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Universal Screening for Lynch Syndrome Cecelia Bellcross, PhD, MS, CGC Emory University School of Medicine Department of Human Genetics Genetics of CRC Sporadic (65%–85%) Rare CRC syndromes (<0.1%) MYH associated polyposis (MAP) (1%) Familial adenomatous polyposis (FAP) (1%) Familial (10%–30%) Lynch syndrome (aka Hereditary nonpolyposis colorectal cancer HNPCC) (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 A Classic HNPCC/Lynch Family CRC dx 50s CRC dx 45 CRC dx 61 CRC dx 48 CRC dx 52 Endometrial Ca, dx 59 CRC dx 75 45 CRC dx 42 Ovarian Ca, dx 64 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% Cumulative Risk Colorectal Cancer (%) CRC RISK 100 90 80 70 60 50 40 30 20 10 0 Male MLH1 Male MSH2 Female MLH1 Female MSH2 18-29 30-39 40-49 50-59 60-69 70-79 Age (years) *Barrow, Clin Genet 2008 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 Surveillance/Prevention Options for Lynch syndrome (Lindor JAMA, 2006;296:1507) Cancer Site Surveillance/ Prevention Colon Rectum Colonoscopy Uterus Transvaginal Ultrasound / Endometrial Biopsy Frequency Every 1-2 years 20-25 (30) (Colectomy) Every year Hysterectomy Ovary Begin Age: 30-35 30+ Transvaginal Ultrasound / CA-125 Every year Oral contraceptives > 5 years Oophorectomy 30-35 30+ Stomach Small Bowel Upper Endoscopy Every 2 years 30-35 Pancreas Biliary Liver function tests & Abdominal Ultrasound Every year 30-35 Urinary Tract Urinalysis cytology Every year 30-35 Renal Ultrasound Every 1-2 years 30-35 Dermatology Exam Every year 20-25 Skin Lesions Percent Impact of Screening 45 40 35 30 25 20 15 10 5 0 Screened Group (n=44) Control Group (n=46) Jarvinen, Gastroent, 2000 Incidence Mortality Jarvinen, JCO, 2009: 242 mutation +, 367 mutation - : >95% screening compliance, no difference in cancer or all cause mortality rates 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 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 Microsatellite Instability Normal Cells -CG-CGCGCGCG -CG-CGCGCGCG -CG -CGCGCGCG- -CG-CGCGCGCG Normal Microsatellites Tumor Cells -CG- -CG- -CGCGCGCGCG- -CGCGCG- -CG-CGCG- -CG-CGCG-CGCGCG-CGCGCGCGCG- Microsatellite Instability Immunohistochemistry Abnormal or missing MSH2 protein Abnormal Gene (MSH2) MSH2+ Normal tissue MSH2- Tumor tissue Lack of MSH2 expression, negative IHC staining for MSH2 protein Testing for Lynch/HNPCC Family/Medical history meets screening criteria Amsterdam/Bethesda MSI-High IHC – loss of protein expression Genetic Testing on blood MSI/IHC on tumor tissue No mutation Identified MSI normal IHC normal No further testing Risks & screening based on history 1. Consider additional genetic testing Mutation Identified 2. Risks & screening based on test results and family/medical history Lynch/HNPCC screening & management Family members offered testing 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 EGAPP Lynch Recommendation Genetics in Medicine January 2009 GIM, 2009;1:35 May, 2007 www.ahrq.gov/downloads/pub/ evidence/pdf/hnpcc/hnpcc.pdf GIM, 2009;1:42 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.” Columbus-area HNPCC study (1999-2005) 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; 352:1851 Hampel et al. J Clin Oncol 2008; 26:5783 Family Studies of 35/44 CRC Probands 35 CRC probands have had genetic counseling Degree of Kinship First Second > Second Total Tested 99 64 86 249 Positive 52 28 29 109 Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008. Theoretical Population Health Benefit Bellcross, Genet Med, 2012 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” 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; 66:7810 Hampel H et al. Cancer Res. 2007;67:9603 Columbus HNPCC study Family studies of 14 EC probands 12/14 EC probands have had genetic counseling Degree of Kinship First Second > Second Total Tested 28 12 8 48 Positive 16 3 2 21 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) 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 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 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 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; 11:812-817 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) It takes a team Surgery Pathology Oncology Gastroenterology Genetics Gynecology Patients Families Healthcare system http://www.lynchscreening.net 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 Membership Data Emory LS Screening Team N. Volkan Adsay, MD Cecelia A. Bellcross PhD, MS, CGC Amanda Eppolito, MS, CGC Alton B. Farris, III, MD Natalyn N. Hawk, MD Ira R. Horowitz, MD John Kauh, MD Namita Khanna, MD Dana M. Meaney-Delman, MD Virginia O. Shaffer, MD Christine Stanislaw, MS, CGC Patrick S. Sullivan, MD Pathology Genetics Genetics Pathology Hem/Onc Gyn/Onc Hem/Onc Gyn/Onc High Risk Gyn Colorectal Surgery Genetics Colorectal Surgery Miranda Chergosky – GC Student Focus Intern Emory LS Screening Protocol IHC Result Interpretation IHC Result MLH1 & PMS2 Absent Frequency 15% Implications Follow-up 80% acquired BRAF (V600E +) and/or MLH1 hypermethylation 20% LS due to MLH1 mutation 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 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 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. 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 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 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 Ideally, Begin Testing With an Affected Person Colon Ca, 42 Colon Ca, 38 d.45 Test first, if possible 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. Understanding Possible Test Results Increased Cancer Risk Positive Negative Uncertain Variant 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) Impact of Genetic Testing Family with known mutation Colon Ca, 52 d. 50 MSH2? * Colon Ca, 45 MSH2 + 30 MSH2+ Mutation Positive: initiate screening Endometrial Ca, 47 37 MSH2 - True negative: no increased risk beyond general population Informed Consent: Potential Risks of Genetic Testing • False sense of security if test negative • Psychological distress • Change in family dynamics • ?? Insurance discrimination 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 Nondiscrimination Act (May, 2008) • Life/disability/long-term care not protected 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 Questions Comments Thoughts Suggestions ? Thank You