universal screening of lynch syndrome

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

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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 - PowerPoint PPT Presentation

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Page 1: Universal Screening of Lynch Syndrome

Universal Screening of Lynch Syndrome

Heather Hampel, MS, CGCClinical Associate Professor, Division of Human Genetics

Page 2: Universal Screening of Lynch Syndrome

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

Page 3: Universal Screening of Lynch Syndrome

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The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Lynch Syndrome Cancer Risks (to 70)

Cancer MLH1& MSH2 MSH6 PMS2

♂ Colon cancer 56% 22% 20%

♀ Colon cancer 48% 10% 15%

Endometrial cancer 35% 26% 15%

♂ Other LS cancers 19.3% 3% 6%

♀ Other LS cancers 5% 11% 6%

Page 4: Universal Screening of Lynch Syndrome

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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;296:1507-17. & Vasen HFA et al. J Med Genet 2007;44:353-62.

Intervention Recommendation

Colonoscopy Every 1-2 y beginning at age 20 (MLH1), 25 (MSH2), or 30 (MSH6 & PMS2)

Endometrial sampling Every 1 y beginning at age 30-35

Transvaginal U/S Every 1 y beginning at age 30-35

Urinalysis with cytology Every 1-2 y beginning at age 25-35

History & Exam w/ review of systems

Every 1 y beginning at age 21

Page 5: Universal Screening of Lynch Syndrome

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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=0.014Death from colorectal cancer 0 9 p<0.001Overall deaths 10 26 p<0.001

Järvinen et al. 1995 and 2000

Page 6: Universal Screening of Lynch Syndrome

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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.

Page 7: Universal Screening of Lynch Syndrome

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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

Page 8: Universal Screening of Lynch Syndrome

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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

Page 9: Universal Screening of Lynch Syndrome

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)

Page 10: Universal Screening of Lynch Syndrome

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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

Page 11: Universal Screening of Lynch Syndrome

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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

PMS2MSH6

Page 12: Universal Screening of Lynch Syndrome

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The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

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

Hampel et al. New Engl J Med 2005; 352:1851-60Hampel et al. J Clin Oncol 2008; 26:5783-88

MSI positive (high & low)n=307 (19.6%)

Deleterious mutationn=44* (2.8%)

*2 had MSI- tumors

Variant of uncertain significancen=55 (3.5%)

SequenceImmunohistochemistry

Methylation of MLH1 promoter

Polymorphism or no mutationn=209 (13.4%)

Colorectal cancer Total accrued (n=1600)

Testing completed (n=1566)

MSI negativen=1259 (80.4%)

Page 13: Universal Screening of Lynch Syndrome

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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;352:1851-60.

Page 14: Universal Screening of Lynch Syndrome

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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 Kinship Tested Positive

First 99 52

Second 64 28

> Second 86 29

Total 249 109

Cascade Testing

Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.

Page 15: Universal Screening of Lynch Syndrome

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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

Page 16: Universal Screening of Lynch Syndrome

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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

Page 17: Universal Screening of Lynch Syndrome

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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, PMS2Consider family history, MSI analysis

BRAF mutation analysis

BRAF mutation present (10-12%)

BRAF mutation absent (3-5%)

Sequence and large

rearrangements for MLH1

Page 18: Universal Screening of Lynch Syndrome

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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

Page 19: Universal Screening of Lynch Syndrome

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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

Page 20: Universal Screening of Lynch Syndrome

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The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Page 21: Universal Screening of Lynch Syndrome

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The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Efficacy of Various Notification Methods

 MD Referral Genetics 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 – 4/3/2012 17 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)

11 16 16

# Needing Contact 13 75 19

Contact by Genetics 0 (0%) 47/75 (63.5%) 16/19 (84.2%)

Lynch syndrome dx 0 (0%) 8 (1.8%) 5 (3%)

Page 22: Universal Screening of Lynch Syndrome

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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; 11:812-817

Page 23: Universal Screening of Lynch Syndrome

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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

Page 24: Universal Screening of Lynch Syndrome

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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

Page 25: Universal Screening of Lynch Syndrome

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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

Page 26: Universal Screening of Lynch Syndrome

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The Ohio State University Comprehensive Cancer Center –

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Acknowledgements

Albert de la Chapelle Jenny Panescu

Judith Westman Jan Lockman

Ilene Comeras Jennifer LaJeunesse

Wendy Frankel Dan Fix

Julie Stephens Leigha Senter

Thomas Prior Mark Clendenning

Jeffrey Fowler Kaisa Sotamaa

David Cohn Yange Zhang

Edward Martin Hidewaki Nakagawa

Mark Arnold Martha Yearsley