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

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

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

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: Courtesy David Euhus, MD

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

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

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

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

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

Options for high risk

Prophylactic Oophorectomy Screening Chemoprevention Options for high risk

HRT Use:Never Post-RRSO RRSO:NoYes Mean age at RRSO ( )40.8 ( ) Mean age at start of follow up34.4 ( )-- Mean follow-up to BC4.8 ( )2.7 ( )4.9 ( ) Mean age at BC40.9 ( )46.3 ( )46.5 ( ) Mean follow-up to censoring (Yrs)5.1 ( )3.6 ( )5.4 ( ) Total Sample (N) BC Diagnosed During FU194 (22%)22 (12%)20 (14%) HR (95% CI)[1]0.56 ( )0.43 ( ) BRCA1 (N) BC Diagnosed During FU118 (23%)16 (14%)17 (16%) HR (95% CI)[1]0.58 ( )0.49 ( ) BRCA2 (N) BC Diagnosed During FU76 (22%)6 (10%)3 (8%) HR (95% CI)[1]0.46 ( )0.22 ( ) Adjusted for age at start of follow up and stratified by center Breast cancer with and without RRSO (+/-HRT)

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

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

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

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

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

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

NCCN 2011, Genetic Testing

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

Data entry to do one computer model

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

Dependant on paper form

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

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

Average EHR today CDS

Average EHR today Click open 4 screens

Average EHR today

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

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

Monitor uptake on counseling

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

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

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