1. Genetics and Ovarian Cancer Jeanne M. Schilder, M.D. Associate Professor, Gynecologic Oncology Indiana University Medical Center September 19, 2012

3. Introduction  Review of ovarian cancer risk factors What decreases risk? What increases risk? What is the role of family history? What is the role of genetic mutations?

4. Female Lifetime Risk of Cancer  Ovarian Cancer General population-1.4% One first-degree relative-4.2%  Breast Cancer General population-12.4% One first-degree relative-24%  Lung Cancer-6.4%  Colon Cancer-4.8%  Endometrial Cancer-2.6%

5. Ovarian Cancer Risk Factors: Decreased Risk FactorRelative Risk Pregnancies None1.0 1 full term pregnancy0.6 >5 full term pregnancies0.29 Use of birth control pills Never1.0 Ever0.75 3 mo-4 yrs0.6-0.7 >10 years0.2 Bilateral Tubal Ligation0.5 Hysterectomy0.5

6. Ovarian Cancer Risk Factors: Increased Risk  Age

7. Ovarian Cancer Risk Factors: Increased Risk FactorRelative Risk Hx of Breast Cancer None1.0 1 st Degree Relative2.1 Personal History10 Hx of Ovarian Cancer None1.0 One 1 st Degree Relative3.1 >2 1 st Degree Relatives4-15 Hereditary Cancer Syndrome12-30

8. Hereditary Gynecologic Cancer Syndromes  1. Hereditary Breast/Ovarian Cancer Syndrome (HBOC)  2. Hereditary Site-Specific Ovarian Cancer Syndrome  3. Hereditary Nonpolyposis Colon Cancer Syndrome (HNPCC or Lynch II)

11. HBOC  ~90% of hereditary ovarian cancers  30-70% of hereditary breast cancers  Increased risk of prostate and possibly colon cancer in some HBOC families  Responsible genes: BRCA1, BRCA2

12. Hereditary Site-Specific Ovarian Cancer  Variant of HBOC  Families with clusters of ovarian cancer, no breast cancer cases  < 5% of hereditary ovarian cancer cases  Responsible genes: BRCA1, BRCA2

14. BRCA 1 and BRCA 2 Function  Tumor suppressor genes Regulate normal cell growth and proliferation Counteract stimulatory effects of oncogenes  Play a role in DNA repair Interact with RAD51, a known DNA repair protein “Caretaker genes”

17. BRCA Mutation Prevalence: Populations General population0.125% (1/800) Ashkenazi Jewish2.5% Ancestry(1/40)

20. BRCA Mutation Prevalence: Personal Cancer History Breast Cancer Dx < 50 years20% Dx > 50 years 7% Ovarian Cancer10% Both Breast and 90% Ovarian Cancer

21. BRCA Mutation Prevalence: Family Cancer History Breast Cancer One 1 st degree relative3.8% > 3 relatives20% Bilateral18% Breast + ovarian cancer40%

22. HNPCC or Lynch Syndrome  ~7% of hereditary ovarian cancer cases  5% of all colorectal cancer cases  Most common cancers: COLON and ENDOMETRIAL  Increased incidence of other adenocarcinomas, including stomach, small bowel, and bile duct malignancies (not breast)

23. HNPCC  Responsible genes: Mismatch repair genes (MMR) including MLH1, MSH2, and MSH6  Autosomal dominant  Prevalence in the general population: 0.1% (1/1000)

27. Penetrance by age 70  BRCA 1 and BRCA 2 Ovarian cancer:16-63% Breast cancer:82-87% Male breast cancer:6%  HNPCC Colorectal cancer:68-75% Endometrial cancer:43-60% Stomach cancer:13-19% Ovarian cancer:9-12% Second primary:90%  Most commonly colorectal or endometrial

28. Red Flags for Hereditary Cancers  Multiple cases within the family  Autosomal dominant transmission  Early age of onset; earlier in successive generations  Bilateral cancers  Synchronous cancers (> 2 at once)  Metachronous cancers (more than one, diagnosed at different times)

29. Obtaining a Family History of Cancer  3-generation family history 1 st Generation: Parents, siblings, children  50% genetic link 2 nd Generation: Grandparents, grandchildren, aunts, uncles, nieces, nephews, ½ siblings  25% genetic link 3 rd Generation: Great-grandparents, great- grandchildren, great aunts/uncles, grand nieces/nephews, first cousins  12.5% genetic link

30. Obtaining a Family History of Cancer  Maternal and paternal data  Include race, ethnic background, current age, all types of cancers, age at diagnosis, age at death  Update at each visit  Confirm with medical records and pathology reports when possible

31. Elevated HNPCC Risk: Amsterdam Criteria  1. At least two successive generations with colorectal cancer  2. Diagnosis of at least one individual before age 50  3. Colon cancer in at least 3 relatives  4. Family history of other cancers including ovarian, endometrial, stomach, urinary tract, small bowel, and bile duct

32. Elevated HNPCC Risk: Bethesda Criteria  1. Very small families with two cases of colon cancer OR two 1 st degree relatives with colon cancer AND  2. A third relative with early-onset cancer or endometrial cancer

33. Identifying Individuals at Risk  Personal and Family History The most important and cost-effective tool in risk assessment  Risk Factors for BRCA1 and BRCA2  Amsterdam Criteria or Bethesda Criteria for HNPCC  Gail Model for Breast Cancer Risk

34. When might genetic testing be considered?  Personal or family hx of pre-menopausal breast cancer AND ovarian cancer (any age)  1 st -degree relative with BRCA1 or 2 mutation  Family hx of > 2 cases of pre-menopausal breast cancer  Family hx of > 2 cases of ovarian cancer

35. Genetic Testing (con’t)  Personal or family hx of bilateral breast cancer  Family hx of male breast cancer  Ashkenazi Jewish ancestry in the setting of a personal or family hx of breast or ovarian cancer

36. Clinical Management  Now that you’ve got it, what do you do with it?! Genetic counseling/testing Screening Prophylactic measures/chemoprevention Consider clinical trials

38. Possible Outcomes of Genetic Testing  Definitive True positive: Deleterious mutation identified True negative: No mutation, individual from family with a known mutation  Uninformative No mutation in individual after full gene sequencing, no mutation in family Mutation of uncertain significance

42. Risk-Reducing Measures  Prophylactic oophorectomy following completion of child-bearing  Chemoprophylaxis in young patients  Interruption of ovulatory cycles

47. Oral Contraceptives  OC use for > 5 years reduces risk of ovarian cancer by 60% in the general population  Protective effect increases with increasing duration of use  Protection continues for 10 years following discontinuation

48. Clinical Trials for Women at High Risk for Ovarian Cancer  GOG 199 Prospective study of RRSO and longitudinal CA-125  GOG 8199 Extended follow-up of GOG 199 participants  GOG 214 Double-blind randomized trial of levonorgestrel vs. placebo prior to RRSO

49. Clinical Management of Women with HNPCC: Screening  Annual ultrasound or endometrial biopsy beginning at age 25-35  Hysterectomy and BSO when childbearing complete Reduces risk of endometrial cancer Reduces risk of ovarian cancer

50. Summary  Identifying women at risk for BRCA and HNPCC mutations can often be done in the primary care setting.  Referral is often appropriate. Genetic counseling Clinical trials Long-term follow-up  Screening and/or prophylaxis can be life saving.

52. Acknowledgments  Melissa Ade  In The Family, a film by Joanna Rudnick Screening privileges/copyright privileges obtained from Kartemquin Films, Chicago www.inthefamilyfilm.com