March 2016 Webinar - Lynch Syndrome & Hereditary Colorectal Cancer
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Genetic counselor, Heather Herrmann, will dive in to the topic of Lynch Syndrome & CRC. 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.
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March 2016 Webinar - Lynch Syndrome & Hereditary Colorectal Cancer
- 1. Our webinar will begin shortly. WELCOME!
- 2. • Speaker(s):Heather Herrmann, MS, LCGC • Archived Webinars: FightColorectalCancer.org/Webinars • AFTER THE WEBINAR: Expect an email with links to the material & a survey. If you fill it out, we’ll send you a Blue Star pin. • Ask a question in the panel on the RIGHT SIDE of your screen • Follow along via Twitter – use the hashtag #CRCWebinar Today’s Webinar:
- 3. 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. Fight Colorectal Cancer never recommends or endorses any specific physicians, products or treatments for any condition.
- 4. 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
- 5. 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.
- 6. Lynch Syndrome and Colorectal Cancer Genetics March 23, 2016 Heather Herrmann, MS, LCGC Saint Thomas Health Cancer Care-Genetics
- 7. Disclosures • No disclosures to share.
- 8. Objectives: • To Define Cancer Risk Assessment • To Describe Management Modifications • To Outline the Process of Genetic Testing for Hereditary Colorectal Cancer conditions
- 9. 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 Dreams Dailymedicalexaminer.com
- 10. Who is at risk? Colon Cancer Average / Sporadic Risk Increased / Familial Risk High / Hereditary Risk
- 11. High Risk Increased Risk Average Risk • High Risk o 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 history o 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 history o No personal history colon polyps, cancer or other significant risk factors
- 12. Hereditary v familial v sporadic risk 0% 20% 40% 60% 80% 100% 120% SPORADIC FAMILIAL HEREDITARY RISK SPORADIC FAMILIAL HEREDITARY
- 13. What are the risks for hereditary colorectal cancer? 0 20 40 60 80 100 120
- 14. 0 10 20 30 40 50 60 70 80 90 APC MLH1, MSH2, EPCAM MSH6 PMS2 BMPR1, SMAD4 STK11 MUTYH biallelic PTEN TP53, CDH1, OTHERS Endometrial Ovarian Gastric Breast Pancreatic, Melanoma, Prostate and Other cancers What are the other cancer risks due to these genes?
- 15. 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
- 16. Colorectal Cancer Risk Assessment Allows for personalized management Should be directed through consultation with a health care provider Guidelines for management may include: – Increased screening – Medications – Surgeries to remove the organ before cancer develops
- 17. 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
- 18. 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
- 19. 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
- 20. 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
- 21. 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
- 22. Genetic Tests • Germline tests -Most often inherited from 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 in cancer treatment decisions
- 23. Germline testing Single Site Single Gene
- 24. 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
- 25. Mutations in Specific Genes are Responsible for Hereditary Risk of Cancer MUTYH MSH2 MSH6 PMS2 MLH1 APC EPCAM TP53 PTEN CDH1 STK11 BMPR1A SMAD4
- 26. 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 OC MUTYH Monoallelic Colon TP53 Colon Breast Ovarian Uterine Pancreatic Prostate Melanoma OC PTEN Colon Uterine Melanoma STK11 Colon Uterine Pancreatic OC CDH1 Colon Ovarian BMPR1A Colon Breast Ovarian Pancreatic OC SMAD4 Colon Breast Ovarian Pancreatic OC AXN2 Colon POLD1 Colon POLE Colon SCG5/GREM1 Colon
- 27. 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
- 28. Variant of Uncertain Significance Variant 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 VUS PERSONAL AND FAMILY HISTORY SHOULD DRIVE MEDICAL MANAGEMENT
- 29. FAMILY TESTING
- 30. 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
- 31. 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
- 32. 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
- 33. 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.”
- 34. 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
- 35. REPRODUCTIVEOPTIONS & 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
- 36. 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 possible Ovarian: bilateral removal of the ovaries after childbearing complete screening by transvaginal ultrasound and / or CA-125 possible Gastric and small bowel: endoscopic ultrasound considered every 3-5 years from age 30-35 Renal / transitional cell cancers: Urinalysis from 25-30 years old Brain: Annual physical / neurologic exam from 25-30 y Breast cancer: Average-risk breast cancer screening
- 37. 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 polyps If 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 20 Annual 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 desmoids Consider 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
- 38. 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.
- 39. 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 25 Upper endoscopy every 2-3 years from late teens Small 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 individualized MRCP or endoscopic ultrasound of the pancreas every 1-2 years from age 30-35 Pelvic exam and Pap smear and consider transvaginal ultrasound annually from age 18-20 Annual testicular exam and observation from age 10 Education about lung cancer symptoms and smoking cessation if applicable
- 40. 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 15and 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
- 41. 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 OR 2 first-degree relatives with CRC at any age At age 50 if: First-degree relative with CRC at age 60 y or older OR 1 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
- 42. 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
- 43. In Summary: • Learn YOUR risk for colon cancer and other potential cancers • Manage that risk effectively!
- 44. Thank you!
Editor's Notes
- No disclosures except that I work at Saint Thomas Health in support of this fine looking group of men. Now let’s take a few minutes to discuss Lynch syndrome and colorectal cancer genetics.
- And as we begin to think about Lynch syndrome and Colorectal Cancer Genetics, it’s important to think about the big picture… In order to know how to optimize medical management, it’s important to understand how to clarify the personalized risk for colorectal cancer. So today, I plan… To Define Risk Assessment: What IS your risk – is it average, increased or high? To Describe Management Modifications - How does risk direct or impact care? To Outline the process of Genetic Testing for Hereditary Colorectal Cancer Conditions – Clarify the Testing process and ensuring that everyone listening knows where and how to find out their own personal risk for colorectal cancer so that they can best manage that risk.
- Colorectal Cancer is the second leading cause of cancer death for men + women combined; it impacts 137,000 patients / year. When caught at an early stage, 5-year survival rate is >90%. Only 4 out of 10 cancers are found at this stage. In general, takes 10-15 years for a colon polyp to develop into colorectal cancer. As you may know, colon polyps are the precursor of colorectal cancer. The colon polyp develops from the lining of the polyp and grow until it becomes a colon cancer. Only ½ of those that should have a colonoscopy people who should be tested for colorectal cancer get screened! 1/3 adults age 50-75 are NOT up to date with recommended screening. Describe the cartoon: So as you see in the cartoon, two colon polyps inside the colon one saying to the Snare that is about to remove it, Don’t Snare Me! I Swear I ‘m benign” and the other says “I’m a yong polyp! Ive got my whole neoplastic transformation ahead of me.” And as you may know “neoplastic transformation” is the technical terminology for transforming from a harmless colon polyp to a cancer.
- The key to early detection is Screening and in order to know when to be screened, we ALL need to know our Risk So….Who is at Risk for colon cancer: We ALL are at risk…. Every single person will fall somewhere in this pie chart of colon cancer risk, the key is to understanding whether you are in the green with most people at average or sporadic risk, whether you are in the yellow with increased or familial risk or perhaps you are among the folks in blue who are in the highest risk due to a hereditary risk. 60% sporadic, 30% familial, up to 10% hereditary
- As we think about risk in three fundamental levels: Average or sporadic risk, Increased or familial risk, and High or hereditary risk While the majority of people face an average risk, many face an increased or high risk of colorectal cancer. Or even an increased or high risk of a second colon cancer. How do you know? Average Risk: These individuals have NO 1st degree relative with colon cancer and no otherwise strong family history, No personal history colon polyps, cancer or other significant risk factors Increased risk: 1st Degree relative with colon cancer or otherwise strong family history, Personal History of colon cancer, colon polyps or other significant risk factors High Risk: Diagnosed gene mutation AND those untested, but 1st degree relatives of someone with a known gene mutation increasing their risk for colon cancer
- And so, when we think about the differences among the risk, it’s important to understand why risk stratification is important we know that there is a significantly elevated risk for individuals with a familial risk and an exponential difference in cancer risk for individuals with a hereditary cancer syndrome. Lifetime Risk of Sporadic Colon Cancer: ~5% Lifetime Risk of Familial Colon Cancer: up to 20% Lifetime Risk of Hereditary Cancer: Up to 100% depending on a specific gene mutation - Increased risk + high risk = 23%
- What are the risks for hereditary colorectal cancer: That depends on the specific gene. These are “UP TO” numbers so not absolute numbers but give an idea of the range of hereditary colon cancer risk and the importance of understanding the specific colon cancer risks to help clarify an individual’s risk compared to the average or familial risk..
- And of course, some of these genes known to cause an increased risk of colon cancer when they are mutated, also cause an increase in other cancers. These other cancer risks may be managed and reduced if they are recognized. So while a history of colon cancer may be the key to understanding risks for other cancers, other cancers in the personal or family history may be the key to helping define the colon cancer risk.
- So, the question we ask is so, what. Does Risk assessment make a difference. And in fact, it does. As was mentioned earlier, the 5 year survival rates for early stage colon cancer is >90% and we know that statistics show that over 60% of deaths from colon cancer could be avoided by colon screening. Additionally, studies show that individuals who know their risk are more likely to seek surveillance or screening.
- And so, as you can see, Colorectal Cancer Risk Assessment, Allows for personalized management of an individuals risk for colon cancer. The management is directed through consultation with a health care provider who will often look to guidelines That are developed by experts from evidence based medicine for optimal medical management which may include: Increased Surveillance – watching closely with monitoring, screening; Colonoscopy would be an example. Chemoprevention – reducing risks by taking medications; Aspirin may be an example for colon cancer. OCPs are an example for reducing the risk of ovarian cancer. Surgeries or what we sometimes call Prophylactic Intervention – treatment removing risks by removing organs before they get cancer.
- When we think about Colorectal Cancer Risk Assessment, we might wonder how does that occur? Consider Red Flags within the personal and family history: These include the personal history of cancer including any personal tumor results from a colon or other cancer Consider the personal history of colon polyps and the types of polyps identified, consider other risk factors such as inflammatory bowel disease and other digestive history. And then, it’s important to note the family history of cancer, the individual’s ancestry, any other medical or social history that might increase the risk of colon cancer within individuals in the family. And genetic test results are also important to consider whether these are somatic from the colon tumor itself or from the germline meaning it is being passed down through the family.
- IHC and MSI are screening tests – done by themselves or in conjunction on colon and or endometrial cancer. Greater than 90% of lynch syndrome tumors are MSI-H and / or lack expression of a protein on IHC. BUT! 10-15% of sporadic colon cancers may have abnormal IHC and are MSI-High. BRAF is a gene that can be tested to look for a change / mutation confirming that it is a sporadic colon cancer. If the BRAF gene is mutated, then their Lynch syndrome genes may not be working in the tumor because of acquired problems and not because of inherited genes mutations. HOWEVER, if the individual meets other personal red flags, genetic testing may still be warranted. Additionally, abnormal MSI and IHC do not guarantee Lynch syndrome. STILL NEED GENETIC TESTING if positive and even if negative….meeting guidelines. These tests are not perfect and sometimes are reported as normal even though there is a genetic mutation present. If additional features are suspicious for hereditary risk, genetic testing is indicated for clarification. How / what / sensitivity and specificity
- 69
- A mutation is found in a gene that does not correlate to history
- Reclassification How / when / who gets updated results methods
- UHC/ CIGNA
- Provide a blood or saliva sample to be sent to the laboratory (not on tumor block)
- Even for those individuals with the increased risk: NCCN guidelines help direct managment Why? What will be the impact to care? Increased surveillance: Screening to catch polyps before they become cancer or to catch cancer at earlier stages Prophylactic Intervention: TAH + BSO before cancer;
- In conclusion, it’s important to remember that every one of us faces a colon cancer risk. Today, we have discussed ways to assess that risk, ways to learn more about to risk through risk assessment. While some have higher risks than others, we ALL have the opportunity to choose healthy lifestyles in an effort to help reduce our risks of colon cancer. And so in conclusion, I’d like to remind us all of the ways that we can choose daily to assist in risk reduction. But this is not enough for those at increased or high risk. And for those folks, it is my hope that the information today will help to inform and empower to take action to learn about their specific risk and risk management. Thank you!
- To Define Risk Assessment: What IS your risk – is it average, increased or high? To Describe Management Modifications - How does risk direct or impact care? To Outline the process of Genetic Testing for Hereditary Colorectal Cancer Conditions – Clarify the Testing process and ensuring that everyone listening knows where and how to find out their own personal risk for colorectal cancer so that they can best manage that risk.