GENETIC CONSIDERATIONS IN CANCER TREATMENT AND SURVIVORSHIP

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1 GENETIC CONSIDERATIONS IN CANCER TREATMENT AND SURVIVORSHIP

2 WHO IS AT HIGH RISK OF HEREDITARY CANCER? Hereditary Cancer accounts for a small proportion of all cancer or approximately 5-10%

3 THE DEVELOPMENT OF HEREDITARY CANCER 2 normal genes 1 damaged gene 2 damaged genes 1 normal gene Tumor develops In hereditary cancer, one damaged gene is inherited. 1 damaged gene 1 normal gene 2 damaged genes Tumor develops 2004 Myriad Genetic Laboratories, Inc.

4 ETIOLOGY OF CANCER ENVIRONMENTAL EXPOSURE CHEMICAL/OCCUPATIONAL AGENTS 4% PHARMACEUTICAL AGENTS 1% INFECTIOUS AGENTS 10% DIETARY AND LIFESTYLE FACTORS 35% RADIATION EXPOSURE 4% HORMONAL EFFECTS?? GENETIC PREDISPOSITION

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6 RED FLAGS FOR INHERITED SUSCEPTIBILITY TO CANCER Early age of onset Bilateral disease in paired organs Cancer in two or more close relatives on the same side of the family Multiple cancers in the same individual Constellation of cancers recognized as part of a known cancer syndrome Evidence of autosomal dominant inheritance Multiple affected generations Presence of congenital anomalies or syndrome- associated benign lesions

7 GENETICS IN BREAST CANCER

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9 FEATURES OF BRCA MUTATION CARRIERS *Multiple cases of early onset breast cancer *Ovarian Cancer (with a family history of breast or ovarian cancer) *Breast and Ovarian in the same woman *Bilateral Breast Cancer *Ashkenazi Jewish Heritage *Male Breast Cancer *ER/PR/Her2 triple negative breast cancer Science 2003;302:

10 BREAST CANCER SUSCEPTIBILITY GENES Gene Contribution to Hereditary Breast Cancer BRCA1 50% BRCA2 30% TP53 <1% PTEN <1% Undiscovered Genes 20%

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12 AGE CUMULATIVE RISK BRCA1 / BRCA2 30 yrs 3.2% to 4.6% 40 yrs 12% to 19.6% 50 yrs 46% to 50.8% 60 yrs 54% to 61% 70 yrs 85% to 86%

13 OTHER BRCA ASSOCIATED CANCERS BRCA 1 Prostate BRCA 2 cancers of the larynx, esophagus, colon, stomach, gallbladder, bile duct, and hematopoietic system, as well as melanomas

14 GENETICS ASSESSMENT Identifies those at risk Pedigree and physical findings head circumference and skin anomalies Evaluates for syndromes Chooses testing and sequencing most appropriate to evaluation Eligibility for BART (large rearrangements)

15 WHAT DO I NEED TO KNOW ABOUT THE FAMILY? 3 generations All individuals Age at cancer diagnosis Age at death and cause Ethnicity and race Pertinent prophylactic surgeries Associated congenital abnormalities Precursor lesions/bilateral multiple cancers

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18 WHAT ELSE TO CONSIDER Ancestry Other types of cancer in the proband Other types of cancer in the family Other disorders in the family Polyp history Truncated family ie unknowns, only males, females with TAH at early ages Pathology

19 COWDEN S SYNDROME Incidence is 1:200,000 however may be underestimated PTEN gene on chromosome 10 q 23 Some of the physical characteristics include mucocutaneous lesions, facial trichilemmomas, papillomas of the face, lips tongue and mucosa Major criteria Breast Cancer Thyroid cancer, usually follicular Macrocephaly Lhermitte-Duclos disease Endometrial Cancer Minor criteria Hamartomatous polyps Fibromas Lipomas GU tumors or malformations Fibrocystic breast disease

20 ASSESSMENT TOOLS Myriad Gail Model Claus Model BRCAPRO MMRPRO MANY, MANY others

21 MANAGING HEREDITARY CANCER RISK Improved outcomes with proven medical interventions Surveillance Chemoprevention Prophylactic surgery JAMA 2000;283:617-24

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23 CASE EXAMPLE 1 42 yo with mammographic abnormality in left breast measuring 1.5 cm, also with multiple cysts on right breast which were benign Left breast biopsy consistent with invasive ductal carcinoma, and associated DCIS, ER/PR +, Her 2 was 2+ (indeterminate), reflex to FISH was negative, Bloom Richardson grade 3 of 3 Options at this point were lumpectomy with radiation versus unilateral mastectomy

24 CASE EXAMPLE 1(CONT) Family History revealed a father who was deceased at age 59 of Prostate Cancer Paternal grandmother with breast cancer diagnosed in her 40 s. Two maternal great aunts with breast cancer, age and history unknown French/Indian ancestry BRCA probability score was.02%

25 CASE EXAMPLE 1 (CONT) BRCA 1&2 testing was performed Found to be BRCA 2 + PET/CT without metastatic disease Opted for bilateral mastectomy with reconstruction, 3 of 7 positive nodes T2, N1a Right Breast with focal DCIS Underwent prophylactic oophorectomy Completed chemotherapy and radiation is planned followed by subsequent Aromatase Inhibitor Therapy

26 LI FRAUMENI SYNDROME Mrs. Smith is a 40 year old with a history of breast cancer. Upon obtaining her family history, she reports a son with a sarcoma at age 17. She also reports that she has a brother who had gastric cancer and a mother who had bilateral breast cancer at age 45.

27 CLASSIC LI FRAUMENI CRITERIA A proband younger than 45 with a Sarcoma AND A first degree relative younger than 45 years with any cancer AND A third family member who is a first- or seconddegree relative younger than 45 years with cancer or with a sarcoma occurring at any age

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30 CLINICAL IMPLICATIONS FOR GENETICS; WHAT S NEXT??

31 EDUCATION Guidelines for genetic testing, psychiatric evaluation and ethical issues Results disclosure Managing risk

32 AMERICAN SOCIETY OF CLINICAL ONCOLOGY GUIDELINES FOR GENETIC TESTING Personal or family history features suggestive of hereditary cancer risk Test can be adequately interpreted Test result will aid in diagnosis or influence medical management of the patient and family JCO 2003; 21:

33 BENEFITS AND LIMITATIONS OF 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 CRC

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35 INTERPRETING GENETIC TEST RESULTS Positive for deleterious mutation(s) No mutation detected Mutation(s) previously identified in the family No known mutation in the family Genetic variant of uncertain clinical significance Favor polymorphism Polymorphism undeterminate

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37 GENETIC DISCRIMINATION MYTH VERSUS REALITY Federal and state laws prohibit the use of genetic information as a preexisting condition Federal HIPAA legislation Majority of states have additional laws Over 100,000 tests for hereditary susceptibility to cancer performed to date No well-documented cases of genetic discrimination GINA law 2008 AJHG 2000;66:

38 INSURANCE COVERAGE OF GENETIC TESTING Most insurers provide coverage for genetic testing Established guidelines Medicare Most major carriers

39 ETHICAL ISSUES Right to know versus the right not to know Information Sharing Coercion Privacy Reproductive decision making Testing of minors

40 Thank You

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