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1、EGAPP Recommendations for Lynch Syndrome Genetic Testing:Impact on Colorectal Cancer Care,Heather Hampel,MS,CGCProfessor,Division of Human GeneticsThe Ohio State UniversityDepartment of Internal MedicineColumbus,OH,Outline,Why determine which cases of CRC have defective mismatch repair?Screening for
2、 Lynch syndrome among newly diagnosed CRC patientsEGAPP recommendations OSU clinical experience doing IHC on all newly diagnosed CRC patients,13%,1%,85%,FAP,Sporadic,MIN(MSI+)(Microsatellite Instability),CIN(Chromosome Instability),Lynch Syn,Sporadic MSI(+),Germline Mutation MMR genesMLH1,MSH2,MSH6&
3、PMS2,15%,2-3%,Epigenetic silencing of MLH1 by hypermethylation of its promoter region,85%,Colorectal Cancer,Acquired APC,p53,DCC,kras,LOH,.,Germline Mutation APC,Why Determine which CRC Cases are MSI+and which have LS?,All MSI+CRC patients have a better prognosisMSI+CRC patients MAY need different t
4、reatment in futureLS patients at high risk for second primary cancers(CRC and others)LS patients have at-risk relatives who could benefit from genetic testing,Prognostic Implications,Pooled data analysis of 32 studies with 7,642 cases found:HR for Overall Survival with MSI=0.65Restricting analysis t
5、o clinical trial patients(HR=0.69)did not alter benefitRestricting to those with locally advanced disease(HR=0.67)did not alter benefit,Popat S,et al.JCO.2005;23:609-618.,Treatment Implications,MSI-H stage II and III patients did not have a significant difference in RFS whether or not they received
6、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.,Patient&Fam
7、ily Implications:Lynch Syndrome,MLH1,MSH2MSH6,PMS2,Carrier Parent,Non-carrier Parent,Autosomal Dominant Inheritance,Lynch Syndrome:Lifetime Risks for Cancer,Lynch Syndrome Surveillance Options,Lindor N et al.JAMA 2006;296:1507-17.44:353-62.,15-year prophylactic colonoscopic screening,Jrvinen et al.1
8、995 and 2000,Lynch Syndrome Prophylactic Surgery Options,Options include subtotal colectomy,hysterectomy,and oophorectomySubtotal colectomy does not eliminate cancer riskHysterectomy eliminates risk of endometrial and ovarian cancerExpert panels made no recommendation for or against surgery due to u
9、nproven efficacy,Schmeler et al.NEJM 2006;354:261-9.,Lynch Syndrome Implications for Patient,16-30%chance of second primary CRC in the 10 years after their first diagnosisNCCN guidelines differ for CRC patients with LS and without LSWith LS,colonoscopy every 1-2 years for lifeWithout LS,colonoscopy
10、1 yr after dx,repeat in 2-3 yrs,then every 3-5 years based on findingsManagement also changes due to the risk for other cancers,Lynch Syndrome Implications for Family,6 relatives tested on average per proband identified with LS50%with LS need increased cancer surveillanceHigh Compliance(96%CRC&97%Gy
11、n)Cancer risk ratio of relatives with LS compared to relatives without LS is 5.8No significant difference in cancer mortality(RR,2.28)or overall death rates(RR,1.26)50%without LS follow the ACS guidelines,Jarvinen HJ et al.J Clin Oncol 2009;27:4793-7.,Tumor Tests to Screen for Lynch Syndrome,Microsa
12、tellite Instability(MSI)testingPerformed on DNA extracted from tumor and normal tissue requires laboratoryTest is positive in 15%of CRC casesTest is positive in 77-89%of LS casesImmunohistochemistry stainingPerformed on thin slide of tumor can be done in pathology department1-2 proteins are absent i
13、n 20%of CRC cases1-2 proteins are absent in 83%of LS cases,MSI testing on Genotyper,Five Possible IHC Results:1.Normal All 4 Stains Present,80%of the time you will get this resultCRC is probably not MSI+Prognosis worse than if MSI+Refer to Genetics ONLY if you suspect polyposis,patient dx 45,patient
14、 has had multiple CRC primaries,or the patient has an first degree relative(FDR)with CRC at any age,2.Abnormal MLH1&PMS2 Absent,15%of the timeCRC is MSI+Better prognosis80%acquired methylation of MLH1 20%will be LS,2.Abnormal MLH1&PMS2 Absent,Either refer all cases to Genetics ORRefer those diagnose
15、d 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 ageORReflex to BRAF or MLH1 methylation testing&refer those without BRAF mutation or without methylation,BRAF and CRC,V600E(1799TA)mutation strongly associated with MSI
16、+and CpG island methylator phenotype(CIMP)Not yet reported in a patient with a germline MLH1 gene mutationMLH1 promoter methylationMLH1 absent on IHC,no MMR gene mutation;68%with V600E in BRAF,3.Abnormal MSH2&MSH6 Absent,3%of the timeCRC is MSI+Better prognosisMost likely LS due to either MSH2 or MS
17、H6 gene mutationAlways refer to Genetics,4.Abnormal MSH6 Absent,1%of the timeCRC is MSI+Better prognosisMost likely LS due to an MSH6 gene mutationAlways refer to Genetics,5.Abnormal PMS2 Absent,1%of the timeCRC is MSI+Better prognosisMost likely LS due to an PMS2 gene mutationAlways refer to Geneti
18、cs,The Family History Is Key to Diagnosing LS or is it?,CRCdx 50s,CRCdx 45,CRCdx 61,CRCdx 75,OvarianCa,dx 64,CRCdx 48,CRCdx 52,EndometrialCa,dx 59,CRCdx 42,45,Amsterdam II criteria,3 or more relatives with verified Lynch-associated cancer in familyTwo or more generationsOne case a first-degree relat
19、ive of the other twoOne CRC dx 50FAP excluded,Vasen HFA et al.Gastroenterology.116:1453,1999,Does not include ovarian,gastric,brain,biliary tract or pancreatic cancer,Bethesda Guidelines,Individual with CRC dx 1 FDR with an Lynch-associated tumor,with one cancer dx 2 FDRs or SDRs with an Lynch-assoc
20、iated tumor,regardless of age,Umar A,et al.JNCI.2004;96(4):261-268.,Warning:Family Histories can be Deceiving,Family size is getting smallerWider use of colonoscopy likely to prevent many colon cancersMSH6&PMS2 may have lower cancer risks,Can predict who is more likely to have LS using family histor
21、y criteria(Amsterdam&Bethesda)Can predict the likelihood of a MMR gene mutation using three new programsPREMM1,2,6 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
22、Can order MSI and/or IHC on tumor to screen for LSCan diagnose Lynch syndrome with genetic testing,Identification of Lynch syndrome in the Genetics Clinic,Identification of Lynch syndrome among all Newly Diagnosed CRC Patients,Unlikely to have good family historyHigh volumeMust rely on screening tes
23、ts 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,Columbus-area HNPCC study(1999-2005),Hampel et al.New Engl J Med 2005;352:1851-60Hampel et al.J Clin Oncol 2008;26:5783-88,CRC probands with deleteri
24、ous mutations(n=44),Age at diagnosis 51.4(range 23-87)50%diagnosed over age 5025%did not meet either Amsterdam or Bethesda criteriaMutations20.5%MLH1 52.3%MSH213.6%MSH613.6%PMS2,Hampel et al.New Engl J Med 2005;352:1851-60Hampel et al.J Clin Oncol 2008;26:5783-88,35 CRC probands have had genetic cou
25、nseling,Family Studies of 35/44 CRC Probands,Hampel et al.NEJM 2005;352:1851-60.;Hampel et al.JCO 2008.,Amsterdam:YesLynch:Yes942+3 at MSH2 mutation,Amsterdam:NoLynch:Yes3155delAG MSH6 mutation,Amsterdam:YesLynch:NoTumors MSI-with intact IHC,EGAPP Recommendations,Evaluation of Genomic Applications i
26、n Practice and PreventionEstablished in 2005 to assess evidence regarding the validity&utility of rapidly emerging genetic tests for clinical practiceIndependent,multidisciplinary panel prioritizes and selects tests,reviews CDC-commissioned evidence reports,finds gaps,and provides guidance,Steps in
27、the EGAPP Working Group Review Process,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 SSRIsMay 2007 Lynch diagnostic strategiesJanuary 2008 Gene
28、 Expression Profiling and Breast Cancer OutcomesJanuary 2009 DNA strategies aimed at reducing morbidity and mortality from Lynch syndromeJanuary 2009 Can UGT1A1 genotyping reduce M&M in pts with metastatic CRC treated w/IrinotecanJune 2009 Outcomes of genetic testing in adults with a history of veno
29、us thromboembolism,Four EGAPP Working Group Recommendations,Insufficient Evidence to recommend for or against Tumor profiling to improve outcomes in patients with breast cancerUGT1A1 genotyping to reduce morbidity and mortality in patients with metastatic CRC treated with IrinotecanUse of CYP450 tes
30、ting to predict response to SSRis in adults with depressionSufficient Evidence to recommend for4.Screening newly diagnosed CRC patients for LS with either MSI or IHC,EGAPP Recommendations,Moderate certainty that testing patients with CRC for LS and then testing their relatives would provide moderate
31、 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 testin
32、g 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 scree
33、ning for LS will reduce EC morbidity or mortality,EGAPP Genet Med 2009;11:35-41;Palomaki G,Genet Med 2010;11:42-65.,Potential Impact,146,970 new cases of CRC in the US in 20094,115 have Lynch syndrome(2.8%)12,345 of their relatives have LS(3 per proband)Total of 16,460 individuals who could be diagn
34、osed with LS this year with universal screening,American Cancer Society Facts&Figures,Choosing the Screening Test:MSI vs.IHC,IHC is available in virtually all hospitals MSI requires molecular diagnostics and normal for comparisonIHC with 4 antibodies is similar in cost to MSI with 5 markersIHC direc
35、ts gene testing saving money Ethical issues surrounding IHC IHC and MSI have limitations,Cost-effectiveness Study,Follow-up to EGAPP evidence reviewModeling used the statistics from the EGAPP reviewMy role on the project was to:Explain the various strategies one might use to screen for LSProvide Med
36、icare reimbursement rates&list prices for various tests,Strategies Compared,Cost-effectiveness Results,Incremental Cost-Effectiveness Ratios per LYS compared to no testing at all,Cost-Effectiveness Evaluation,Universal screening detects nearly twice as many cases of LS as targeting younger patientsS
37、trategy 1 is the most cost effective strategyCost-effectiveness ratio of universal screening is$25,000 per life-year saved relative to no testingICER comparable with other preventive services(colonoscopy every 10 years has ICER of$25,000),Universal IHC screening for CRC:OSU experience,Genetics notif
38、ied by pathology of all abnormal CRC resultsPermission from ordering physician to contact patientPatient contactedTake limited family historyMake recommendation for genetic consultationLetter sentIf contact cannot be made,letter is sent explaining results with our contact informationGyn/Oncs notify
39、their own patients regarding their IHC results,Universal IHC screening for CRC:OSU experience,Began March 1,2006270 cases of CRC in first 2 years57(21.1%)absent for one or two MMR proteins54 contacted by genetics with physician consent5 deceased,reported to next of kin7 prisoners34 appropriate for c
40、onsultation18 scheduled appointment 9 completed appointment7 tested2 confirmed Lynch,3 with MLH1 methylation,South et al,Genet Med 2009;11:812-817,All proteins present(80%),MSH2 and/or MSH6 absent;PMS2 only absent(5%),How to Follow-up on IHC Results,MLH1 and PMS2 absent(15%),STOP,Sequence and large
41、rearrangements for absent one(s),No germline mutation in MLH1,MSH2,MSH6,PMS2Consider family history,MSI analysis,BRAF mutation analysis,BRAF mutation present(10-12%),BRAF mutation absent(3-5%),Sequence and large rearrangements for MLH1,Universal IHC-Challenges,These patients are not as motivated to
42、seek genetic counseling and testingMany who likely have Lynch syndrome declined further counseling/testingPrisoners?Many do NOT have Lynch syndrome but we cannot rule these out without further testing-not easy to order and costBRAF testing has helped with this tremendously,OSU Successes and Pitfalls
43、,SuccessesProven need for tumor testing rather than family history relianceProven equivalence of MSI vs IHCInstitutional buy-in for universal screeningIHC plus BRAF to optimize effortsPitfallsNeed for multi-provider communication of tumor results to increase patient follow throughIHC only routine on
44、 primary CRC resectionsUninformative on many polypsIHC should be done on initial biopsy for rectal cancers since neoadjuvant radiation reduces available cancer cellsCan be ordered on any specimenEach institution requires adherence to pathology standards to assure equivalence of results,Conclusions,1 out of every 35 CRC patients has LSFamily history criteria will miss 25%of CRC patients with LS Lives can be saved by diagnosing LS earlyUniversal Screening for LS among all newly diagnosed CRC patientsIs feasibleIs recommendedIs cost-effective,Acknowledgements,
