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Genetics of Pancreatic CancerMarch 11, 2015If you experience technical difficulty during the presentation:Contact WebEx Technical Support directly at:US Toll Free: 1-866-779-3239Toll Only: 1-408-435 -7088orSubmit a question to the Event Producer via the Q&A PanelFor international support numbers rs.htQuestions may be submitted anytime during the presentation.To submit questions:Type your questions in the text entry boxClick the Send ButtonPlease direct your questions to “AllPanelists” in the drop down1

Inherited Pancreatic Cancer:Causes and ManagementTeresa A. BrentnallUniversity of WashingtonAbout 10% of patients with PCwill have a positive familyhistory of the disease2

Family history gives cluesHopkins Registry of 362 families Risk of Pancreatic cancer:4% (familial) vs 0.6% (non-familial) Risk of Non-pancreatic cancer:27% (familial) vs 12% (non-familial) breast, colon, lung3

Familial Risk—Break down the 4% Dependent on the gene involved Not all gene carriers get cancer Penetrance of the genePenetrance Just because you have a gene mutation—will you really get the disease? Low penetrance: probably won’t get thedisease High penetrance: likely to get the disease4

Some families inherit only PCSome families inherit PC andother cancers as wellSpectrum of cancers Breast—often developing age 50LungColonGastricOsteosarcomaProstateOvarian5

Syndromes with PancreaticCancer and Colon Cancer Lynch Syndrome Familial Adenomatous Polyposis (FAP) 5xSyndromes with PancreaticCancer and Breast Cancer Peutz-Jegherslifetime risk 36% BRCA1 & 210x (5%)6

Pancreatic Cancer Plus Familial Atypical Mole Melanoma(FAMM) 13-20x (19%) Hereditary pancreatitis 53x (40%) Cystic Fibrosis32x (25%)Probably 80% of FamilialPancreatic Cancer is due togenes yet to be identified7

eractions251 members of 28 families Smokingdiabetesgendernumber of affected family membersRulyak et al.8

50smokersp 0.00125non-smokers0050AGE100Occupation 3 dry cleaners in 251 family members Anticipated 0.5 dry cleaners Early data9

SURVEILLANCEWhy is pancreatic cancer sohard to diagnose? Most patients have no symptoms The pancreas can not be felt onphysical exam No good tests to find early cancer andpre-cancer.10

SmallductsDigestiveenzymesPancreaticcancerMain pancreaticductPancreatic cancer forms in thesmall and mid-size ducts first.Surveillance of high riskfamilies 2 or more family members with PC; or 1family member 50 one first degree relative data derived from 100 patients from 75different families11

Precursors of PancreaticCancerPrecursor lesion to pancreatic cancerPancreatic intraductal neoplasia (PanIN)Shares histologic & molecular features of cancerNot invasive12

Pancreatic Dysplasia: PanIN IIPanIN III: Carcinoma in-situ13

Management of patients whohave positive family historyWho is at risk? 2 or more affected relatives, one ofwhom is a first degree relative one first degree relative at early age(50’s or younger) Some individuals with known genemutations14

ProphylacticPancreatectomyNot all genecarriers getcancerMorbidity andmortalityDecades mayprecede cancerThe task at handIdentify patients .after they have started down theneoplastic pathway .before the neoplasia becomes invasive15

Family History presenting symptoms duration of symptoms ages of affected family membersEndoscopic Surveillance Endoscopic Ultrasound ERCP Centers with experience16

Endoscopic Ultrasound FindingsIf EUS and ERCP are abnormalconsider getting a piece of thepancreas histologic diagnosis17

PanIN III: Carcinoma in-situIf Carcinoma in-situ is present Discuss risks and benefits of totalpancreatectomy There is no right or wrong answer Patients who have surgery will bediabetics18

Endoscopic Screening: Cost-Effective? Cost-effectiveness ratio 17,000(mammography 22K; pap smear 250K; CRC 6-92k) Procedure costs have limited impact Screening after age 70 is not cost effective50Screening is effective403020Screening not effective1015060708090100Sensitivity of EUS19

Summary 10% of PC may be due to geneticsMost FPC is probably from unknown genesPenetrance plays a key roleFamilies that inherit PC may get other cancersSummaryGene/environment interactions influencepenetrance and age at onsetEndoscopic surveillance appears to bepromising; more biomarkers are neededScreening is cost-effective as long asprevalence of dysplasia is 16%20

Familial Pancreatic Cancer Mike SaundersIrl HirschMary BronnerSteve RulyakDave ByrdJosephine MaurerMike KimmeyJoo Ha Hwang21

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