1. Kevin S.Hughes, MD, FACS Co-Director, Avon Comprehensive Breast Evaluation Center Massachusetts General Hospital Surgeon The Newton-Wellesley Hospital Breast Center High Risk Gene Profiles in Breast Cancer Management Genetic Risk Factors in Primary Management of Breast and Colorectal Cancer Tuesday, April 3, 2012 Crowne Plaza Hotel at the Crossings

2. DISCLOSURES HughesRiskApps.Net Open Access Solution http://www.HughesRiskApps.com Speaker’s Bureau Myriad Genetics kshughes@partners.org http://www.HughesRiskApps.com kshughes@partners.org

3. Inherited Susceptibility to Breast Cancer Sporadic BRCA1 BRCA2 CHK2 ATM p53 PTEN p16 LKB1 Unknown Genetic Component (~29%) Courtesy David Euhus, MD

4. Li-Fraumeni (p53) Clinical Features Early onset breast, sarcoma, leukemia, CNS, adrenal cortical, lung, melanoma, pancreas, cervix, prostate. Breast most common Very early onset (20’s) Courtesy David Euhus, MD

5. Peutz-Jegher Syndrome (LKB1) Clinical Features Gastrointestinal hamartomatous polyps Melanin pigmentation of lips and mouth Small bowel cancers Colorectal cancer Pancreas, ovary, endometrium, cervix, lung, testicle Cancer risk 47% by age 65 Early onset breast cancer (RR = 5) Lim W, Brit J Cancer 2003;89:308-313 Courtesy David Euhus, MD

6. Diffuse Gastric Cancer (CDH1) Infiltrating lobular breast cancer – Lifetime risk 39% Diffuse gastric cancer – Lifetime risk 67 – 83% (F>M) – Mean age 38 – Earliest age 14 Courtesy David Euhus, MD

7. Cowden Syndrome (PTEN) Clinical Features Facial trichilemmomas Macrocephaly (> 58 cm) Oral papules Benign and malignant thyroid disease (10%) Endometrial Cancer Hamartomatous ileal and colonic polyps Breast cancer risk 30 – 50% Male breast cancer Benign Breast Disease –adenosis or lobular atrophy –hamartoma –fibrosis –fibroadenoma Schrager CA, Human Pathol 1998;29:47-53 Courtesy David Euhus, MD

8. Cancer Risk Breast 50-87% 50-87% Ovary 40-60% 10-20% Breast 6% FemaleMaleFemaleMale BRCA1BRCA2

9. Hereditary vs Sporadic Cancer Knudson’s 2 hit hypothesis HEREDITARY CANCER SPORADIC CANCER

10. Family history Multiple relatives affected Young age at diagnosis Multiple primary cancers Male breast cancer

11. Options for high risk

13. Prophylactic Oophorectomy Screening Chemoprevention Options for high risk

14. HRT Use:Never Post-RRSO RRSO:NoYes Mean age at RRSO--45.0 (20.5-79.0)40.8 (29.4-63.4) Mean age at start of follow up34.4 (18.1-90.4)-- Mean follow-up to BC4.8 (0.5-17.6)2.7 (0.5-6.0)4.9 (0.8-20.2) Mean age at BC40.9 (22.2-71.9)46.3 (33.3-63.3)46.5 (36.1-63.1) Mean follow-up to censoring (Yrs)5.1 (0.5-27.8)3.6 (0.5-18.8)5.4 (0.6-27.4) Total Sample (N)867177144 BC Diagnosed During FU194 (22%)22 (12%)20 (14%) HR (95% CI)[1]0.56 (0.34-0.93)0.43 (0.26-0.72) BRCA1 (N)520115105 BC Diagnosed During FU118 (23%)16 (14%)17 (16%) HR (95% CI)[1]0.58 (0.32-1.05)0.49 (0.28-0.86) BRCA2 (N)3476239 BC Diagnosed During FU76 (22%)6 (10%)3 (8%) HR (95% CI)[1]0.46 (0.18-1.13)0.22 (0.05-1.00) Adjusted for age at start of follow up and stratified by center Breast cancer with and without RRSO (+/-HRT)

15. BRCA1/2 Mutation carriers in the US nCarriers Non-Jewish (1/350) 294,985,491842,816 Jewish (1/40) 6,635,665165,892 Total301,621,1571,008,707 ~1,000,000 BRCA1/2 carriers

16. BRCA1/2 Mutation carriers in the US Females 20 and above Close to 400,000 BRCA1/2 carriers nCarriers Non-Jewish (1/350) 110,278,045315,080 Jewish (1/40) 2,480,69262,017 Total112,758,738377,097

17. 13 years of genetic testing: BRCA1/2 carriers found to date ~20,000 to 30,000 –2 to 3% of the ~1,000,000 carriers

18. BRCA1/2 14 years of genetic testing We have identified about 60,000 of the estimated 1,000,000 carriers in the U.S. Likely the best of any adult hereditary syndrome

19. Family history & selective testing Population based genetic testing Find all mutation carriers Adult syndromes Newborn screening

20. Memory-Based Medicine “Current medical practice relies heavily on the unaided mind to recall a great amount of detailed knowledge” Crane, Raymond, The Permanente Journal 7:62, 2003

21. NCCN 2011, Genetic Testing

22. Know models or use a computer BRCAPRO: Bayes-Mendel Model

23. Data entry to do one computer model

24. Clinician synthesizes patient data, compares to guidelines/models, determines next steps Who is at risk

25. Dependant on paper form

26. Currently: Paper + memory Patient completes paper form Reviews data using memory of guidelines Orders Genetic Testing

27. EHR: Paper + extra work + memory Patient completes paper form Reviews data using guidelines and algorithms Orders Genetic Testing Staff enters data into the EHR

28. Average EHR today CDS

29. Average EHR today Click open 4 screens

30. Average EHR today

31. Clinical Decision Support (CDS) Apply Algorithms/Guidelines to patient data Identify best course of action Results displayed as intuitive Visualizations BRCAPRO Mutation Risk 25% Suggest Genetic Testing Facilitates best action as part of workflow

32. HughesRiskApps.Net Patient enters data into Tablet PC or iPad Flag for risk assessment Patient educational materials Clinical Decision Support

33. Monitor uptake on counseling

34. Newton Wellesley Hospital Since 4/2007 Over 50,000 unique patients 2255 (4.5%) mutation risk 10% or greater

35. Not Jewish No Cancer Jewish No Cancer Not Jewish Cancer Jewish Cancer Mammography patients needing risk assessment

36. DISCLOSURES HughesRiskApps.Net Open Access Solution http://www.HughesRiskApps.com kshughes@partners.org http://www.HughesRiskApps.com kshughes@partners.org

37. Demo

39. Simplify Contact

40. Simplify contact and record outcome

41. If patient declines, record reason

42. Module