Update on Hereditary Gastric Cancer. Dr. Savtaj Brar MD MSc Surgical Oncologist Assistant Professor of Surgery
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1 Update on Hereditary Gastric Cancer Dr. Savtaj Brar MD MSc Surgical Oncologist Assistant Professor of Surgery
2 Disclosures None
3 Outline 1. Discuss new consensus guidelines on hereditary diffuse gastric cancer 2. Describe updates in the diagnosis of hereditary gastric cancer 3. Describe the local experience in the testing and treatment of hereditary gastric cancer
4 Background Gastric cancer is the third most common cause of cancer death in the world Estimated that 10% of gastric cancers show familial clustering Approximately 3-fold increased risk of gastric cancer among first degree relatives
5
6 CDH1 Gene 3 Maori families with hereditary diffuse gastric cancer found to have germline mutations in CDH1 The cell-cell adhesion molecule E-cadherin is encoded by the CDH1 gene
7 E-Cadherin
8 CDH1 Gene Mutations identified in families worldwide ~ 20-30% of families fulfilling the criteria of hereditary diffuse gastric cancer have germline CDH1 mutation
9 Risk of Cancer
10 Risk of Cancer
11 Risk of Cancer
12 CDH1 Testing In 2015, International Gastric Cancer Linkage Consortium (IGCLC) outlined criteria for testing for CDH1 mutations 1. Two DGC in family, diagnosis at any age 2. DGC diagnosed before age Personal or family history of DGC and LBC, one < age 50
13 IGCLC Guidelines 2015 Consensus guidelines recommend: people of age 20 who harbor a CDH1 mutation undergo prophylactic total gastrectomy (PTG) Breast cancer surveillance with annual breast MRI starting at age 30
14 IGCLC Guidelines Standardised annual endoscopic surveillance with minimum 30 biopsy for: CDH1 carriers opting not to have gastrectomy CDH1 variants of uncertain significance those that fulfil HDGC criteria without germline CDH1 mutations
15 GAPPS Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal dominant syndrome Increased risk of gastric cancer, no increase in colonic polyps Gene was mapped to 5q22 and isolated point mutation in APC promoter 1B
16 FIGC Familial intestinal gastric cancer where an autosomal dominant inheritance pattern is noted Intestinal-type pathology without polyposis No recommendations on testing or surveillance
17 FGICR Experience Familial Gastrointestinal Cancer Registry (FGICR) established in 1980 CDH1 testing began in tested for CDH1 mutations First prophylactic gastrectomy for CDH1 in January 2009
18 FGICR Experience 69 pathology confirmed gastric cancer with germline results 51 met the IGCLC criteria CDH1 mutations were found in: 4 of 69 (5.8%) all tested 3 of 51 (5.8%) meeting IGCLC criteria
19 FGICR Experience 2 DGC, any age DGC & LBC, One dx <50 DGC < 40
20 FGICR Experience 2 DGC, any age 4 (20%) 2 MLH1, 1 MSH2, 1 CDH1 2 CDH1, 1 BRCA2 3 (43%) 0 0 DGC & LBC, One dx < (50%) 1 (10%) DGC < 40 1 STK11 1 MSH2
21 FGICR Experience 12 of 18 patients who underwent genetic testing but did not meet IGCLC criteria were germline positive CDH1= 1 MSH2 = 7 MLH1 = 1 STK11 = 1 APC = 2
22 FGICR Experience
23 Beyond CDH1
24 QoL Study 70 patients identified Excluded 20 known gastric cancer 21 offered PTG 18 patients enrolled 2 died of other malignancies 12 had no CDH1 mutation 10 kin died prior to testing 4 refused 2 awaiting consultation 13 PTG & 5 no PTG
25 QoL Study Series of questionnaires at 5 time points OR 2 4 weeks preop 2 4 weeks postop 6 mo 1 yr 2 yrs
26 Global QoL
27 Decision Conflict
28 Pathology Lauren Classification Intestinal type Cohesive, forms glands Associated with atrophic gastritis Metastasizes to nodes, liver Diffuse type Poorly cohesive, little or no gland formation Metastasizes to nodes, ovaries, serosa
29 Future classification
30 Summary CDH1 mutations identified in only 6% of patients who met HDGC criteria Families tested for hereditary gastric cancer need to be tested for genes associated with HDGC including CTNNA and other cancer syndromes including BRCA2, STK11, MSH2, MLH1 and APC Prophylactic gastrectomy has significant effects on QOL in CDH1 mutation carriers and long-term effects need to be studied
31
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