1. Identifying and Managing Hereditary Cancer Syndromes © 2005 Myriad Genetic Laboratories, Inc. Monica Trout, MS Genetic Counselor / Regional Medical Specialist Myriad Genetic Laboratories

2. Learning Objectives At the conclusion of this presentation participants should understand the following: Features of hereditary breast/ovarian cancer, colon cancer and melanoma Cancer risks associated with mutations Use of genetic test results in medical management Relevant health insurance issues © 2006 Myriad Genetic Laboratories, Inc.

3. Impact of Hereditary Cancer in Your Practice Hereditary cancer is more common than previously thought –Approximately 20% of breast cancer and colorectal cancer patients are at-risk for a hereditary cancer syndrome Mutations in genes associated with hereditary cancer dramatically increase the risks for cancer development Specific medical management options are available to reduce cancer risks Cancer. 2005 Dec 15;104(12):2807-16 Cancer Res 2006; 66(15): 7810-7) J Clin Oncol. 2003;21(23):4364-70 Cancer. 2002 Jan 15;94(2):305-1 Cancer. 2005 Nov ;104(9):1849-53

4. The Development of Hereditary Cancer 1 damaged gene 1 normal gene Tumor develops 2 normal genes 2 damaged genes In hereditary cancer, one damaged gene is inherited. 1 damaged gene 1 normal gene Tumor develops 2 damaged genes © 2006 Myriad Genetic Laboratories, Inc.

5. Hereditary Breast and Ovarian Cancer Sporadic AJHG 1998;62:676-89 JCO 2002;20:1480-1490 BRCA1 BRCA2 7-10% Hereditary Most cases caused by a BRCA1 or BRCA2 mutation Other genes 52%32% 16%

6. “Red Flags” for Hereditary Breast and Ovarian Cancer Breast cancer before age 50 Ovarian cancer at any age Male breast cancer at any age Multiple primary cancers Ashkenazi Jewish ancestry Relatives of a BRCA mutation carrier Science 2003;302: 643-6 www.nccn.org

7. A BRCA Mutation Increases Breast and Ovarian Cancer Risks AJHG 1995;56:265-271 Science 2003: 643-646 JCO 2005 23 (8): 1656-63 NCI 2005 20 40 60 80 100 Breast cancer by age 50 Breast cancer by age 70 Ovarian cancer by age 70 2% Up to 50% 8% Up to 87% Risk of Cancer (%) <1% Up to 44% General Population BRCA Mutation Lancet 1994;343:692-695 NEJM 1997;336:1401-1408 AJHG 2003;72:1117-1130

8. A BRCA Mutation Increases Risk of Second Breast Cancer Lancet 1998;351:316-21 JCO 2004;22:2328-35 Lancet 1994;3343:692-5 Gynecol Oncol. 2005 Jan;96(1):222-6 0 20 40 60 Breast Cancer after 5 years Breast Cancer by age 70 Up to 3.5% Up to 27% Up to 11% Up to 64% Risk of Cancer (%) General Population BRCA Mutation Ca Epi Biomarkers Prev. 1999;8(10):855-61 JNCI 1999;15:1310-6 JCO 1998;16:2417-25

9. Ovarian Cancer AFTER Breast Cancer in BRCA carriers 10-fold increased risk compared to noncarriers –No effective ovarian cancer screening –Prophylactic bilateral salpingo-oophorectomy recommended (NCCN) J Clin Oncol. 1998 16:2417-242 Gynecol Oncol. 2005 Jan;96(1):222-6 www.nccn.org

10. Risks in Men With a BRCA Mutation JCO 2004;22: 735-42 NCI 2005 Breast Cancer by age 80 Prostate Cancer by age 80 General Population BRCA Mutation* 5 10 15 20 25 <1% 7% 15% 20% Risk of Cancer (%) *Risks refer to BRCA2 mutation carriers. Risks for male BRCA1 mutation carriers are less characterized

11. Medical Management Options for Hereditary Breast and Ovarian Cancer Increased Surveillance Breast- Self exam, clinical exams, mammograms, MRI Ovary- CA-125, pelvic exam, transvaginal ultrasound Chemoprevention Breast- Tamoxifen Ovary- Oral Contraceptives Prophylactic surgery Bilateral Mastectomy Bilateral Salpingo-oophorectomy JAMA 2000; 283:617-24

12. Surveillance for Breast Cancer www.nccn.org Cancer 2004;100:479-89 NEJM 2004;351:427-37 ProcedureAge to beginFrequency Breast self-exam18 yrsMonthly Clinical breast exam 25 yrsTwice a year Mammography25 yrsYearly MRI25 yrsYearly

13. Chemoprevention of Breast Cancer Tamoxifen Affected BRCA carriers: 50% decrease for contralateral breast cancer Unaffected BRCA2 carriers: 62% decrease Unaffected high-risk: 45% decrease Aromatase inhibitors are currently under investigation Int J Cancer. 2006;118(9):2281-4 Lancet 2000;356:1876-81 JAMA 2001;286:2251-6 JNCI 1998; 90:1371-88

14. Chemoprevention of Ovarian Cancer Oral Contraceptives NEJM 1998; 339:424-8 NEJM 2001;345:235-40 JNCI 2002;94:1773-9 Ca Epi Biomarkers Prev. 2005 Feb;14(2):350-6 Up to 60% risk reduction for ovarian cancer Current literature supports there is no evidence that current low-dose oral contraceptive formulations increase the risk of early onset breast cancer for mutation positive individuals

15. Prophylactic Mastectomy Greater than 90% breast cancer risk reduction in BRCA carriers Total (simple) mastectomy more effective than subcutaneous mastectomy NEJM 2001;345:159-64 JNCI 2001;93:1633-7 JCO 2004;22:1055-62 BJC 93(3):287-92

16. Prophylactic Oophorectomy Recommend bilateral salpingo-oophorectomy (BSO) at age 35 or after childbearing is complete ~96% ovarian cancer risk reduction in BRCA carriers Can reduce breast cancer risk by up to 68% for both BRCA1 and BRCA2 mutation carriers JAMA. 2006;296:185-92 Clin Oncol. 2005 Mar 10;23(8):1656-63 NEJM 2002;346:1609-15 www.nccn.org

17. Managing Hereditary vs Sporadic Breast and Ovarian Cancer Breast Cancer PatientSporadicBRCA1/BRCA2 2 nd Primary (after Br Ca) Breast Cancer Ovarian Cancer 2-11% 1-2% 50-64% 10x increase Surveillance Annual Mammography Annual MRI TV US, Pelvic, CA-125 Yes Not Indicated Yes Chemoprevention Tamoxifen Dependant on ER/PR status ↓ Contralateral br ca 50% Surgical Options Mastectomy Oophorectomy (BSO) Based on tumor Not Indicated ↓ Br ca >90% ↓ Ov ca 96%, ↓ Br ca 68%

18. Interpreting Test Results Breast ca 47 d.65 MI 45 22 47 Breast ca 49 BRCA1 + 23 25 55 Prostate ca 60 80 Diabetes Breast cancer Prostate cancer d.71d.82

19. Interpreting Test Results Breast ca 47 d.65 MI 45 22 47 Breast ca 49 BRCA negative 23 25 55 Prostate ca 60 80 Diabetes Breast cancer Prostate cancer d.71d.82

20. Positive vs. Negative Result Positive BRCA1/2Negative BRCA1/2 Patient 2 nd breast ca 27% within 5 years1% per year Patient ovarian cancer 10-fold increase over general population Not significantly increased Management considerations BSO; bilateral mastectomy; use of MRI if breast conserved Consider mammo for relatives at younger age Relatives’ riskHigh – breast and ovarian cancer, offer genetic testing Moderately increased for breast cancer only

21. Epidemiology of Colorectal Cancer Cancer 1996;78:1149-67 Am J Med 1999;107:68-77 Gastroenterology 2000;119:837-53 Am J Path 2003;162:1545-8

22. Hereditary Colorectal Cancer (CRC) Syndromes Nonpolyposis (few to no adenomas) HNPCC – CRC and/or endometrial cancer (EC) Polyposis (multiple adenomas) FAP – Severe colonic polyposis +/- CRC AFAP – Less severe colonic polyposis +/- CRC MAP – Varying degrees of colonic polyposis +/- CRC

23. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Cancer 1996;78:1149-67 J Clin Oncol 2003;21:1174-9 J Clin Oncol 2004;22:4486-94

24. “Red Flags” for HNPCC/Lynch Syndrome Early onset colorectal cancer (<50y) Early onset endometrial cancer (<50y) Two or more HNPCC cancers in an individual or family* *HNPCC cancers: colorectal, endometrial, gastric, ovarian, ureter/renal pelvis, biliary tract, small bowel, pancreas, brain, sebaceous adenoma

25. HNPCC Increases Lifetime Cancer Risk Risk of Cancer (%) 7% Up to 80% 1.5% Up to 71% Gastroenterology 1996;110:1020-7; Int J Cancer 1999;81:214-8; Gastroenterology 2004;127:17-25; Gastroenterology 1996;110:1020-7; Int J Cancer 1999;81:214-8 12% 2% <1% 13% <1% <5% *Ureter/renal pelvis *Biliary tract *Small bowel *Pancreas *Brain *Sebaceous adenoma

26. HNPCC Increases Risk of Second Cancer Risk of Cancer (%) Cancer 1977;40:1849 Dis Colon Rectum 1986;29:160 Cancer 1993;36:388-93 3.5% 30% 5% 50%

27. Hereditary vs Sporadic Colorectal Cancer Colon Cancer PatientSporadicHNPCC/Lynch 2 nd HNPCC cancer (**colorectal/endometrial) 5%/1.5%50% Ovarian Cancer<1%N/A Surveillance Colonoscopy TV US, Pelvic, CA-125 1 yr, then every 2-3yr Not Indicated annual 25-35y Surgical Options Colectomy TAH-BSO Not Indicated Consider at CRC diagnosis ↓ Endo ca 100%,↓ Ov ca 95%

28. Rationale for Frequent Colonoscopy Accelerated progression from adenoma to cancer –HNPCC, 1-3 years –General population, 5-10 years Adenomas/cancers are often right-sided in HNPCC Reduces CRC risk by more than 50%, overall mortality reduced by 65% Gastroenterology 1993;104:1535-49 Am J Med 1999;107:68-77 Gastroenterology 2000;118:829-34

29. HNPCC Surgical Guidelines Colorectal cancer or more than one advanced adenoma –Colectomy With ileorectal anastomosis (IRA) May be considered for patients unable/unwilling to undergo frequent colonoscopies –Hemicolectomy With yearly colonoscopy Endometrial/Ovarian cancer –Hysterectomy/salpingo-oophorectomy Option for HNPCC patients at time of any intra-abdominal surgery Option after childbearing is complete

30. Hereditary Colorectal Cancer Adenomatous Polyposis Syndromes The majority of colonic adenomatous polyposis is caused by mutations in one of two genes –APC –MYH The conditions associated with mutations in these genes include: –Familial Adenomatous Polyposis (FAP) –Attenuated Familial Adenomatous Polyposis (AFAP) –MYH-Associated Polyposis (MAP) Am J Gastroenterol 2006;101(2):385-98.

31. Various Presentations of Adenomatous Polyposis Syndromes Condition:FAPAFAPMAP Gene:APC MYH Inheritance Pattern: Autosomal Dominant Autosomal Recessive Polyp Number: 100 or moreLess than 1000 - 1000 Additional Information 20-30% of cases will be first affected individual in family Variable presentation and clinical overlap necessitates testing for all three conditions Am J Gastroenterol 2006;101(2):385-98.

32. Hereditary Melanoma Other genes: CDK4, p14ARF (~2%) Sporadic © 2006 Myriad Genetic Laboratories, Inc. Hereditary Unknown Genes (~ 60%) p16 (20%-40%) ~10%

33. “Red Flags” for Hereditary Melanoma ≥ 2 melanomas in an individual or family Melanoma and pancreatic cancer in the same individual or family Relatives of individuals with a known p16 mutation © 2006 Myriad Genetic Laboratories, Inc.

34. A p16 Mutation Increases Melanoma Risk J Natl Cancer Inst 2002;94:894-903 Int J Cancer 2000;87:809-11 *US population

35. American Society of Clinical Oncology Guidelines for Genetic Testing Personal or family history features suggestive of a genetic cancer susceptibility condition Test can be adequately interpreted Test results will aid in diagnosis or influence medical management of the patient and/or family JCO 2003; 21:2397-2406

36. Societal Standards and Guidelines ACCC- Association of Community Cancer Centers AMA- American Medical Association ASBS- American Society of Breast Surgeons ASCO- American Society of Clinical Oncology NCCN- National Comprehensive Cancer Network ONS- Oncology Nurses Society SGO- Society of Gynecologic Oncologists SSO- Society of Surgical Oncology USPSTF- U.S. Preventive Services Task Force

37. Genetic Testing Benefits –Allows for individualized medical management –Accurate risk assessment –Alleviates uncertainty and anxiety Limitations –Positives and true negatives are most informative results –Genetic testing does not identify all causes of hereditary cancer © 2006 Myriad Genetic Laboratories, Inc.

38. Insurance Coverage of Genetic Testing All major carriers provide coverage for genetic testing Established guidelines –Medicare –Most major carriers © 2007 Myriad Genetic Laboratories, Inc.

39. Genetic Discrimination Myth versus Reality Federal and state laws prohibit the use of genetic information as a ‘pre-existing condition’ –Federal HIPAA legislation –The majority of states have additional laws Over 175,000 clinical tests performed to date No documented cases of genetic discrimination AJHG 2000;66:293-307

40. In Summary: 1.Screen for “Red Flags” Cancer <50 (Breast, Colorectal, Endometrial) Multiple primaries Constellation of specific cancers Family history Jewish ancestry 2.Discuss genetic testing options 3.Establish appropriate medical management plan