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.


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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


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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.)


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Tumor testing Revised Bethesda Criteria: meant to identify candidates for

tumor testing


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


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


to an MSH6 gene mutation

MLH-1 MSH-2

MSH-6 PMS-2

PMS2 Absent


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)


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


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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


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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.


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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?


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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

[email protected]

Thank You To learn more about Ohio State’s cancer program, please visit cancer.osu.edu or

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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

Health & Medicine

Familial predisposition for colorectal cancers: Who to screen?