Download Emory University - Lynch Syndrome Screening Network

Universal Screening for
Lynch Syndrome
Cecelia Bellcross, PhD, MS, CGC
Emory University School of Medicine
Department of Human Genetics
Genetics of CRC
Sporadic
(65%–85%)
Rare CRC
syndromes
(<0.1%)
MYH associated
polyposis (MAP)
(1%)
Familial adenomatous
polyposis (FAP) (1%)
Familial
(10%–30%)
Lynch syndrome
(aka Hereditary
nonpolyposis
colorectal cancer HNPCC) (3%)
Clinical Features of Lynch/HNPCC
• Early but variable age at
CRC diagnosis (~45 years)
• Tumor site in proximal
colon predominates
• Metachronous/synchronous
CRCs
• Extracolonic cancers:
endometrium, ovary,
stomach, urinary tract,
small bowel, bile duct,
pancreatic, sebaceous skin
tumors; brain tumors
A Classic HNPCC/Lynch Family
CRC
dx 50s
CRC
dx 45
CRC
dx 61
CRC
dx 48
CRC
dx 52
Endometrial
Ca, dx 59
CRC
dx 75
45
CRC
dx 42
Ovarian
Ca, dx 64
Other Features of Lynch Syndrome
• Autosomal dominant inheritance
• Genes belong to DNA mismatch repair
(MMR) family
• Genetic heterogeneity (MLH1, MSH2,
MSH6, PMS2)
• CRC lifetime risk 30-80%
• Endometrial cancer lifetime risk 30-60%
Cumulative Risk Colorectal Cancer
(%)
CRC RISK
100
90
80
70
60
50
40
30
20
10
0
Male MLH1
Male MSH2
Female MLH1
Female MSH2
18-29 30-39 40-49 50-59 60-69 70-79
Age (years)
*Barrow, Clin Genet 2008
Extra-colonic/Extra Endometrial
Lifetime Cumulative Incidence to age 70 yo:
• Urologic tract (8.4% overall)
– MLH1: female =1.1%, Male = 3.7%
– MSH2: female =11.9%, Male = 27.8%
•
•
•
•
Ovary = 6.7%
Gastric = 5.8%
Small Bowel = 4.3%
Biliary/Pancreatic = 4.1%
Watson, Int. J. Cancer, 2008
Surveillance/Prevention Options for
Lynch syndrome (Lindor JAMA, 2006;296:1507)
Cancer
Site
Surveillance/ Prevention
Colon
Rectum
Colonoscopy
Uterus
Transvaginal Ultrasound /
Endometrial Biopsy
Frequency
Every 1-2 years
20-25 (30)
(Colectomy)
Every year
Hysterectomy
Ovary
Begin Age:
30-35
30+
Transvaginal Ultrasound / CA-125
Every year
Oral contraceptives
> 5 years
Oophorectomy
30-35
30+
Stomach
Small Bowel
Upper Endoscopy
Every 2 years
30-35
Pancreas
Biliary
Liver function tests & Abdominal
Ultrasound
Every year
30-35
Urinary Tract
Urinalysis cytology
Every year
30-35
Renal Ultrasound
Every 1-2 years
30-35
Dermatology Exam
Every year
20-25
Skin Lesions
Percent
Impact of Screening
45
40
35
30
25
20
15
10
5
0
Screened Group
(n=44)
Control Group
(n=46)
Jarvinen, Gastroent, 2000
Incidence
Mortality
Jarvinen, JCO, 2009: 242 mutation +, 367 mutation - : >95%
screening compliance, no difference in cancer or all cause mortality
rates
Amsterdam II Criteria





3 or more relatives with verified HNPCC
associated tumor (CRC, endometrial, ovarian,
gastric, small bowel, urinary tract) in family
One case a first-degree relative of the other
two
Two or more generations involved
One or more cancer diagnosed by age 50
FAP excluded
Failure to meet these criteria does not
exclude HNPCC
Revised Bethesda Guidelines:
• CRC < age 50
• Patient with 2 HNPCC related tumors
• Patient with CRC < age 60 with MSI-H
histology
• Patient with CRC with 1st degree relative with
HNPCC related cancer; one of the cancers at
< 50 years
• Patient with CRC and 2 or more relatives with
HNPCC-related cancer regardless of age
Umar, JNCI, 2004
Microsatellite Instability
Normal Cells
-CG-CGCGCGCG
-CG-CGCGCGCG
-CG
-CGCGCGCG-
-CG-CGCGCGCG
Normal Microsatellites
Tumor Cells
-CG-
-CG-
-CGCGCGCGCG-
-CGCGCG-
-CG-CGCG-
-CG-CGCG-CGCGCG-CGCGCGCGCG-
Microsatellite Instability
Immunohistochemistry
Abnormal or missing
MSH2 protein
Abnormal Gene (MSH2)
MSH2+
Normal tissue
MSH2-
Tumor tissue
Lack of MSH2
expression,
negative IHC
staining for
MSH2 protein
Testing for Lynch/HNPCC
Family/Medical history meets screening criteria
Amsterdam/Bethesda
MSI-High
IHC – loss of protein
expression
Genetic Testing
on blood
MSI/IHC
on tumor tissue
No mutation
Identified
MSI normal
IHC normal
No further testing
Risks & screening
based on history
1. Consider additional genetic testing
Mutation
Identified
2. Risks & screening based on test results
and family/medical history
Lynch/HNPCC screening & management
Family members offered testing
Rationale for HNPCC/Lynch Syndrome
Screening of Newly Diagnosed CRC
• Common: ~ 3% of all CRC
• Age/screening criteria miss up to 25%
• Accurate methods (MSI/IHC) using easily
accessible tumor tissue
• Benefits of medical intervention
– Cascade testing of family members
– Surveillance/prevention
– CRC treatment decisions
• Evidence of cost-effectiveness
EGAPP Lynch Recommendation
Genetics in Medicine January 2009
GIM, 2009;1:35
May, 2007
www.ahrq.gov/downloads/pub/
evidence/pdf/hnpcc/hnpcc.pdf
GIM, 2009;1:42
Summary Statement
“The Evaluation of Genomic Applications in Practice
and Prevention (EGAPP) Working Group found
sufficient evidence to recommend offering genetic
testing for Lynch syndrome to individuals with newly
diagnosed colorectal cancer (CRC) to reduce morbidity
and mortality in relatives.
We found insufficient evidence to recommend a specific
genetic testing strategy among the several examined.”
Columbus-area HNPCC study (1999-2005)
2.8% of CRC probands with deleterious
mutations (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. New Engl J Med 2005; 352:1851
Hampel et al. J Clin Oncol 2008; 26:5783
Family Studies of 35/44 CRC Probands
35 CRC probands have had genetic counseling
Degree of Kinship
First
Second
> Second
Total
Tested
99
64
86
249
Positive
52
28
29
109
Hampel et al. NEJM 2005;352:1851-60.; Hampel et al. JCO 2008.
Theoretical
Population
Health Benefit
Bellcross, Genet
Med, 2012
Healthy People 2020
Approved Genomics Objective
(Developmental)
“Increase the proportion of persons with newly diagnosed
colorectal cancer who receive genetic testing to identify
Lynch syndrome”
Endometrial cancer
2.5 % with deleterious mutations (n=14)
• Age at diagnosis – 54.1 (range 39-69)
• 65% diagnosed over age 50
• 65% did not meet either Amsterdam or Bethesda
criteria
• Mutations
–
–
–
–
14.3% MLH1
21.4% MSH2
64.3% MSH6
No PMS2
Hampel H et al. Cancer Res. 2006; 66:7810
Hampel H et al. Cancer Res. 2007;67:9603
Columbus HNPCC study
Family studies of 14 EC probands
12/14 EC probands have had genetic counseling
Degree of Kinship
First
Second
> Second
Total
Tested
28
12
8
48
Positive
16
3
2
21
EGAPP Data Interpretation
Concerns
• “To reduce morbidity and mortality in
relatives”
– Implies no benefit to proband
• Increasing evidence of impact on CRC management
– chemotherapy, surgery
• Known increased risk for 2nd primary colorectal
cancers and other tumors impacts medical
management
• Does not take into account current practice and
insurance coverage (including Medicare)
Potential Impact on CRC
treatment
• MSI-H tumors
– Better prognosis (Popat, JCO 2005;23:609)
– Lack of impact of 5FU on RFS/OS (DesGuetz, Eur J
Cancer 2009;45:1890)
• Surgical (Gut 2011;60:950 – 382 LS gene mutation carriers
– Extensive colectomy – 0/50 metachronous tumors
vs. Segmental resection – 74/322 (22%)
– Cumulative risk of metachronous CRC at 10, 20,
& 30 yrs = 16%, 41% & 62% respectively
Cost effectiveness Data
Targeting screening only to CRCs < age 50 would miss over 50% of LS cases
Mvundura M, et al. Genet Med. 2010;12:93-104
Business Analysis by a Healthcare
System
• Evidence review & computerized simulation
models – Intermountain Healthcare
• Cost of screening all (unselected) CRC
patients for Lynch syndrome <$25,000/LYS
• IHC with methylation studies, reflexing to
BRAF most efficient
Gudgeon, Am J Managed Care, 2011;17:e288
Universal IHC screening for CRC: OSU experience
• Began March 1, 2006
• 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 completed appt
– 7/9 tested
• 2 confirmed Lynch, 3 with MLH1 methylation
South et al, Genet Med 2009; 11:812-817
Challenges to Implementation









Lack of provider knowledge of Lynch syndrome and
testing issues
Question of informed consent
Availability of genetic services
Cost and coverage
Psychosocial impact
Informing relatives – who is responsible?
Patient and provider compliance
Infrastructure needs
Testing limitations (e.g. IHC accuracy by site)
It takes a team
Surgery
Pathology
Oncology
Gastroenterology
Genetics
Gynecology
Patients
Families
Healthcare system
http://www.lynchscreening.net
LSSN Vision and Mission
• LSSN Vision:
– to reduce the cancer burden associated with Lynch
syndrome.
• LSSN Mission:
– to promote universal Lynch syndrome screening on all
newly diagnosed colorectal and endometrial cancers; to
facilitate the ability of institutions to implement appropriate
screening by sharing resources, protocols and data through
network collaboration; and to investigate universal screening
for other Lynch syndrome related malignancies
Membership Data
Emory LS Screening Team
N. Volkan Adsay, MD
Cecelia A. Bellcross PhD, MS, CGC
Amanda Eppolito, MS, CGC
Alton B. Farris, III, MD
Natalyn N. Hawk, MD
Ira R. Horowitz, MD
John Kauh, MD
Namita Khanna, MD
Dana M. Meaney-Delman, MD
Virginia O. Shaffer, MD
Christine Stanislaw, MS, CGC
Patrick S. Sullivan, MD
Pathology
Genetics
Genetics
Pathology
Hem/Onc
Gyn/Onc
Hem/Onc
Gyn/Onc
High Risk Gyn
Colorectal Surgery
Genetics
Colorectal Surgery
Miranda Chergosky – GC Student Focus Intern
Emory LS Screening Protocol
IHC Result Interpretation
IHC Result
MLH1 & PMS2
Absent
Frequency
15%
Implications
Follow-up
80% acquired
BRAF (V600E +) and/or
MLH1 hypermethylation
20% LS due to
MLH1 mutation
Genetics referral & MLH1
DNA analysis
MSH2 & MSH6
Absent
3%
Most LS due to
MSH2 mutation
Genetics referral & MSH2
DNA analysis
MSH6 or PMS2
Absent
2%
Most LS due to
MSH6 or PMS2
mutation
Genetics referral &
MSH6/PMS2 DNA analysis
Genetics Follow-up
• Access to CoPath – automatic search for all
CRC specimens
– Monitor if IHC being done – interface with GI
path fellows
– Review IHC/BRAF results
• Enter into LSSN database
• Abnormal IHC results
• Follow-up letter to MD via EMR
• Coordination with RN staff to ensure genetics referral
• Subset of IHC positive screens to be seen at point of
care (post-op or oncology appt)
• Enter follow-up/outcome data into LSSN db
What Is Cancer Genetic Counseling?
• Cancer genetic counseling is NOT genetic
testing!
• It is a process of information gathering, risk
assessment and education.
• The goal of cancer genetic counseling is to
provide the individual, family and their health
care providers with accurate cancer risk
information to facilitate personal management
decisions.
Initial Genetic Counseling Visit
•
•
•
•
Review medical history and family history
Assess risk for hereditary cancer
Discuss cancer biology and genetics
Discuss genetic testing options and/or referrals
for additional evaluation if appropriate
• Discuss implications of testing for the patient
and their family
• Coordinate testing including review of
insurance issues
Informed Consent:
Potential Benefits of Genetic Testing
• Improved cancer risk management
– Prevention
– Early detection
– Avoidance of unnecessary and costly screening and
surgery
• Relief from uncertainty and anxiety about cancer
risk
• Information for individual and family members
• Lifestyle decision making
Informed Consent:
Limitations of Genetic Testing
• Not all mutations are detectable
• Uncertain significance of some mutations
• Negative result is fully informative only if
mutation has been identified in family
• Results indicate probability, not certainty, of
developing cancer
• Management/screening strategies continually
evolving as new data collected
Ideally, Begin Testing
With an Affected Person
Colon Ca, 42
Colon Ca, 38
d.45
Test first, if
possible
Colon
Ca, 45
Person seeking
counseling
(proband)
If a mutation is found in an affected person, testing
will be more informative for other family members.
Understanding Possible Test Results
Increased Cancer Risk
Positive
Negative
Uncertain
Variant
Has a mutation
been found in the
family?
Y
N
NO Increased Cancer
Risk
Cancer Risk Not
Altered
(individualized empiric
risk based on family
history)
Impact of Genetic Testing
Family with known mutation
Colon Ca, 52
d. 50
MSH2?
*
Colon
Ca, 45
MSH2 +
30
MSH2+
Mutation Positive:
initiate screening
Endometrial
Ca, 47
37
MSH2 -
True negative: no increased
risk beyond general
population
Informed Consent:
Potential Risks of Genetic Testing
• False sense of security if test negative
• Psychological distress
• Change in family dynamics
• ?? Insurance discrimination
The Myth of Genetic Discrimination
• No well-documented cases of health
insurance loss, denial, or rate
increase based on cancer genetic
testing
• State and Federal laws exist
which address health insurance and
employment
• GINA – Genetic Information Nondiscrimination Act (May, 2008)
• Life/disability/long-term care not
protected
Result Disclosure and Post-test
Counseling
•
•
•
•
•
•
Assess cancer risk based on test results
Discuss any additional testing recommendations
Review of implications for family members
Present screening and management options
Discuss risk reduction strategies
Explore psychosocial adjustment to cancer risk and/or
genetic risk
Questions
Comments
Thoughts
Suggestions
?
Thank You