Genetic Testing: who, what, why?

Transcription

1 Genetic Testing: who, what, why? Gina Westhoff MD LMG Gynecologic Oncology March 16, 2019 Disclosures Speaker for Merck (unrelated to today s topic) Objectives Determine who should undergo genetic risk assessment and testing Describe what genetic testing evaluates, pros and cons of testing Discuss ways to improve access to genetic testing and risk assessment 3/13/2019 LEGACY HEALTH 3 1

2 Hereditary Cancer Syndromes Autosomal dominant inheritance > BRCA carrier rate in US population: 1 in 400 women > 1 in 40 if Ashkenazi Jewish > 322, ,000 women carry BRCA mutations > Many other mutations identified Usually underlying mutation results in increased risk of cancer in multiple organ sites Need to identify early to initiate screening and risk reduction (age 20-30) > 25,826 cases of breast cancer in women <45 > 2,659 cases of ovarian cancer in women <45 How likely are we to find a germline mutation? Breast Cancer Sporadic Familial Hereditary Ovary Cancer Sporatic Familial Hereditary 17% 8% 75% 10% 15% 75% National Cancer Institute Fact sheet, cancer.gov Syndrome Gene Breast Ovary Uterus Colon Hereditary Breast and Ovarian Cancer BRCA1 X X BRCA2 X X BRIP1 X X RAD51C RAD51D X X PALB2 X X BARD1 X X ATM CHEK2 Lynch Syndrome MMR X X X X X EPCAM X X X Li-Fraumeni TP53 X X X X Cowden/PTEN PTEN X X X Hereditary diffuse gastric cancer CDH1 X X Peutz-Jeghers STK11/LKB1 X X X X 2

3 BRCA mutation and cancer risk Breast Cancer Lifetime Risk 87% Ovarian Cancer Lifetime Risk 54% 12% 25% 1.70% 5.30% General Familial Hereditary BRCA1/2 General Familial Hereditary BRCA 1/2 Which patients with cancer should be referred for genetic evaluation? Known mutation in the family or mutation found on tumor testing Individual diagnosed at any age with: > Ovarian cancer > Pancreatic cancer > Metastatic prostate cancer > Breast cancer or high grade prostate cancer and Ashkenazi Jewish ancestry Breast cancer age </=50 Triple negative breast cancer age </=60 Two breast cancer primaries Breast cancer at any age and >/= 1 relative with: > Breast cancer age <50 > Ovarian cancer > Male breast cancer > Pancreatic cancer > High grade or metastatic prostate cancer > >/= 2 close relatives with breast cancer at any age NCCN Guidelines 2019 What family history should prompt referral for genetic evaluation? First or second degree relative with: > Breast cancer age <45 > Ovarian cancer > Male breast cancer > Pancreatic cancer > Metastatic prostate cancer > >/=2 breast cancer primaries in one individual > >/= 2 or more individuals with breast cancer on the same side of the family, one age <50 Known mutation in the family Three or more of the following cancers: breast, sarcoma, adrenocortical, brain, leukemia, colon, endometrial, thyroid, kidney, lobular breast, diffuse gastric, testicular Sertoli cell tumors NCCN Guidelines

4 What does genetic counseling visit include? Review of personal cancer history Review family history and create a 3 generation pedigree > Includes type of primary cancer, age of onset, lineage (maternal v. paternal) Results of cancer genetic testing in any relative Ethnic background > Ashkenazi Jewish descent Targeted physical exam Estimate cancer risk and likelihood of identifying a germline mutation Review types of results and that a negative result does not mean no risk of malignancy > Positive, negative, variant of unknown significance Counsel regarding risk reduction strategies if mutation identified Review consequences of positive results > Psychological > Disability/life insurance Genetics /13/2019 LEGACY HEALTH 11 Human DNA Khanacademy.org 3/13/2019 LEGACY HEALTH 12 4

5 Central Dogma of Genetics London Health Sciences Center 3/13/2019 LEGACY HEALTH 13 What does genetic testing look for? What is a SNP? 5

6 Timeline of genetic testing Xcelris Medical Genetics 3/13/2019 LEGACY HEALTH 16 Timeline 1994 Location and sequence of BRCA1/2 reported 1996 Myriad offers first commercial test for BRCA1/ Myriad patents BRCA1/ Human genome sequence completed 2006 Myriad BART, rearrangement test for BRCA 2011 FDA approves next generation sequencing 2012 Ambry hereditary cancel panel 2013 Supreme Court rules genes cannot be patented 2013 Ambry offers BRCA-related panel after Supreme Court Decision 2013 Myriad Myrisk test for 25 genes April 2015: COLOR available as direct to consumer genetic test March 2018: FDA approves 23andMe DTC test What are the options for genetic testing? Clinical test Ordered by a licensed provider Pre- and post-test counseling Bill insurance Direct to consumer Ordered by you Post-test counseling only Pay out of pocket > Invitae: 47 or 83 genes > Myriad: 35 genes > Ambry: genes > COLOR: 30 genes > 23andMe: 3 variants in BRCA1/2 > COLOR: 30 genes 3/13/2019 LEGACY HEALTH 18 6

7 How do DTC and clinical genetic testing differ? Clinical genetic test Full gene sequencing Sample from medical office Actionable High degree of accuracy Healthcare provider interprets results DTC genetic test SNP only Sample from home Requires confirmation Questionable accuracy Limited result interpretation 3/13/2019 LEGACY HEALTH 19 What do the experts say? 7

8 23andMe: very limited analysis 23andme.com How accurate are these tests? Tandy-Connor et al. Genetics in Medicine

9 False positive rate: 40% Genetics in Medicine March /13/2019 LEGACY HEALTH 25 No counseling Insurance denial, discrimination Negative test No risk We are not very good at testing JCO

10 Family history is not a great predictor of carrier status 50% of BRCA carriers did not meet published guideline criteria for testing Manickam et al JAMA Network Open 2018 NCCN criteria also not a good predictor of carrier status 959 patients at genetic testing centers 50% met 2017 NCCN criteria, 50% did not Overall mutation rate: 8.65% (83 patients) 45pts met NCCN criteria, 38pts did not Beitsch et al JCO /13/2019 LEGACY HEALTH 29 Is it time to change NCCN guidelines? 3/13/2019 LEGACY HEALTH 30 10

11 BUT majority of cancers are sporadic Rates of breast cancer are going up New cases New cases Rates are increasing 0.3% each year over the last 10 years > 2005: 126.7/100,000 > 2015: 131.1/100,000 White women <50yo: 1.7%/yr Black women <50yo: -2.4%/yr Half of all breast cancers are PREVENTABLE Decrease your risk by 50%: weight loss of 10kg in menopause > Avoid weight gain Decrease your risk by 19%: walk 1hr/day Avoid alcohol: any intake increases risk > Increase your risk by 10-15%: 1 drink per day Decrease risk by 50%: Chemoprevention > White women, <50yo with 5-yr risk of breast cancer >1.5% > Black women, <50yo need higher breast cancer risk for benefit to be seen > Refer to High Risk Breast Clinic to discuss pros/cons Colditz et al Cancer

12 Strategies to decrease cancer risk Improve access to appropriate genetic testing Recognize we have control over modifiable risk factors > Healthy weight > Exercise > Alcohol and tobacco Don t be fooled or falsely reassured 3/13/2019 LEGACY HEALTH 34 Thank you! 12