Lynch Syndrome and Colorectal Cancer Genetics

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• Speaker(s):Heather Herrmann, MS, LCGC

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Today’s Webinar:

Disclaimer:

The information and services provided by Fight Colorectal Cancer are for general informational purposes only. The information and services are not intended to be substitutes for professional medical advice, diagnoses or treatment.

If you are ill, or suspect that you are ill, see a doctor immediately. In an emergency, call 911 or go to the nearest emergency room.

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Brought to you by the One Million Strong Collection:

One Million Strong Showcase panelist and genetic counselor, Heather Herrmann, will dive in to the topic of Lynch Syndrome to set the stage for our conversation in Nashville about Colorectal Cancer under 50.

Join us in Nashville, TN on April 1st

Speaker:Heather Herrmann, MS, LCGC is a licensed genetic counselor in Nashville, Tennessee.  Heather obtained a Bachelor of Science degree from Vanderbilt University in 1995 with a major in Biology and a minor in Chemistry.  She obtained a Master of Science degree in Genetic Counseling from the University of Pittsburgh in 2000.  Heather has enjoyed working in both pediatric genetics and cancer genetics throughout her career.  She has focused the last eight years in the area of hereditary cancer syndromes and hereditary cancer risk assessment.  She currently works at Saint Thomas Health Cancer Care – Genetics where she provides genetic counseling and risk assessment for individuals with a personal and/or family history of cancer.

Lynch Syndrome and Colorectal Cancer Genetics

March 23, 2016Heather Herrmann, MS, LCGC

Saint Thomas HealthCancer Care-Genetics

Disclosures

• No disclosures to share.

Objectives:• To Define Cancer Risk Assessment• To Describe Management Modifications• To Outline the Process of Genetic Testing for

Hereditary Colorectal Cancer conditions

The Facts• ~137,000 men and women per year diagnosed with

colorectal cancer • 5-year survival rate for early stage colorectal cancer is

>90% • 4 out of 10 cancers are found at an early stage• Polyps are the precursor to colorectal cancer• Only ½ of the people that are due for colon screening pursue screening!

Cancer.org

Even Polyps Have DreamsDailymedicalexaminer.com

Who is at risk?

Colon Cancer

Average / Sporadic RiskIncreased / Familial RiskHigh / Hereditary Risk

High Risk

Increased Risk

Average Risk

• High Risko Diagnosed or undiagnosed gene mutation o Untested, but have a 1stdegree relative

with diagnosed gene mutation

• Increased Risk o 1st Degree relative with colon cancer or

otherwise strong family historyo Personal History of colon cancer, colon

polyps or other significant risk factors

• Average Risk o No 1st degree relative with colon cancer and

no otherwise strong family historyo No personal history colon polyps, cancer or

other significant risk factors

Hereditary v familial v sporadic risk

SPORADIC FAMILIAL HEREDITARY0%

20%

40%

60%

80%

100%

120%

RISK

RISK

What are the risks for hereditary colorectal cancer?

APC

MLH1, M

SH2, E

PCAMMSH

6PMS2

BMPR1, SMAD4

STK11

MUTYH biallelic

MUTYH monoall

elicPTEN

TP53, CDH1, O

THERS0

20

40

60

80

100

120

APC

MLH1, M

SH2, E

PCAMMSH

6PMS2

BMPR1, SMAD4

STK11

MUTYH biallelic

PTEN

TP53, CDH1, O

THERS0

10

20

30

40

50

60

70

80

90Endometrial

Ovarian

Gastric

Breast

Pancreatic, Melanoma, Prostate and Other cancers

What are the other cancer risks due to these genes?

Does Risk Assessment Make a Difference?

5 year survival rates for early stage colorectal cancer > 90%

Over 60% of deaths from colon cancer could be avoided by screening

Studies show that individuals who know their risk are more likely to seek surveillance. 73% of patients known to have Lynch syndrome had a colonoscopy within 12 months after testing.

-Halbert et al. 2004

Colorectal Cancer Risk Assessment

Allows for personalized managementShould be directed through consultation with a health care providerGuidelines for management may include:– Increased screening– Medications– Surgeries to remove the organ before cancer

develops

Colorectal Cancer Risk Assessment

Red Flags • Personal history

– Cancer history• Tumor test results

– Polyp history– Inflammatory Bowel disease– Other risk factors

• Family history– Cancer history– Ancestry– Other medical or social history

• Genetic test results– Somatic– Germline

Red Flags for Personal History• Colorectal cancer BEFORE AGE 50• ≥ 2 Lynch syndrome cancers including colorectal diagnosed at any age• Abnormal tumor testing by MSI or IHC• Specific colorectal tumor features < age 60

• Endometrial cancer before age 50 (Red Flag for Lynch syndrome)• MMRPro, PREMM 1,2,6, or MMRpredict score of ≥ 5% risk of Lynch

syndrome

• ≥ 10 colon polyps• Inflammatory Bowel Disorders• Features beyond the colon including: Desmoid tumors, papillary

thyroid cancer, hepatoblastoma and others

Tumor testing

• Microsatellite Instability (MSI)• Immunohistochemistry (IHC)• BRAF testing ***• Screening tests for abnormal gene

function • Automatically ordered on all colon

cancers at SOME hospitals • If abnormal, further testing is

indicated to identify hereditary cancer.

• STILL NEED GENETIC TESTING if tumor testing is positive OR if negative but meet other Red Flags for testing.

Openi.nlm.nih.gov

Red flags for Family history alone(No personal history of cancer)

• Family history of a known genetic mutation• First or second degree relative meeting any of

the previous personal Red Flags• ≥ 2 first- or second-degree relatives with Lynch

syndrome cancers at any age• 3 first-, second- or third-degree relatives

diagnosed with colorectal or other Lynch syndrome associated cancers at any age

Degree of relation

• First Degree– Mother– Father– Siblings– Children

• Third Degree– Great-grandparents– Great-aunts and Great-

uncles– Cousins

• Second Degree– Grandparents– Aunt and Uncles– Grandchildren– Nieces & Nephews

– Great-grandchildren– Great-nieces & great-

nephews

Genetic Tests• Germline tests -Most often inheritedfrom a parent

– Single Site test – Single or multi-gene tests– Panel test results

• Somatic tests– Acquired gene mutation found via tumor tests, may be used incancer treatment decisions

Germline testing

Single Site

Single Gene

Germline Genetic Tests– Single Site test

• Evaluates the specific site on the specific gene• When a gene mutation is known in the family; the known

mutation / result must be available for single site testing– Single or multi-gene tests

• Many locations along one or many genes are evaluated to see if there is an alteration or mutation

• When clinical features indicate that a certain gene(s) may hold a mutation

– Panel test results• Many genes evaluated in one single test• When multiple genes may be considered for testing

Mutations in Specific Genes are Responsible for Hereditary Risk of Cancer

MUTYH MSH2

MSH6

PMS2

MLH1

APC

EPCAM

TP53

PTEN

CDH1

STK11

BMPR1A

SMAD4

Genes Colon Breast Ovarian Uterine Pancreatic Prostate Melanoma Other Cancer

Lynch- MLH1, MSH2, MSH6, PMS2, EPCAM

Colon Ovarian Uterine Pancreatic OC

APC Colon Pancreatic OC

MUTYH Biallelic Colon OCMUTYH Monoallelic

Colon

TP53 Colon Breast Ovarian Uterine Pancreatic Prostate Melanoma OCPTEN Colon Uterine Melanoma

STK11 Colon Uterine Pancreatic OCCDH1 Colon Ovarian

BMPR1A Colon Breast Ovarian Pancreatic OCSMAD4 Colon Breast Ovarian Pancreatic OCAXN2 ColonPOLD1 ColonPOLE ColonSCG5/GREM1 Colon

Genetic Test Results

• Positive / Clinically Significant – Increased cancer risks

• Negative / No known mutation– May have ruled out hereditary cancer risk– Management based on personal and family

history• Variant of Unknown Significance / Variant of

Uncertain Significance

Variant of Uncertain SignificanceVariant of Unknown Significance

VUS

A Variant is any sequence variation that is different from the normal.

A VUS is a Variant that May or MAY NOT be causing cancer in the person or family

Additional information will be needed to determine whether or not the change is clinically significant

Information assessed by some laboratories constantly

VUS determinations may take days, months, years

No clinical action should be taken on the basis of a VUSPERSONAL AND FAMILY HISTORY SHOULD DRIVE MEDICAL MANAGEMENT

FAMILY TESTING

Who orders genetic testing?

• Knowledgeable provider• MD, GC, NP, PA, or other• Genetic counselor or APNG

– Genetic counselors are certified, licensed in some states

• Telephone genetic counseling services • NSGC.org – FIND A GENETIC • COUNSELOR

Process for genetic testing

• Gather your history = can be done today!– Family history gathering – Surgeon General’s“My Family Health Portrait”https://familyhistory.hhs.gov/FHH/html/index.html# – Maternal and paternal history are important– Types of cancer, age of diagnosis, current age or age of death

• Share your history / talk to your doctor• Find a provider for risk assessment / genetic counseling

– May need a referral • Provide a blood or saliva sample to be sent to the laboratory

for testing• Review results with your provider

Genetic Counseling

Consultation may include:• Review of personal medical history• Review of family history• Risk assessment• Discussion of genetics• Informed consent discussion for genetic testing• Coordination of genetic testing • Result interpretation• Resource identification• Family testing coordination

Genetic Testing

Many labs, many tests

How do providers decide what to order?– Clinical assessment of history and likelihood of inherited genes– ACMG Guidelines (what is the placement of these)

What to look for in a lab or lab result?– Reputable quality– Analytical Standards

• Test Validation• Variant Classification

– Reporting Standards– Genetic counselor on staff

“ASCO believes that the tests used to detect those abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients,” ASCO President Peter Paul Yu, MD, FACP, FASCO, wrote. “Our patients depend on high quality tests as much as they depend on carefully studied, safe and effective drugs to achieve the best possible outcomes.”

How to utilize your lab result for improved health

• If Positive:– Gene related cancer risks may exist– Management is based on guidelines for high cancer risk– Family members test for risk assessment:

If positive = gene associated cancer risks If negative = cancer risks may be back to average; assess for remaining history not attributed to mutation

• If negative:– Management is based on personal and family history

• If VUS:– Management is based on personal and family history

REPRODUCTIVE OPTIONS & CONSIDERATIONS

• Prenatal diagnosis – Testing for Adult onset conditions at age of adult onset

• Assisted Reproduction• Preimplantation diagnosis = PGD

• CCMRD = Constitutional Mismatch Repair Deficiency A condition that is possible if two parents carry a mutation in the same mismatch repair gene

High Risk / Hereditary Risk medical management: NCCN guidelines and personalized management

Patients with Lynch syndrome (MLH1, MSH2, MSH6, EPCAM, PMS2 mutations)Colonoscopy is indicated every 1-2 years…..

NOT every 5 or 10 years.Colonoscopy begins at age 20-25 with MLH1, MSH2, EPCAM, or 25-30 with MSH6 or PMS2 or 2-5 years younger than the earliest person in the family with colon cancer…

NOT to begin at average screening age.Aspirin may decrease risk but not currently a recommendation for standard use

Additional cancer risks should be managed:Endometrial: hysterectomy considered after childbearing complete

evaluation of abnormal uterine bleeding screening by endometrial biopsy and transvaginal ultrasound possibleOvarian: bilateral removal of the ovaries after childbearing complete

screening by transvaginal ultrasound and / or CA-125 possibleGastric and small bowel: endoscopic ultrasound considered every 3-5 years from age 30-35Renal / transitional cell cancers: Urinalysis from 25-30 years oldBrain: Annual physical / neurologic exam from 25-30 yBreast cancer: Average-risk breast cancer screening

High Risk / Hereditary Risk medical management: NCCN guidelines and personalized management

Patients with FAP (APC mutations)Proctocolectomy or colectomy with surveillance based on treatment:If colectomy with IRA, rectal endoscopy every 6-12 months, depending on polypsIf TPC with ileal pouch-anal anastomosis or ileostomy, endoscopic evaluation every 1-3 years based on polyps and up to every 6 months based on findings

Additional cancer risks should be managed:Upper endoscopy from age 20-25 or earlier if colectomy before age 20Annual thyroid exam from late teenage years, consider annual thyroid ultrasound Annual physical / neurologic exam and annual abdominal palpation.

If family history of desmoids, consider abdominal MRI or CT 1-3 years after colectomy and then every 5-10 years with abdominal symptoms prompting immediate abdominal imaging.

Consider small bowel CT or MRI for desmoidsConsider helpatoblastoma screening via clinical trial or based on other high risk recommendations.

* If AFAP (APC mutations) and small burden of polyps, colonoscopy and polypectomy every 1-2 years with surgical intervention as polyp burden warrants

High Risk / Hereditary Risk medical management: NCCN guidelines and personalized management

Patients with MAP (two MUTYH mutations - biallelic)Colonoscopy from age 25-30 and every 2-3 years if negative. If small burden of polyps, colonoscopy and polypectomy every 1-2 years with surgical intervention as polyp burden warrants

Additional cancer risks:Consider upper endoscopy and side viewing duodenoscopy from 30-35.

High Risk / Hereditary Risk medical management: NCCN guidelines and personalized management

Patients with Peutz-Jeghers syndrome (STK11 mutations)Colonoscopy every 2-3 years from late teens

Additional cancer risk management:Breast mammogram and breast MRI annually from age 25Upper endoscopy every 2-3 years from late teensSmall bowel CT or MRI enterography at age 8-10 with follow-up based on findings until age 18 and then every 2-3 years or individualizedMRCP or endoscopic ultrasound of the pancreas every 1-2 years from age 30-35Pelvic exam and Pap smear and consider transvaginal ultrasound annually from age 18-20Annual testicular exam and observation from age 10Education about lung cancer symptoms and smoking cessation if applicable

High Risk / Hereditary Risk medical management: NCCN guidelines and personalized management

For patients with Juvenile Polyposis syndrome (SMAD4 and BMPR1A mutations)Colonoscopy annually found from age 15 and every 2-3 years if polyps are not

Additional cancer risks should be managed:Upper endoscopy annually from age 15 and every 2-3 years if polyps are found If SMAD4 mutation exists, screen for HHT within the first 6 months of life

Increased Risk / Familial Risk medical management: NCCN guidelines and personalized management

At age 40 OR 10 years before the earliest diagnosis of Colorectal cancer if:

1 first-degree relative with CRC before age 60 OR2 first-degree relatives with CRC at any age

At age 50 if:First-degree relative with CRC at age 60 y or older OR1 second-degree relative with CRC before age 50

At age 50 or at age of onset of adenoma in relative, whichever is first if:

First-degree relative with confirmed advanced adenoma(s)nccn.org

Risk-reducing opportunities– Don’t smoke– If you do smoke, stop– Increase your physical activity– Maintain a healthy body weight– Avoid overall body fat, especially fat around your

waist– Reduce how much red meat and processed meats

you eat– Use alcohol in moderation

FightColorectalCancer.org

In Summary:

• Learn YOUR risk for colon cancer and other potential cancers

• Manage that risk effectively!

Thank you!

Question & Answer: