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
 Extracolonic cancers:
endometrium, ovary, stomach,
urinary tract, small bowel, bile
ducts, sebaceous skin tumors
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
2
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%
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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Lynch syndrome Surveillance Options
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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
Lindor N et al. JAMA 2006;296:1507-17. & Vasen HFA et al. J Med Gen
4
15-year prophylactic colonoscopic screening
Screened
n=133
Colorectal cancer
Death from colorectal cancer
Overall deaths
Not screened
n=119
8
0
10
19
9
26
n=0.014
p<0.001
p<0.001
Järvinen et al. 1995 and 2000
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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Abnormal IHC:
MSH2 & MSH6 Absent
MLH1
MSH2
MSH6
PMS2
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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Columbus-area HNPCC study (1999-2005):
Colorectal Cancer
Colorectal cancer
Total accrued (n=1600)
Testing completed (n=1566)
MSI positive (high & low)
MSI negative
n=307 (19.6%)
n=1259 (80.4%)
Sequence
Immunohistochemistry
Methylation of MLH1 promoter
Deleterious mutation
n=44* (2.8%)
*2 had MSI- tumors
Variant of uncertain
significance
Polymorphism
or no mutation
n=55 (3.5%)
n=209 (13.4%)
Hampel et al. New Engl J Med 2005; 352:1851-60
The Ohio State University Comprehensive Cancer Center –
G. James Cancer Hospital and Richard J. Solove
Hampel et al. J Clin Oncol 2008; 26:5783-88 Arthur
Research Institute
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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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
13
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.
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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OSU Universal Screening Algorithm-up on IHC
All proteins present
(80%)
MLH1 and PMS2
absent
(15%)
BRAF mutation
analysis
BRAF mutation
present (10-12%)
BRAF mutation
absent (3-5%)
MSH2 and/or
MSH6 absent;
PMS2 only absent
(5%)
Sequence and
large
rearrangements
for absent one(s)
Sequence and
large
rearrangements
for MLH1
STOP
No germline mutation in MLH1, MSH2, MSH6, PMS2
Consider family history, MSI analysis
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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Efficacy of Various Notification Methods
MD Referral

Time Period
# CRC cases
screened
Abnormal IHC
Genetics Phone Genetics In
Contact
Person Contact
3/1/06 – 12/31/06 1/1/07 – 11/30/10 12/1/10 –
10 months
47 months
4/3/2012
17 months
138 (13.8/mo)
447 (9.5/mo)
163 (9.6/mo)
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%)
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
25
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
The Ohio State University Comprehensive Cancer Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute
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