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Universal Screening for Lynch Syndrome

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Presentation on theme: "Universal Screening for Lynch Syndrome"— 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%) Rare CRC syndromes (<0.1%) Lynch syndrome (aka Hereditary nonpolyposis colorectal cancer -HNPCC) (3%) MYH associated polyposis (MAP) (1%) Familial adenomatous polyposis (FAP) (1%)

3 Clinical Features of Lynch/HNPCC
Early but variable age at CRC diagnosis (~45 years) Tumor site in proximal colon predominates Metachronous/synchronous CRCs Extracolonic 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 45 CRC dx 42

5 Other Features of Lynch Syndrome
Autosomal dominant inheritance Genes belong to DNA mismatch repair (MMR) family Genetic heterogeneity (MLH1, MSH2, MSH6, PMS2) CRC lifetime risk 30-80% 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) MLH1: female =1.1%, Male = 3.7% MSH2: female =11.9%, Male = 27.8% Ovary = 6.7% Gastric = 5.8% Small Bowel = 4.3% Biliary/Pancreatic = 4.1% Watson, Int. J. Cancer, 2008

8 Surveillance/ Prevention
Surveillance/Prevention Options for Lynch syndrome (Lindor JAMA, 2006;296:1507) Cancer Site Surveillance/ Prevention Frequency Begin Age: Colon Rectum Colonoscopy Every 1-2 years 20-25 (30) (Colectomy) Uterus Transvaginal Ultrasound / Endometrial Biopsy Every year 30-35 Hysterectomy 30+ Ovary Transvaginal Ultrasound / CA-125 Oral contraceptives > 5 years Oophorectomy Stomach Small Bowel Upper Endoscopy Every 2 years Pancreas Biliary Liver function tests & Abdominal Ultrasound Urinary Tract Urinalysis cytology Renal Ultrasound Skin Lesions Dermatology Exam 20-25

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

11 Revised Bethesda Guidelines:
CRC < age 50 Patient with 2 HNPCC related tumors Patient 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 years Patient with CRC and 2 or more relatives with HNPCC-related cancer regardless of age Umar, JNCI, 2004

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

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

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

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

16 EGAPP Lynch Recommendation Genetics in Medicine January 2009
GIM, 2009;1:35 May, 2007 GIM, 2009;1:42

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)
Columbus-area HNPCC study ( ) 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 Hampel et al. New Engl J Med 2005; 352: Hampel et al. J Clin Oncol 2008; 26:5783 18

19 Family Studies of 35/44 CRC Probands
35 CRC probands have had genetic counseling Degree of Kinship Tested Positive First Second > Second Total Hampel et al. NEJM 2005;352: ; Hampel et al. JCO 2008.

20 Theoretical Population Health Benefit
Bellcross, Genet Med, 2012

21 Approved Genomics Objective (Developmental)
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 2.5 % with deleterious mutations (n=14)
Endometrial cancer 2.5 % with deleterious mutations (n=14) 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 Hampel H et al. Cancer Res. 2006; 66: Hampel H et al. Cancer Res. 2007;67:9603 22

23 Columbus HNPCC study Family studies of 14 EC probands
12/14 EC probands have had genetic counseling Degree of Kinship Tested Positive First Second > Second Total

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 2nd 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
Targeting screening only to CRCs < age 50 would miss over 50% of LS cases Mvundura M, et al. Genet Med. 2010;12:93-104

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, 2006 270 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


32 LSSN Vision and Mission
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, CGC Genetics Amanda Eppolito, MS, CGC Genetics Alton B. Farris, III, MD Pathology Natalyn N. Hawk, MD Hem/Onc Ira R. Horowitz, MD Gyn/Onc John Kauh, MD Hem/Onc Namita Khanna, MD Gyn/Onc Dana M. Meaney-Delman, MD High Risk Gyn Virginia O. Shaffer, MD Colorectal Surgery Christine Stanislaw, MS, CGC Genetics Patrick S. Sullivan, MD Colorectal Surgery Miranda Chergosky – GC Student Focus Intern

35 Emory LS Screening Protocol

36 IHC Result Interpretation
Frequency Implications Follow-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


39 What Is Cancer Genetic Counseling?
Cancer genetic counseling is NOT genetic testing! 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.

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

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

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

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

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

45 Impact of Genetic Testing
Family with known mutation Colon Ca, 52 d. 50 MSH2? Colon Ca, 45 MSH2 + Endometrial Ca, 47 * 30 MSH2+ 37 MSH2 - Mutation Positive: initiate screening True negative: no increased risk beyond general population

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

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

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

49 Questions Comments Thoughts Suggestions ?
Thank You

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