Universal Screening of Lynch Syndrome
Heather Hampel, MS, CGCClinical Associate Professor, Division of Human Genetics
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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)
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%
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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
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=0.014Death from colorectal cancer 0 9 p<0.001Overall deaths 10 26 p<0.001
Järvinen et al. 1995 and 2000
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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.
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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
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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
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
PMS2MSH6
12
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%)
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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.
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 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.
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, PMS2Consider 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 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%)
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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
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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
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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
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 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