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Universal Screening of Lynch Syndrome

Universal Screening of Lynch Syndrome. Heather Hampel, MS, CGC Clinical Associate Professor, Division of Human Genetics. Lynch Syndrome. Early but variable age at CRC diagnosis (~45 years) Tumor site in proximal colon predominates

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Universal Screening of Lynch Syndrome

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

  2. 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. Lynch Syndrome Cancer Risks (to 70)

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

  5. 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 10 26 p<0.001 Järvinen et al. 1995 and 2000

  6. 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. 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. 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. 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. 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. MSH2 MLH1 PMS2 MSH6 Abnormal IHC:MSH2 & MSH6 Absent

  12. Columbus-area HNPCC study (1999-2005):Colorectal Cancer 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

  13. 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;352:1851-60.

  14. Cascade Testing 35 CRC probands have had genetic counseling Degree of Kinship Tested Positive First 99 52 Second 64 28 > Second 86 29 Total 249 109 Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.

  15. 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. 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. OSU Universal Screening Algorithm-up on IHC MLH1 and PMS2 absent (15%) MSH2 and/or MSH6 absent; PMS2 only absent (5%) All proteins present (80%) BRAF mutation analysis Sequence and large rearrangements for absent one(s) BRAF mutation present (10-12%) BRAF mutation absent (3-5%) Sequence and large rearrangements for MLH1 STOP No germline mutation in MLH1, MSH2, MSH6, PMS2 Consider family history, MSI analysis

  18. 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. 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. Efficacy of Various Notification Methods

  21. 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; 11:812-817

  22. 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

  23. 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

  24. 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

  25. Acknowledgements

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