Universal Screening of Lynch Syndrome Heather Hampel, MS, CGC Clinical Associate Professor, Division of Human Genetics

2 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Lynch Syndrome  Early but variable age at CRC diagnosis (~45 years)  Tumor site in proximal colon predominates  Extracolonic cancers: endometrium, ovary, stomach, urinary tract, small bowel, bile ducts, sebaceous skin tumors

3 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Lynch Syndrome Cancer Risks (to 70) CancerMLH1& MSH2MSH6PMS2 ♂ Colon cancer56%22%20% ♀ Colon cancer48%10%15% Endometrial cancer35%26%15% ♂ Other LS cancers19.3%3%6% ♀ Other LS cancers5%11%6%

4 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Lynch syndrome Surveillance Options Lindor N et al. JAMA 2006;296: & Vasen HFA et al. J Med Genet 2007;44: InterventionRecommendation ColonoscopyEvery 1-2 y beginning at age 20 (MLH1), 25 (MSH2), or 30 (MSH6 & PMS2) Endometrial samplingEvery 1 y beginning at age Transvaginal U/SEvery 1 y beginning at age Urinalysis with cytologyEvery 1-2 y beginning at age History & Exam w/ review of systems Every 1 y beginning at age 21

5 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 15-year prophylactic colonoscopic screening Screened Not screened n=133 n=119 Colorectal cancer 8 19 n=0.014 Death from colorectal cancer 0 9 p<0.001 Overall deaths p<0.001 Järvinen et al and 2000

6 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 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.

7 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 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

8 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Lynch Syndrome Implications for Family  6 relatives tested on average per proband identified with LS  50% with LS need increased cancer surveillance  Compliance with surveillance is good (96% for CRC and 97% for 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 can follow the ACS guidelines

9 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Can We Screen for LS Among all CRC Patients?  High volume  Pathologists will know  Age at dx  Synchronous primaries  Some metachronous primaries  Pathologists unlikely to know  Family history  Must rely on tumor screening tests for LS (MSI/IHC)

10 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 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

11 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Abnormal IHC: MSH2 & MSH6 Absent MLH1 MSH2 PMS2 MSH6

12 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Columbus-area HNPCC study ( ): Colorectal Cancer Hampel et al. New Engl J Med 2005; 352: Hampel et al. J Clin Oncol 2008; 26: MSI positive (high & low) n=307 (19.6%) Deleterious mutation n=44* (2.8%) *2 had MSI- tumors Variant of uncertain significance n=55 (3.5%) Sequence Immunohistochemistry Methylation of MLH1 promoter Polymorphism or no mutation n=209 (13.4%) Colorectal cancer Total accrued (n=1600) Testing completed (n=1566) MSI negative n=1259 (80.4%)

13 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute CRC patients with Lynch syndrome (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. NEJM 2005;352:

14 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 35 CRC probands have had genetic counseling Degree of KinshipTested Positive First9952 Second6428 > Second8629 Total Cascade Testing Hampel et al. NEJM 2005;352: ; Hampel et al. JCO 2008.

15 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Conclusions  1 out of every 35 CRC patients has LS  1 out of every 40 EC patients has LS  Family history criteria will miss 25% of CRC patients with LS and 65% of EC patients with LS  Lives can be saved by diagnosing LS early  Screening for LS among all newly diagnosed CRC and EC patients is feasible

16 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Impact for the United States  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 in the U.S. with universal screening American Cancer Society Facts & Figures

17 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute All proteins present (80%) MSH2 and/or MSH6 absent; PMS2 only absent (5%) OSU Universal Screening Algorithm -up on IHC MLH1 and PMS2 absent (15% ) STOP Sequence and large rearrangements for absent one(s) No germline mutation in MLH1, MSH2, MSH6, PMS2 Consider family history, MSI analysis BRAF mutation analysis BRAF mutation present (10-12%) BRAF mutation absent (3-5%) Sequence and large rearrangements for MLH1

18 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Challenges  Logistics!  Informed consent  Access/cost barriers for genetic counseling and testing  Psychosocial issues  Notification of at-risk relatives (duty to warn)  Compliance with counseling, testing, follow-up cancer surveillance is critical to success  Not as easy clinically as it was in the research setting

19 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Informed Consent  At OSU patients are Informed but not Consented  Recent survey of NCI-CCCs, ACS COMPS and CHCPs found that:  0/69 hospitals that responded required written informed consent  4/69 did include an opt out option  1/69 provided pre-operative information  Ethicist Richard Sharp has argued that consent is not necessary for MSI but stopped short of saying this for IHC  Triple negative breast cancers are more likely to have BRCA1 mutations but informed consent is not obtained for ER, PR, and her-2/neu status

20 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

21 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Efficacy of Various Notification Methods  MD ReferralGenetics Phone Contact Genetics In Person Contact Time Period 3/1/06 – 12/31/06 10 months 1/1/07 – 11/30/10 47 months 12/1/10 – 4/3/ months # CRC cases screened 138 (13.8/mo)447 (9.5/mo)163 (9.6/mo) Abnormal IHC 24 (17%; 2.4/mo)91 (20%; 1.9/mo)36 (22%; 2.1/mo); 1 pending *Probable methylated cases (by BRAF or hx) 1116 # Needing Contact Contact by Genetics 0 (0%)47/75 (63.5%)16/19 (84.2%) Lynch syndrome dx 0 (0%)8 (1.8%)5 (3%)

22 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Universal IHC screening for CRC: OSU experience  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 (26.5%) completed appointment  7 (21%) tested  2 (0.7%) confirmed Lynch, 3 with MLH1 methylation  YIKES!!! South et al, Genet Med 2009; 11:

23 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Universal IHC - Challenges  These patients are not as motivated to seek genetic counseling and testing  Do not know us  Another appointment at a different location  Concerns about cost  Elderly, probably MLH1 methylated cases  EtOH/drug use  Prisoners??  Many do NOT have Lynch syndrome but we cannot rule these out without further testing  BRAF testing has helped with this tremendously  Plan to either add or switch to MLH1 promoter methylation testing in next 6 months

24 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute OSU Successes and Pitfalls  Successes  Proven need for tumor testing rather than family history reliance  Proven equivalence of MSI vs IHC  Institutional buy-in for universal screening  IHC plus BRAF to optimize efforts  Pitfalls  Need for multi-provider communication of tumor results to increase patient follow through  IHC only routine on primary CRC resections  Uninformative on many polyps  IHC should be done on initial biopsy for rectal cancers since neoadjuvant radiation reduces available cancer cells  Can be ordered on any specimen  Each institution requires adherence to pathology standards to assure equivalence of results

25 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Conclusions  Universal Screening for Lynch syndrome:  Saves Lives  Is feasible  Is cost-effective  BUT, Institutional protocols need:  To be established before you start  Genetic counseling should be involved  Set up QA systems to ensure success  Multi-disciplinary support  To evolve over time

26 The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute Acknowledgements Albert de la ChapelleJenny Panescu Judith WestmanJan Lockman Ilene ComerasJennifer LaJeunesse Wendy FrankelDan Fix Julie StephensLeigha Senter Thomas PriorMark Clendenning Jeffrey FowlerKaisa Sotamaa David CohnYange Zhang Edward MartinHidewaki Nakagawa Mark ArnoldMartha Yearsley