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).table 1

4. Percent of Population Percent of All Cases Average Risk to age 70 Positive Family History of Breast cancer 1015-2010-13 Positive BRCA 1 or 2 mutation0.15-650-85 General Population without positive family history or BRCA mutation 9080-857 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 10 6 cell divisions Probability of two acquired gene mutations, same locus: 1 x 10 12 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: BRCA1 BRCA2

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 10 6 cell divisions Probability of two acquired gene mutations, same locus: 1 x 10 12 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? Non Jewish Families High risk Breast- ovarian: any one of the following One case of breast cancer < 40 years old in first or second degree relative One first or second degree relative with both breast and ovarian cancer Two cases of breast cancer in first or second degree relative if one is diagnosed <50 years of age or is bilateral One first or second-degree relative with breast cancer diagnosed at ≤50-years-old or bilateral and one first or second-degree relative with ovarian cancer Three cases of breast and ovarian cancer (at least one case of ovarian cancer) in first or second-degree relatives Two cases of ovarian cancer in first or second-degree relative One case of male breast cancer in a first or second-degree relative if another first or second degree relative has (male or female) breast or ovarian cancer Moderate risk* breast; any of the following: Two first-degree relatives if both diagnosed between 51 and 60 years of age One first degree and one second-degree relative (mother or sister and maternal aunt or maternal grandmother), if the sum of their ages is ≤118-years-old Moderate risk ovarian: One first-degree relative with ovarian cancer

14. Jewish Families High risk* breast-ovarian; any of the following: One case of breast cancer ≤50-years-old in a first or second-degree relative One case of ovarian cancer at any age in a first or second-degree relative A first or second degree relative with breast cancer at any age if another first or second degree relative has breast and/or ovarian cancer at any age One case of male breast cancer in a first or second-degree relative 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 CuredChr Disease Term Phase 35% 50% 15%