Clinical Cancer Genetics in Breast and Ovarian Cancers The Role of Cancer Genetics in Precision Medicine April 17, 2018 & May 1, 2018 Kamel Abou Hussein, MD Assistant Professor of Medicine Division of Hematology and Oncology Preeti Sudheendra, MD Assistant Professor of Medicine Division of Hematology and Oncology

Why Does Cancer Occur?

When to Suspect Hereditary Cancer Breast cancer diagnosed ≤ 50 years Ashkenazi Jewish ancestry and breast/ovarian (or pancreatic) cancer Triple negative breast cancer ≤ 60 Multiple primary cancers Breast cancer in a male Ovarian cancer at any age Family history and/or known familial mutation NCCN version 1.2018 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

Cancer Risk Assessment Basics Patient meets criteria for genetic testing NCCN criteria Insurance criteria Meet with certified genetic counselor (CGC) and MD or APN 3-4 generation pedigree Reproductive and medical history Risk factor review Selection of appropriate genes to be tested Blood drawn at visit Results disclosure Via phone or in person Discussion point – review both maternal and paternal family history for all types of cancers

Benefits of Genetic Testing For those with cancer: Implications for medical management A possible answer to “Why?” For those without cancer: Implications for risk reduction and increased surveillance For all: Impact on risk of family members

Limitations and Risk of Testing Negative result Still doesn’t answer the “why?” Doesn’t mean a person without cancer will never get cancer Cancer risk may still be elevated Variant of uncertain significance Doesn’t clarify risk Can cause anxiety Positive result Can cause anxiety especially in family members Genetics is a “family affair” Concerns about genetic discrimination

Next Steps Positive Result (i.e. pathogenic mutation) Medical management based on risk by gene Negative or VUS result Breast cancer risk assessment (if personal or family risk factors) Short term (5 year) risk > 1.67% Discuss risk reduction endocrine therapy Long term (lifetime) risk > 20% Discuss breast MRI for surveillance Gail and Tyrer-Cusick (IBIS) risk models

Managing High Breast Cancer Risk due to Personal and Family History

Principles of Chemoprevention If 5 year risk > 1.67%  consider endocrine therapy for risk reduction (i.e. chemoprevention) Duration of therapy 5 years Choice of agents: Tamoxifen Raloxifene Aromatase inhibitors – not currently approved

Principles of Increased Surveillance If lifetime risk > 20%  consider use of breast MRI MRI used in conjunction with mammogram Optimal schedule unknown Commonly staggered every 6 months Particularly useful for patients with dense breasts Discuss pros and cons of MRI

Managing Hereditary Breast and Ovarian Cancer (HBOC) Risk

Hereditary Breast Cancer Genes High Risk Moderate Risk Increased Risk BRCA1 ATM BARD1 BRCA2 CHEK2 BRIP1 CDH1 PALB2 NBN PTEN   RAD50 STK11 RAD51C TP53 RAD51D others… Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) **possible increased risk of breast cancer for carriers**

BRCA 1&2 Lifetime Cancer Risks Petrucelli N et al. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated 2016 Dec 15]. In: Adam MP et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Prophylactic Mastectomy 639 FHx + s/p B/L prophylactic mastectomy 214 “high risk” Expected 156 Actual 3 425 “moderate risk” 37.4 4 ~14 year follow up

Prophylactic Mastectomy for BRCA carriers 105 Bilat mastectomy 2 breast cancer cases (1.9%) 378 No breast surgery 189 breast cancer cases (48.7%)

NSABP P1 (BCPT) Other results: No difference in mortality Most significant benefit in predicted risk >/= 5% Adverse events: Endometrial cancer: 36 incidences in tam vs 15 in placebo group Sig increase in incidence of PE and cataracts Fisher B, et al. "Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study". Journal of the National Cancer Institute. 1998. 90(18):1371-1388.

Tamoxifen in BRCA Carriers BRCA 1 – tend to be ER negative cancers No risk reduction benefit of Tamoxifen (NSABP-P1) BRCA 2 – tend to be ER positive cancers 62% risk reduction with tamoxifen (NSABP P1) King M et al. Tamoxifen and Breast Cancer Incidence Among Women With Inherited Mutations in BRCA1 and BRCA2 National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286(18):2251–2256

Risk Reducing Salpingo-Oophorectomy (RRSO) for BRCA carriers 80% risk reduction in tumor of ovary or fallopian tube Decreased mortality esp in BRCA 1 carriers 4% incidence of finding occult malignancy Reduction in breast cancer risk Greatest benefit in BRCA1 carriers who had RRSO ≤ age 40 Rebbeck TR et al. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oopherectomy in BRCA 1 or 2 mutation carriers. J Natl Cancer Inst. 2009; 101: 80-87. Sherman ME et al. Pathologic findings at risk-reducing salpingo-oopherectomy. J Clin Oncol. 2014; 32: 3275-3283. Eisen A et al. Breast cancer risk following bilateral oophorectomy in BRCA 1 and 2 mutation carriers. J Clin Oncol 2005; 23: 7491-7496.

NCCN Guidelines for BRCA Carriers Women Men Breast screening Annual MRI – start age 25-29 Annual mammo – start age 30 Discuss risk-reducing mastectomy Recommend risk-reducing salpingo-oophorectomy -between age 35-40 + done with childbearing -uncertain benefit of screening Ca 125 + US Breast self exam and clinical breast exam – start age 35 Prostate cancer screening – start at age 45 Both Pancreatic screening protocol Possible dermatology eval for melanoma

Cancer Genetics Program Practice Locations 2 Cooper Plaza, Camden 900 Centennial Blvd, Voorhees 100 Salem Drive, Willingboro Locations for Inspira patients: Vineland, Mickleton, Mullica Hill

Cancer Genetics Program Team Oncologists Generosa Grana, MD (Program Director) Christina Brus, MD Alexandre Hageboutros, MD A. Kamel Abou Hussein, MD Pallav Mehta, MD Jamin Morrison, MD Kumar Rajagopalan, MD Kanu Sharan, MD Robert Somer, MD Christian Squillante, MD Preeti Sudheendra, MD Advanced Practice Nurses (APNs) Jennifer Bonafiglia, APN-C Phyllis Duda, APN-C Kristi Kennedy, APN-C Helen Nichter, APN-C Evelyn Robles-Rodriguez, APN-C Genetic Counselors Brooke Levin, MS, LCGC Vanessa Manso, MS, LCGC Kristin Mattie, MS, LCGC Matthew Share, MS, LCGC Jennie Stone, MS, LCGC Program Staff Manager Evelyn Robles-Rodriguez, RN, MSN, APN, AOCN Administrative Coordinator Brandi Ford, CCMA, AAS (Camden) Medical Assistant Myra Salcedo, RMA (Camden)