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EGAPP Recommendations for Lynch Syndrome Genetic Testing: Impact on Colorectal Cancer Care

EGAPP Recommendations for Lynch Syndrome Genetic Testing: Impact on Colorectal Cancer Care. Heather Hampel, MS, CGC Professor, Division of Human Genetics The Ohio State University Department of Internal Medicine Columbus, OH . Outline.

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EGAPP Recommendations for Lynch Syndrome Genetic Testing: Impact on Colorectal Cancer Care

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  1. EGAPP Recommendations for Lynch Syndrome Genetic Testing: Impact on Colorectal Cancer Care Heather Hampel, MS, CGC Professor, Division of Human Genetics The Ohio State University Department of Internal Medicine Columbus, OH 

  2. Outline Why determine which cases of CRC have defective mismatch repair? Screening for Lynch syndrome among newly diagnosed CRC patients EGAPP recommendations OSU clinical experience doing IHC on all newly diagnosed CRC patients

  3. ColorectalCancer 15% 85% MIN (MSI+) (Microsatellite Instability) CIN (Chromosome Instability) 2-3% 13% <1% 85% Sporadic MSI(+) Lynch Syn FAP Sporadic Germline Mutation APC Acquired APC, p53, DCC, kras, LOH,... Germline Mutation MMR genes MLH1, MSH2, MSH6 & PMS2 • Epigenetic silencing of MLH1 by hypermethylation of its promoter region

  4. Why Determine which CRC Cases are MSI+ and which have LS? All MSI+ CRC patients have a better prognosis MSI+ CRC patients MAY need different treatment in future LS patients at high risk for second primary cancers (CRC and others) LS patients have at-risk relatives who could benefit from genetic testing

  5. Prognostic Implications • Pooled data analysis of 32 studies with 7,642 cases found: • HR for Overall Survival with MSI = 0.65 • Restricting analysis to clinical trial patients (HR=0.69) did not alter benefit • Restricting to those with locally advanced disease (HR=0.67) did not alter benefit Popat S, et al. JCO. 2005;23:609-618.

  6. Treatment Implications • MSI-H stage II and III patients did not have a significant difference in RFS whether or not they received 5-FU (HR, 0.96; 95% CI, 0.62 to 1.49; P=.86) • MSI-H patients did not have a significant difference in OS whether or not they were treated with 5-FU (HR, 0.70; 95% CI, 0.44 to 1.09; P=.12) • MSS patients do benefit from 5-FU (HR, 0.77; 95% CI 0.68 to 0.87; P<.001) Des Guetz G, et al. Euro J Cancer 45:1890-6,2009.

  7. Patient & Family Implications: Lynch Syndrome MSH2 MSH6 MLH1 PMS2

  8. Aa aa aa aa Aa Aa Carrier Carrier Non-carrier Non-carrier 1/2 1/2 Autosomal Dominant Inheritance Carrier Parent Non-carrier Parent

  9. Lynch Syndrome: Lifetime Risks for Cancer

  10. Lynch Syndrome Surveillance Options Lindor N et al. JAMA 2006;296:1507-17. & Vasen HFA et al. J Med Genet 2007;44:353-62.

  11. 15-year prophylactic colonoscopic screening Järvinen et al. 1995 and 2000

  12. Lynch Syndrome Prophylactic Surgery Options Options include subtotal colectomy, hysterectomy, and oophorectomy Subtotal colectomy does not eliminate cancer risk Hysterectomy eliminates risk of endometrial and ovarian cancer Expert panels made no recommendation for or against surgery due to unproven efficacy Schmeler et al. NEJM 2006;354:261-9.

  13. Lynch Syndrome Implications for Patient • 16-30% chance of second primary CRC in the 10 years after their first diagnosis • NCCN guidelines differ for CRC patients with LS and without LS • With LS, colonoscopy every 1-2 years for life • Without LS, colonoscopy 1 yr after dx, repeat in 2-3 yrs, then every 3-5 years based on findings • Management also changes due to the risk for other cancers

  14. Lynch Syndrome Implications for Family • 6 relatives tested on average per proband identified with LS • 50% with LS need increased cancer surveillance • High Compliance (96% CRC & 97% Gyn) • Cancer risk ratio of relatives with LS compared to relatives without LS is 5.8 • No significant difference in cancer mortality (RR, 2.28) or overall death rates (RR, 1.26) • 50% without LS follow the ACS guidelines JarvinenHJ et al. J Clin Oncol 2009;27:4793-7.

  15. Tumor Tests to Screen for Lynch Syndrome • Microsatellite Instability (MSI) testing • Performed on DNA extracted from tumor and normal tissue – requires laboratory • Test is positive in 15% of CRC cases • Test is positive in 77-89% of LS cases • Immunohistochemistry staining • Performed on thin slide of tumor – can be done in pathology department • 1-2 proteins are absent in 20% of CRC cases • 1-2 proteins are absent in 83% of LS cases

  16. MSI testing on Genotyper

  17. Five Possible IHC Results:1. Normal – All 4 Stains Present 80% of the time you will get this result CRC is probably not MSI+ Prognosis worse than if MSI+ Refer to Genetics ONLY if you suspect polyposis, patient dx <45, patient has had multiple CRC primaries, or the patient has an first degree relative (FDR) with CRC at any age

  18. 2. Abnormal – MLH1 & PMS2 Absent 15% of the time CRC is MSI+ Better prognosis 80% acquired methylation of MLH1 20% will be LS MSH2 MLH1 MSH6 PMS2

  19. 2. Abnormal – MLH1 & PMS2 Absent Either refer all cases to Genetics OR Refer those diagnosed under age 60, those with multiple primary LS cancers, and those with an first or second degree relative (SDR) with a LS cancer at any age OR Reflex to BRAF or MLH1 methylation testing & refer those without BRAF mutation or without methylation

  20. BRAF and CRC • V600E (1799T>A) mutation strongly associated with MSI+ and CpG island methylator phenotype (CIMP) • Not yet reported in a patient with a germline MLH1 gene mutation • MLH1 promoter methylation • MLH1 absent on IHC, no MMR gene mutation; 68% with V600E in BRAF

  21. 3. Abnormal – MSH2 & MSH6 Absent 3% of the time CRC is MSI+ Better prognosis Most likely LS due to either MSH2 or MSH6 gene mutation Always refer to Genetics MSH2 MLH1 PMS2 MSH6

  22. 4. Abnormal – MSH6 Absent 1% of the time CRC is MSI+ Better prognosis Most likely LS due to an MSH6 gene mutation Always refer to Genetics MSH-2 MLH-1 MSH-6 PMS-2

  23. 5. Abnormal – PMS2 Absent 1% of the time CRC is MSI+ Better prognosis Most likely LS due to an PMS2 gene mutation Always refer to Genetics MLH1 MSH2 PMS2 MSH6

  24. The Family History Is Key to Diagnosing LS – or is it? CRC dx 50s CRC dx 45 CRC dx 61 CRC dx 75 OvarianCa, dx 64 CRC dx 48 CRC dx 52 EndometrialCa, dx 59 45 CRC dx 42

  25. Amsterdam II criteria • 3 or more relatives with verified Lynch-associated cancer in family • Two or more generations • One case a first-degree relative of the other two • One CRC dx <50 • FAP excluded Does not include ovarian, gastric, brain, biliary tract or pancreatic cancer Vasen HFA et al. Gastroenterology. 116:1453, 1999

  26. Bethesda Guidelines Individual with CRC dx <50 Individual with synchronous or metachronous CRC, or other Lynch-associated tumors regardless of age Individual with CRC with MSI-H histology dx <60 Individual with CRC with >1 FDR with an Lynch-associated tumor, with one cancer dx <50 Individual with CRC with >2 FDRs or SDRs with an Lynch-associated tumor, regardless of age Umar A, et al. JNCI. 2004;96(4):261-268.

  27. Warning: Family Histories can be Deceiving Family size is getting smaller Wider use of colonoscopy likely to prevent many colon cancers MSH6 & PMS2 may have lower cancer risks

  28. Identification of Lynch syndrome in the Genetics Clinic • Can predict who is more likely to have LS using family history criteria (Amsterdam & Bethesda) • Can predict the likelihood of a MMR gene mutation using three new programs • PREMM1,2,6 http://www.dana-farber.org/pat/cancer/gastrointestinal/crc-calculator/ • MMRpro http://www4.utsouthwestern.edu/breasthealth/cagene/ • MMRpredict http://www1.hgu.mrc.ac.uk/Softdata/MMRpredict.php • Can order MSI and/or IHC on tumor to screen for LS • Can diagnose Lynch syndrome with genetic testing

  29. Identification of Lynch syndrome among all Newly Diagnosed CRC Patients Unlikely to have good family history High volume Must rely on screening tests for LS (MSI/IHC) Pathologists will know age at dx, synchronous primaries, but not likely to know all metachronous primary or family history of patients

  30. Columbus-area HNPCC study (1999-2005) Colorectal cancer Total accrued (n=1600) Testing completed (n=1566) MSI positive (high & low) n=307 (19.6%) MSI negative n=1259 (80.4%) Sequence Immunohistochemistry Methylation of MLH1 promoter Deleterious mutation n=44* (2.8%) *2 had MSI- tumors Variant of uncertain significance n=55 (3.5%) Polymorphism or no mutation n=209 (13.4%) Hampel et al. New Engl J Med 2005; 352:1851-60 Hampel et al. J Clin Oncol 2008; 26:5783-88

  31. 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; 352:1851-60 Hampel et al. J Clin Oncol 2008; 26:5783-88

  32. Family Studies of 35/44 CRC Probands 35 CRC probands have had genetic counseling Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.

  33. Amsterdam: Yes Lynch: Yes 942+3 a>t MSH2 mutation

  34. Amsterdam: No Lynch: Yes 3155delAG MSH6 mutation

  35. Amsterdam: Yes Lynch: No Tumors MSI- with intact IHC

  36. EGAPP Recommendations • Evaluation of Genomic Applications in Practice and Prevention • Established in 2005 to assess evidence regarding the validity & utility of rapidly emerging genetic tests for clinical practice • Independent, multidisciplinary panel prioritizes and selects tests, reviews CDC-commissioned evidence reports, finds gaps, and provides guidance

  37. Steps in the EGAPP Working Group Review Process

  38. Seven Evidence Reports Available to Date • October 2006 - Genomic Tests for Ovarian Cancer Detection and Management • January 2007 – Testing for CYP450 Polymorphisms in adults with depression before trtmnt with SSRIs • May 2007 – Lynch diagnostic strategies • January 2008 – Gene Expression Profiling and Breast Cancer Outcomes • January 2009 – DNA strategies aimed at reducing morbidity and mortality from Lynch syndrome • January 2009 – Can UGT1A1 genotyping reduce M&M in pts with metastatic CRC treated w/Irinotecan • June 2009 – Outcomes of genetic testing in adults with a history of venous thromboembolism

  39. Four EGAPP Working Group Recommendations Insufficient Evidence to recommend for or against • Tumor profiling to improve outcomes in patients with breast cancer • UGT1A1 genotyping to reduce morbidity and mortality in patients with metastatic CRC treated with Irinotecan • Use of CYP450 testing to predict response to SSRis in adults with depression Sufficient Evidence to recommend for 4. Screening newly diagnosed CRC patients for LS with either MSI or IHC

  40. EGAPP Recommendations • Moderate certainty that testing patients with CRC for LS and then testing their relatives would provide moderate population benefit. • Adequate evidence to conclude that the analytic sensitivity and specificity of the preliminary and diagnostic tests were high. • Adequate evidence to describe the clinical sensitivity and specificity of three preliminary tests and four testing strategies. • Adequate evidence for testing uptake, compliance with surveillance, relatives approachable, harms associated with f/u and effectiveness of routine c-scope supporting the use of genetic testing strategies to reduce morbidity and mortality in relatives with LS. • No one test strategy was clearly superior. • Inadequate evidence that screening for LS will reduce EC morbidity or mortality EGAPP Genet Med 2009;11:35-41; Palomaki G, Genet Med 2010;11:42-65.

  41. Potential Impact • 146,970 new cases of CRC in the US in 2009 • 4,115 have Lynch syndrome (2.8%) • 12,345 of their relatives have LS (~3 per proband) • Total of 16,460 individuals who could be diagnosed with LS this year with universal screening American Cancer Society Facts & Figures

  42. Choosing the Screening Test: MSI vs. IHC IHC is available in virtually all hospitals MSI requires molecular diagnostics and normal for comparison IHC with 4 antibodies is similar in cost to MSI with 5 markers IHC directs gene testing saving money Ethical issues surrounding IHC IHC and MSI have limitations

  43. Cost-effectiveness Study • Follow-up to EGAPP evidence review • Modeling used the statistics from the EGAPP review • My role on the project was to: • Explain the various strategies one might use to screen for LS • Provide Medicare reimbursement rates & list prices for various tests

  44. Strategies Compared

  45. Cost-effectiveness Results

  46. Incremental Cost-Effectiveness Ratios per LYS compared to no testing at all

  47. Cost-Effectiveness Evaluation • Universal screening detects nearly twice as many cases of LS as targeting younger patients • Strategy 1 is the most cost effective strategy • Cost-effectiveness ratio of universal screening is < $25,000 per life-year saved relative to no testing • ICER comparable with other preventive services (colonoscopy every 10 years has ICER of $25,000)

  48. Universal IHC screening for CRC: OSU experience Genetics notified by pathology of all abnormal CRC results Permission from ordering physician to contact patient Patient contacted Take limited family history Make recommendation for genetic consultation Letter sent If contact cannot be made, letter is sent explaining results with our contact information Gyn/Onc’s notify their own patients regarding their IHC results

  49. 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 appointment 7 tested 2 confirmed Lynch, 3 with MLH1 methylation South et al, Genet Med 2009; 11:812-817

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