus, to become clinically relevant, a tumor requires neovascularization or angiogenesis to survive

27. Epidermal Growth Factor Receptor Inhibitor • EGFR overexpressed on many epithelial cancers • Correlates with poor outcome • Acts as a tyrosine kinase • Blocking this receptor can lead to cell cycle arrest and apoptosis • EGFR blockade can improve survival in many cancers • Only effective in tumors with wild-type kras

28. Fig 1. Mechanisms of receptor activation Mendelsohn, J. J Clin Oncol; 20:1s-13s 2002

29. Esophageal Cancer • 12,000 cases in US per year • More common in Asia, blacks, males, age >50 • Two Cell Types • Squamous – • associated with smoking, etoh, nitrities, pickled vegetaqble, lye, achalasia, esophageal web, diet • Incidence decreasing • Adenocarcinoma – • associated with reflux, Barrett’s, obesity • Incidence increasing esp in white males

30. Location 15% upper 1/3 40% middle 1/3 45% lower third Symptoms Dysphagia Weight loss Pain vomiting Spread Adjacent lymph nodes Lung Liver Pleura Diagnosis Endoscopy CT scans PET Clinical Features

31. Treatment • Most patients present with advanced disease and prognosis is <5% 5 year survival • Resection for early stage disease • Chemoradiation for locally advanced disease • Chemotherapy for advanced disease • PEG tube or stents for nutrition

32. Gastric Cancer • Incidence decreasing • 21,500 new cases per year • More common in Asia • 85% adenocarcinomas • Diffuse – infiltrate and thicken the stomach wall causing linitis plastica • Intestinal type – glandlike structures

33. Etiology Ingestion of nitrates H pylori Loss of gastric acidity Presentation Upper abdominal pain Anorexia +/- nausea Weight loss dysphagia Spread Directly to perigasatric tissues Peritoneal seeding Intra-abdominal and supraclavicular lymph nodes Ovary (Krukenberg) Periumbilical (sister Mary Joseph) Peritoneal cul-de-sac (Blummers shelf) Liver Features

34. Treatment • Resection for early stage • Lymph node dissection • 20% 5 year survival • Palliative even in advanced disease • Chemotherapy for advanced disease • Palliative benefit • ? Prolongs survival • Radiation only for palliation

35. Pancreatic Cancer • Incidence increasing – 28,299 cases in 2000 • Risk factors • Smoking • Age • Male • Blacks • Chronic pancreatitis • Diabetes • obesity

36. Treatment • Resection • Only 15% have resectable lesions • 5 year survival 10% • Maybe improved with chemoradiation • Unresectable or metastatic • Survival 6 months • Chemo offers palliation

37. Clincal Features • 90% adenocarcinomas • 70% in head, 30% in body and tail • Onset insidious • Jaundice • Pain • Weight loss • Diagnosis • Ct scan • MRI • EGD, ERCP, EUS • Ca 19-9

42. Median Survival: 18.8 months with Gemzaar vs. 16.7 months for 5-FU

45. Current Research at PHD • Colon Cancer • SPIRITT: Folfiri with panitumimab or avastin 2nd line MCRC in kras wild-type • Folfiri +/- AMG479 or AMG 655 or placebo in 2nd line kras mutant colon cancer • Gastric • Docetaxel and Oxaliplatin +/- cetuximab for metastatic gastric adenoca • Pancreatic • Gemcitabine +/- amplimexon for met pancreatic cancer • Gemcitabine +/- GI-4000 for resected pancreatic cancer