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Universal Screening for Lynch Syndrome Cecelia Bellcross, PhD, MS, CGC Emory University School of Medicine Department of Human Genetics.

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Presentation on theme: "Universal Screening for Lynch Syndrome Cecelia Bellcross, PhD, MS, CGC Emory University School of Medicine Department of Human Genetics."— Presentation transcript:

1 Universal Screening for Lynch Syndrome Cecelia Bellcross, PhD, MS, CGC Emory University School of Medicine Department of Human Genetics

2 Genetics of CRC Sporadic (65 %– 85%) Familial (10 %– 30%) Lynch syndrome (aka Hereditary nonpolyposis colorectal cancer - HNPCC) (3%) Familial adenomatous polyposis (FAP) (1%) Rare CRC syndromes (<0.1%) MYH associated polyposis (MAP) (1%)

3 Clinical Features of Lynch/HNPCC Early but variable age at CRC diagnosis (~45 years)Early but variable age at CRC diagnosis (~45 years) Tumor site in proximal colon predominatesTumor site in proximal colon predominates Metachronous/synchronous CRCsMetachronous/synchronous CRCs Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile duct, pancreatic, sebaceous skin tumors; brain tumorsExtracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile duct, pancreatic, sebaceous skin tumors; brain tumors

4 A Classic HNPCC/Lynch Family CRC dx 50s CRC dx 45 CRC dx 61 CRC dx 75 Ovarian Ca, dx 64 CRC dx 48 CRC dx 52 Endometrial Ca, dx 59 CRC dx 42 45

5 Other Features of Lynch Syndrome Autosomal dominant inheritanceAutosomal dominant inheritance Genes belong to DNA mismatch repair (MMR) familyGenes belong to DNA mismatch repair (MMR) family Genetic heterogeneity (MLH1, MSH2, MSH6, PMS2)Genetic heterogeneity (MLH1, MSH2, MSH6, PMS2) CRC lifetime risk 30-80%CRC lifetime risk 30-80% Endometrial cancer lifetime risk 30-60%Endometrial cancer lifetime risk 30-60%

6 CRC RISK *Barrow, Clin Genet 2008

7 Extra-colonic/Extra Endometrial Lifetime Cumulative Incidence to age 70 yo: Urologic tract (8.4% overall)Urologic tract (8.4% overall) –MLH1: female =1.1%, Male = 3.7% –MSH2: female =11.9%, Male = 27.8% Ovary = 6.7%Ovary = 6.7% Gastric = 5.8%Gastric = 5.8% Small Bowel = 4.3%Small Bowel = 4.3% Biliary/Pancreatic = 4.1%Biliary/Pancreatic = 4.1% Watson, Int. J. Cancer, 2008

8 Cancer Site Surveillance/ Prevention Frequency Begin Age: Colon Rectum ColonoscopyEvery 1-2 years20-25 (30) (Colectomy) UterusTransvaginal Ultrasound / Endometrial Biopsy Every year30-35 Hysterectomy30+ OvaryTransvaginal Ultrasound / CA-125Every year30-35 Oral contraceptives> 5 years Oophorectomy30+ Stomach Small Bowel Upper EndoscopyEvery 2 years30-35 Pancreas Biliary Liver function tests & Abdominal Ultrasound Every year30-35 Urinary TractUrinalysis cytologyEvery year30-35 Renal UltrasoundEvery 1-2 years30-35 Skin LesionsDermatology ExamEvery year20-25 Surveillance/Prevention Options for Lynch syndrome (Lindor JAMA, 2006;296:1507)

9 Impact of Screening Percent Jarvinen, Gastroent, 2000 Jarvinen, JCO, 2009: 242 mutation +, 367 mutation - : >95% screening compliance, no difference in cancer or all cause mortality rates

10 Amsterdam II Criteria l 3 or more relatives with verified HNPCC associated tumor (CRC, endometrial, ovarian, gastric, small bowel, urinary tract) in family l One case a first-degree relative of the other two l Two or more generations involved l One or more cancer diagnosed by age 50 l FAP excluded Failure to meet these criteria does not exclude HNPCC

11 Revised Bethesda Guidelines: CRC < age 50CRC < age 50 Patient with 2 HNPCC related tumorsPatient with 2 HNPCC related tumors Patient with CRC < age 60 with MSI-H histologyPatient with CRC < age 60 with MSI-H histology Patient with CRC with 1st degree relative with HNPCC related cancer; one of the cancers at < 50 yearsPatient with CRC with 1st degree relative with HNPCC related cancer; one of the cancers at < 50 years Patient with CRC and 2 or more relatives with HNPCC-related cancer regardless of agePatient with CRC and 2 or more relatives with HNPCC-related cancer regardless of age Umar, JNCI, 2004

12 Microsatellite Instability -CG--CGCGCGCG-CG--CGCGCGCG -CG--CGCGCGCG -CG-CGCGCGCG- -CG- -CGCGCGCGCG- -CG- -CGCGCG- -CG- -CGCG- -CG--CGCG--CGCGCG--CGCGCGCGCG- Normal Cells Tumor Cells Microsatellite Instability Normal Microsatellites

13 Abnormal or missing MSH2 protein Immunohistochemistry Abnormal Gene (MSH2) MSH2- Lack of MSH2 expression, negative IHC staining for MSH2 protein Normal tissue Tumor tissue MSH2+

14 Testing for Lynch/HNPCC Family/Medical history meets screening criteria Amsterdam/Bethesda MSI/IHC on tumor tissue MSI normal IHC normal No further testing Risks & screening based on history MSI-High IHC – loss of protein expression Genetic Testing on blood Mutation Identified No mutation Identified 1. Consider additional genetic testing 2. Risks & screening based on test results and family/medical history Lynch/HNPCC screening & management Family members offered testing

15 Rationale for HNPCC/Lynch Syndrome Screening of Newly Diagnosed CRC Common: ~ 3% of all CRCCommon: ~ 3% of all CRC Age/screening criteria miss up to 25%Age/screening criteria miss up to 25% Accurate methods (MSI/IHC) using easily accessible tumor tissueAccurate methods (MSI/IHC) using easily accessible tumor tissue Benefits of medical interventionBenefits of medical intervention –Cascade testing of family members –Surveillance/prevention –CRC treatment decisions Evidence of cost-effectivenessEvidence of cost-effectiveness

16 EGAPP Lynch Recommendation Genetics in Medicine January 2009 May, evidence/pdf/hnpcc/hnpcc.pdf GIM, 2009;1:42 GIM, 2009;1:35

17 Summary Statement “The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer (CRC) to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.”

18 2.8% of CRC probands with deleterious mutations (n=44) Age at diagnosis – 51.4 (range 23-87) 50% diagnosed over age 50 25% did not meet either Amsterdam or Bethesda criteria Mutations –20.5% MLH1 –52.3% MSH2 –13.6% MSH6 –13.6% PMS2 Columbus-area HNPCC study ( ) Hampel et al. New Engl J Med 2005; 352:1851 Hampel et al. J Clin Oncol 2008; 26:5783

19 35 CRC probands have had genetic counseling Degree of KinshipTested Positive First9952 Second6428 > Second8629 Total Family Studies of 35/44 CRC Probands Hampel et al. NEJM 2005;352: ; Hampel et al. JCO 2008.

20 Theoretical Population Health Benefit Bellcross, Genet Med, 2012

21 Healthy People 2020 Approved Genomics Objective (Developmental) “Increase the proportion of persons with newly diagnosed colorectal cancer who receive genetic testing to identify Lynch syndrome”

22 Endometrial cancer Hampel H et al. Cancer Res. 2006; 66:7810 Hampel H et al. Cancer Res. 2007;67:9603 Age at diagnosis – 54.1 (range 39-69) 65% diagnosed over age 50 65% did not meet either Amsterdam or Bethesda criteria Mutations –14.3% MLH1 –21.4% MSH2 –64.3% MSH6 –No PMS2 2.5 % with deleterious mutations (n=14)

23 12/14 EC probands have had genetic counseling Degree of KinshipTested Positive First2816 Second12 3 > Second8 2 Total Columbus HNPCC study Family studies of 14 EC probands

24 EGAPP Data Interpretation Concerns “To reduce morbidity and mortality in relatives” –Implies no benefit to proband Increasing evidence of impact on CRC management – chemotherapy, surgery Known increased risk for 2 nd primary colorectal cancers and other tumors impacts medical management Does not take into account current practice and insurance coverage (including Medicare)

25 Potential Impact on CRC treatment MSI-H tumors –Better prognosis (Popat, JCO 2005;23:609) –Lack of impact of 5FU on RFS/OS (DesGuetz, Eur J Cancer 2009;45:1890) Surgical (Gut 2011;60:950 – 382 LS gene mutation carriers –Extensive colectomy – 0/50 metachronous tumors vs. Segmental resection – 74/322 (22%) –Cumulative risk of metachronous CRC at 10, 20, & 30 yrs = 16%, 41% & 62% respectively

26 Cost effectiveness Data Mvundura M, et al. Genet Med. 2010;12: Targeting screening only to CRCs < age 50 would miss over 50% of LS cases

27 Business Analysis by a Healthcare System Evidence review & computerized simulation models – Intermountain Healthcare Cost of screening all (unselected) CRC patients for Lynch syndrome <$25,000/LYS IHC with methylation studies, reflexing to BRAF most efficient Gudgeon, Am J Managed Care, 2011;17:e288

28 Universal IHC screening for CRC: OSU experience Began March 1, cases of CRC in first 2 years –57 (21.1%) absent for one or two MMR proteins –54 contacted by genetics with physician consent 5 deceased, reported to next of kin 7 prisoners –34 appropriate for consultation –18 scheduled appointment/9 completed appt –7/9 tested 2 confirmed Lynch, 3 with MLH1 methylation South et al, Genet Med 2009; 11:

29 Challenges to Implementation  Lack of provider knowledge of Lynch syndrome and testing issues  Question of informed consent  Availability of genetic services  Cost and coverage  Psychosocial impact  Informing relatives – who is responsible?  Patient and provider compliance  Infrastructure needs  Testing limitations (e.g. IHC accuracy by site)

30 It takes a team Surgery Pathology Oncology Gastroenterology Genetics Gynecology Patients Families Healthcare system

31

32 LSSN Vision and Mission LSSN Vision: –to reduce the cancer burden associated with Lynch syndrome. LSSN Mission: –to promote universal Lynch syndrome screening on all newly diagnosed colorectal and endometrial cancers; to facilitate the ability of institutions to implement appropriate screening by sharing resources, protocols and data through network collaboration; and to investigate universal screening for other Lynch syndrome related malignancies

33 Membership Data

34 Emory LS Screening Team N. Volkan Adsay, MD Pathology Cecelia A. Bellcross PhD, MS, CGCGenetics Amanda Eppolito, MS, CGCGenetics Alton B. Farris, III, MDPathology Natalyn N. Hawk, MDHem/Onc Ira R. Horowitz, MDGyn/Onc John Kauh, MDHem/Onc Namita Khanna, MDGyn/Onc Dana M. Meaney-Delman, MDHigh Risk Gyn Virginia O. Shaffer, MDColorectal Surgery Christine Stanislaw, MS, CGCGenetics Patrick S. Sullivan, MDColorectal Surgery Miranda Chergosky – GC Student Focus Intern

35 Emory LS Screening Protocol

36 IHC Result Interpretation IHC ResultFrequencyImplicationsFollow-up MLH1 & PMS2 Absent 15% 80% acquired 20% LS due to MLH1 mutation BRAF (V600E +) and/or MLH1 hypermethylation Genetics referral & MLH1 DNA analysis MSH2 & MSH6 Absent 3%Most LS due to MSH2 mutation Genetics referral & MSH2 DNA analysis MSH6 or PMS2 Absent 2%Most LS due to MSH6 or PMS2 mutation Genetics referral & MSH6/PMS2 DNA analysis

37 Genetics Follow-up Access to CoPath – automatic search for all CRC specimens –Monitor if IHC being done – interface with GI path fellows –Review IHC/BRAF results Enter into LSSN database Abnormal IHC results Follow-up letter to MD via EMR Coordination with RN staff to ensure genetics referral Subset of IHC positive screens to be seen at point of care (post-op or oncology appt) Enter follow-up/outcome data into LSSN db

38

39 What Is Cancer Genetic Counseling? Cancer genetic counseling is NOT genetic testing!Cancer genetic counseling is NOT genetic testing! It is a process of information gathering, risk assessment and education.It is a process of information gathering, risk assessment and education. The goal of cancer genetic counseling is to provide the individual, family and their health care providers with accurate cancer risk information to facilitate personal management decisions.The goal of cancer genetic counseling is to provide the individual, family and their health care providers with accurate cancer risk information to facilitate personal management decisions.

40 Initial Genetic Counseling Visit Review medical history and family historyReview medical history and family history Assess risk for hereditary cancerAssess risk for hereditary cancer Discuss cancer biology and geneticsDiscuss cancer biology and genetics Discuss genetic testing options and/or referrals for additional evaluation if appropriateDiscuss genetic testing options and/or referrals for additional evaluation if appropriate Discuss implications of testing for the patient and their familyDiscuss implications of testing for the patient and their family Coordinate testing including review of insurance issuesCoordinate testing including review of insurance issues

41 Informed Consent: Potential Benefits of Genetic Testing Improved cancer risk managementImproved cancer risk management –Prevention –Early detection –Avoidance of unnecessary and costly screening and surgery Relief from uncertainty and anxiety about cancer riskRelief from uncertainty and anxiety about cancer risk Information for individual and family membersInformation for individual and family members Lifestyle decision makingLifestyle decision making

42 Informed Consent: Limitations of Genetic Testing Not all mutations are detectableNot all mutations are detectable Uncertain significance of some mutationsUncertain significance of some mutations Negative result is fully informative only if mutation has been identified in familyNegative result is fully informative only if mutation has been identified in family Results indicate probability, not certainty, of developing cancerResults indicate probability, not certainty, of developing cancer Management/screening strategies continually evolving as new data collectedManagement/screening strategies continually evolving as new data collected

43 Ideally, Begin Testing With an Affected Person If a mutation is found in an affected person, testing will be more informative for other family members. Colon Ca, 42 Colon Ca, 38 d.45 Colon Ca, 45 Person seeking counseling (proband) Test first, if possible

44 Understanding Possible Test Results Positive Negative Uncertain Variant Increased Cancer Risk Has a mutation been found in the family? Y N NO Increased Cancer Risk Cancer Risk Not Altered (individualized empiric risk based on family history)

45 Impact of Genetic Testing Family with known mutation True negative: no increased risk beyond general population Colon Ca, 52 Endometrial Ca, 47 Colon Ca, 45 MSH MSH2  d. 50 MSH2? * 30 MSH2+ Mutation Positive: initiate screening

46 Informed Consent: Potential Risks of Genetic Testing False sense of security if test negativeFalse sense of security if test negative Psychological distressPsychological distress Change in family dynamicsChange in family dynamics ?? Insurance discrimination?? Insurance discrimination

47 The Myth of Genetic Discrimination No well-documented cases of health insurance loss, denial, or rate No well-documented cases of health insurance loss, denial, or rate increase based on cancer genetic testing State and Federal laws exist State and Federal laws exist which address health insurance and employment GINA – Genetic Information Non- discrimination Act (May, 2008) GINA – Genetic Information Non- discrimination Act (May, 2008) Life/disability/long-term care not protected Life/disability/long-term care not protected

48 Result Disclosure and Post-test Counseling Assess cancer risk based on test resultsAssess cancer risk based on test results Discuss any additional testing recommendationsDiscuss any additional testing recommendations Review of implications for family membersReview of implications for family members Present screening and management optionsPresent screening and management options Discuss risk reduction strategiesDiscuss risk reduction strategies Explore psychosocial adjustment to cancer risk and/or genetic riskExplore psychosocial adjustment to cancer risk and/or genetic risk

49 Questions Comments Thoughts Suggestions ? Thank You


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