Familial predisposition for colorectal cancers: Who to screen?
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Transcript of Familial predisposition for colorectal cancers: Who to screen?
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Familial predisposition for colorectal cancers: Who to screen? Peter P. Stanich, MD Division of Gastroenterology, Hepatology & Nutrition 4.9.2016
• Genetics Clinic Overview
• Who to screen with CRC
• Who to screen with polyps
• How to screen everyone
Outline
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Genetic counseling Cancer genetics appointments are about 90 min They include: 1. Review of clinical history (personal and family) 2. Differential diagnosis 3. Discussion of pros/cons of genetic testing 4. Ordering, drawing and routing of genetic testing if indicated and patient provides informed consent (with knowledge of insurance and lab rules) 5. Perhaps most importantly post-result counseling
Genetic counseling Benefits of genetic counseling and testing:
Accurate counseling for patients of risks for cancers (both another colon cancer as well as other cancers) Predictive testing of at risk family members
*If positive, prevent colon cancer through screening! *If negative, save patient from a lot of colonoscopies!
Federal laws protecting against employment or health insurance discrimination
Genetic testing Consists of single blood draw or mouthwash kit performed
during visit Can now test for multiple genes (even 70+) if needed for
same cost Labs have guaranteed maximum out of pocket costs and
often as little as $100 independent of insurance coverage
Why are hereditary colorectal cancer syndromes important?
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Lynch Syndrome
Who to screen? Everyone with colon cancer and high risk personal or family
history?
Everyone with colon cancer?
Everyone with a family history of colon cancer?
Eventual answer… maybe everyone.
The hard part is how? And what type of screening?
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Screen patients with CRC High risk personal history High risk family history Abnormal tumor testing
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When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
High risk personal history
Prevalence of Lynch syndrome among early onset CRC patients (from highly selected patient populations) 8.4% dx <50 1,2 12% dx <35 3 13.6% dx <50 4
Prevalence of other cancer syndromes among early onset CRC patients (from highly selected patient populations) 4% dx <50 4 11% dx <35 3
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1Hampel et al. New Engl J Med 2005; 352:1851-60 2Hampel et al. J Clin Oncol 2008; 26:5783-88
3Mork et al. J Clin Oncol 2015; 33 4Yurgelun et al. Gastroenterology 2015; 149:604-613
Ohio Colon Cancer Prevention Initiative All patients with CRC resection in OH in 2013 – 2016 are
eligible
Free testing and counseling for patients and if mutation identified for their at-risk relatives
Ohio Colorectal Cancer Prevention Initiative (OCCPI)
Statewide initiative began 1/1/2013 Establish prevalence of
hereditary CRC in Ohio Increase colonoscopy
compliance among relatives Establish research
infrastructure 50 collaborating hospitals
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Ohio
Columbus
Cleveland
Cincinnati
Toledo
Dayton
Akron
OCCPI data 365 Ohioans under 50 with CRC in the study 53 (14.5%) had at least 1 clinically actionable mutations 8.5% Lynch syndrome 5.5% other syndrome (including 6 with BRCA1/2!) 0.5% 2 syndromes (PMS2 and APC mutation)
If only targeted-testing had been performed, 17 (31%) would have been missed All early-onset CRC patients should be referred for genetic
testing with a comprehensive hereditary cancer gene panel. 14
Pearlman et al. Personal Communication.
Overall OCCPI data to this point: 2601 CRC patients enrolled Lynch: 3.7% Other hereditary syndromes: 2.2% Stay tuned for updated recommendations on who needs referred based on this data
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
Lynch syndrome Amsterdam II Criteria The 3-2-1 rule
*Many would also include ovary, stomach, HB and brain
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.
Oncologists and family history Difficult to obtain family history during busy office visits CRC lagging behind breast cancer…
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Wood et al. Quality of Cancer Family History and Referral for Genetic Counseling and Testing Amoung Oncology Practices. JCO 2014.
Oncologists and family history Furthermore, lower percentage of increased risk
for hereditary CRC are referred…
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Wood et al. Quality of Cancer Family History and Referral for Genetic Counseling and Testing Amoung Oncology Practices. JCO 2014.
Oncologists and family history Gold standard for Genetics: 3 generations Goal for Oncologists: 2 generations
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Lu et al. ASCO Expert Statement: Collection and Use of a cancer Family History for Oncology Providers. JCO 2014.
High risk personal and family history There are clinical predictive models available
*If concerned, recommend Genetics referral for providers with expertise and most importantly time!
http://premm.dfci.harvard.edu/
Lynch syndrome Previously labeled “hereditary non-polyposis colorectal
cancer” in past, but this is vague and potentially misleading De novo mutations rare (2.3%), or less likely than paternal
discrepancy (3.7%) [Win, J Med Genet. 2011 and Bellis, J Epidemiol Community Health 2005]
Clinical manifestations of Lynch syndrome Development of colorectal and extracolonic malignancies at
young ages
Lynch syndrome There is rapid progression from adenoma to CRC in
comparison to accepted 10-15 year interval for sporadic polyps
Edelstein et al. Rapid development of colorectal neoplasia in patients with Lynch syndrome. Clin Gastroenterol Hepatol. 2011 Apr;9(4):340-3.
Lynch syndrome
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50 weeks later Index colonoscopy
Clinical care of Lynch patients Large-scale surveillance programs have achieved a 62 %
reduction in incidence of CRC and a 65–70 % decrease in mortality. (Fam Cancer. 2013 Jun;12(2):261-5.)
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
Tumor testing Revised Bethesda Criteria: meant to identify candidates for
tumor testing
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.
Tumor testing Bethesda criteria misses 28% of Lynch syndrome
Why Bethesda criteria is often inadequate…
Family size shrinking
Success of CRC screening in decreasing cancer incidence
Difficulty obtaining full family history in busy clinical setting
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.
Colorectal (and Endometrial) tumor testing OSU, USMSTF and NCCN favor universal tumor testing:
1. Greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies
2. Cost-effectiveness ratio comparable to other accepted preventive services (e.g., colonoscopy for average risk patients)
Hampel H. Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer. JNCCN 2010. Moreira L. Identification of Lynch syndrome among patients with colorectal cancer. JAMA 2012.
Tumor testing Immunohistochemistry (IHC) is our standard test at OSU
More commonly performed in US centers
Utilizes antibodies to the Lynch genes
Absence of staining is abnormal
Mismatch Repair Immunohistochemistry
Normally present If protein absent, gene
not being expressed (mutation/methylation) Benefit over MSI testing
is this can direct gene testing by predicting likely involved gene
MSH2 MLH1
MSH6 PMS2
MLH1 & PMS2 Absent
15% of the time if CRC is MSI 80% acquired
methylation of MLH1 20% will be LS Reflex to test for
BRAF or MLH1 hypermethylation to clarify
MLH-1 MSH-2
MSH-6 PMS-2 *If BRAF mutation or MLH1 hypermethylation positive, tumor is sporadic and no further testing needed.
MSH2 & MSH6 Absent
3% of the time if CRC is MSI Most likely LS due
to MSH2 (MSH6 or EPCAM less likely) gene mutation
MLH-1 MSH-2
PMS-2 MSH-6
MSH6 Absent
1% of the time if CRC is MSI Most likely LS due
to an MSH6 gene mutation
MLH-1 MSH-2
MSH-6 PMS-2
PMS2 Absent
1% of the time if CRC is MSI Most likely LS due
to a PMS2 gene mutation
MLH-1 MSH-2
MSH-6 PMS-2
Tumor testing Which is better initial test – MSI or IHC?
Pro of IHC – Faster, Can direct genetic testing to a specific gene, better detection of PMS2 and MSH6
Con of IHC – Operator and lab dependent, who refers for counseling/testing after result?
Pro of MSI – May affect Onc plans for chemotherapy
Con of MSI – Not available in most labs, Does not direct genetic testing, increased need for 2nd tests (IHC and/or BRAF and/or hypermethylation and/or genetic)
Giardiello et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. AJG 2014.
Tumor testing Don’t need to memorize, but remember where to look for this (NCCN
guidelines) If any question, refer to Genetics
Case 70 year old female with IC valve mass and hepatic flexure
large 2.5 cm polyp Mother had CRC at 65 and maternal Aunt with CRC at 55
What to do next with path?
Final diagnosis Sporadic CRC
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
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• Bullet point one
• Bullet point two
• Bullet point three
PTEN hamartoma tumor syndrome (AKA Cowden syndrome) Increased risk for CRC (newly described, SIR 10) Recommend colonoscopy at age 35
High risk of other cancers with standardized incidence ratio included: Breast cancer – 25 (example of SIR: expected 2.6 in cohort, had 67)
Thyroid cancer - 52 Endometrial – 43 Kidney – 30 Melanoma – 8.5
43 Tan et al. AACR 2012.
Cowden syndrome clinical manifestations:
• Skin and oral findings are pathognomic and most common:
1. Trichilemommas – hair follicle hamartomas
Brownstein et al. Tichilemmomas in Cowden’s disease. JAMA 1977.
PTEN hamartoma tumor syndrome
2. Acral keratoses – papules on hands and feet
3. Facial papules and mucocutaneous papilloma – often form cobblestone appearance
Stanich et al. CGH 2011.
PTEN hamartoma tumor syndrome
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
Li Fraumeni syndrome
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Villani et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011.
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
Flowchart for Hereditary Colon Cancer Differential Diagnosis
Presence of >10 polyps
Type of polyps - Lynch syndrome
- Familial Colorectal Cancer syndrome type X
- Peutz-Jeghers syndrome
- Juvenile Polyposis - Cowden syndrome
-Serrated Polyposis syndrome -Hereditary mixed polyposis syndrome
- Familial Adenomatous Polyposis -MYH-Associated Polyposis
- Polymerase Proofreading-Associated Polyposis
No Yes
Adenomatous Other
Presence of >10 adenomas or
non-adenomatous polyps
Familial adenomatous polyposis
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When to refer to Genetics? Can we diagnose patients before they develop colon
cancer?
When to refer to Genetics?
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Hampel et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2014.
Pre-endoscopy history questionnaire A simple and validated risk assessment tool to identify high
risk patients for hereditary colon cancer syndromes
The questions identified 77 % of high-risk individuals in large cohorts (Brigham and MN GI) and 95% of Lynch mutation carriers (Commercial lab database).
Also endorsed by USMSTF Lynch syndrome guidelines
(published 2014)
Kastrinos et al. Development and validation of a colon cancer risk assessment tool for patients undergoing colonoscopy. AJG 2009.
Pre-endoscopy history questionnaire
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OSU GI Genetics clinics Cancer Genetics appointments Genetic counselor Genetics physician
- Focused on diagnostics - Clinical recommendations given with results
Hereditary colon cancer syndrome clinic - Dr Peter Stanich - Focused on consultative long term care of patients diagnosed with or
suspected of having an inherited cancer predisposition - Close collaboration with The James CRC group and Cancer Genetics
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Thank you I am happy to answer questions
now or in the future I would love to help arrange any
referrals to Cancer Genetics or GI as needed GI office - 614 293 – 6255 Genetics office - 614 293 – 6694
Thank You To learn more about Ohio State’s cancer program, please visit cancer.osu.edu or
follow us in social media:
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12% <1% 85% FAP
Sporadic
MIN (MSI+) (Microsatellite Instability)
CIN (Chromosome Instability)
Lynch Sx Sporadic MSI(+)
Germline Mutation MMR genes
15%
3%
•Epigenetic silencing of MLH1 by hypermethylation of its promoter region
85%
Colorectal cancer tumor testing
Germline Mutation APC