The Cancer Pedigree

1. The Cancer Pedigree BRCA What?

2. Outline • Introduction: Understanding the weight of genetics in Ovarian Breast Cancer • BRCA 1 and BRCA 2 Genes • Function • Incidence • Cancer Risk • Who should get tested? • Family History • Genetic Testing • A positive result • What does it mean? • What are your options?

3. Understanding the weight of genetics in Ovarian Breast Cancer • Association of Cancer with Germline mutations • Less than 10 percent of all breast cancers • less than 15 percent of ovarian cancers • The majority of hereditary breast and ovarian cancers are associated with mutations in two genes: breast cancer type 1 and 2 susceptibility genes (BRCA1 and BRCA2) (table 1).

4. COMPARISON OF RISK BETWEEN FAMILY HISTORY, GENETIC MUTATION CARRIERS and THE GENERAL POPULATION

5. BRCA 1 and BRCA 2 • Why are they so important? • BRCA 1 and 2 are tumor suppressor genes • Role: • Maintenance of genome integrity • Repair of double strand DNA breaks • Control of cell cycle check point responses • Chromosomal segregation • GERM LINE Mutations: • loss of one wild type one functional allele vs two • those with tumors usually demonstrate loss of other wild type through somatic mutation or loss of heterozygosity

6. Genetics: • Random mutation rate: 1 per 106 cell divisions • Probability of two acquired gene mutations, same locus: 1 x 1012 • Hereditary cancers occur because one inherited gene copy is already damaged at birth • Shifts prevalence and age incidence for hereditary cancers

7. Cell Cycle: Made Easy DNA Repair Genes:BRCA1BRCA2

8. Cell cycle image

9. INCIDENCE • Estimated at 1/800- 1/1000 per gene • Higher prevalence in individuals with personal or family history of breast or ovarian cancer • Usually younger onset • Geographic/ Ethnic Variation • Ashkenazi Jews: up to 2 % • Also Netherlands, Sweden, Hungary, Iceland, French Canada

10. Cancer Risk in Positive Individuals • Autosomal Dominance • High Penetrance • Women • Lifetime risk: • Breast: 50-85% • Ovarian: 15-40% • Males (BRCA 2 data) • Lifetime risk: • Breast : 10% • Prostate: 5-7 fold increase

11. Genetics: • Random mutation rate: 1 per 106 cell divisions • Probability of two acquired gene mutations, same locus: 1 x 1012 • Hereditary cancers occur because one inherited gene copy is already damaged at birth • Shifts prevalence and age incidence for hereditary cancers

13. Should I get tested?

14. Jewish Families High Risk: this means you have a family history suggestive of hereditary cancer susceptibility syndrome and may benefit from referral to a cancer genetics professional and increased surveillance. Note: Those women with family history and known BRCA mutation should follow different guidelines Moderate risk: family history not diagnostic for increased risk, but still with increased risk for cancer and requiring increased surveillance.

15. General Information about the BRCA genetic testing • Should be done by an expert. • Expensive test  roughly $3000.00 • www.genetests.org • Insurance Reimbursement: most insurance companies cover roughly 90% • May need letter of medical necessity • Do the results affect my health or life insurance? • You are protected by a federal law known as the “Genetic Information Nondiscrimination Act (GINA) • This prohibits health insurers and employers from using your genetic information

16. What Your Result Means • If you test positive: • This means a deleterious mutation was identified in BRCA1 or BRCA2 • This mutation is known to be associated with increased risk for cancer • If you test negative: • If you have a family history of familial BRCA mutation, this means your risk of developing cancer is lower • Chances of false negative results exist, should still undergo surveillance if coming from high risk family

17. What a positive test means for Cancer • Your lifetime risk of breast cancer is: • 55-85% for BRCA1 • 50-85% for BRCA 2 • Your lifetime risk of ovarian cancer is: • 35-46 % for BRCA1 • 13-23% for BRCA2

18. You tested positive: What are your options? • Screening • Starting at 18 years of age: • Monthly Breast Self Exam: table with instructions • Starting at 25 years of age: • Professional Breast Exam every 6 months • Yearly mammogram • Yearly MRI • Ovarian: less accurate than breast • Includes blood test and pelvic ultrasound every 6 months beginning at age 35 or 5-10 years before youngest known cancer case • Surgical Intervention: preventative • Mastectomy: both breasts removed “bilateral prophylactic mastectomy), decreases development of breast cancer by 90% • Removal of ovaries:: “prophylactic bilateral salpingo-oopherectomy”. Reduces risk of cancer development in the pelvis by 80-90 % and breast cancer by 50-60% • Medical Management: • Tamoxifen Therapy: reduces risk of breast cancer in women who have a BRCA mutation • Hormonal birth control: decrease risk of ovarian cancer (however concerns regarding risk of increased breast cancer risk) • Combination of all 3

19. Bilateral Mastectomy

20. Robotic Surgery: TOH BOS

21. Ovarian Cancer Paradigm of Illness: Future Shift Trimodal Survival Distribution 15% 50% 35% Cured Chr Disease Term Phase