HBOC Syndrome A review of BRCA 1/2 testing, Cancer Risk Assessment, Counseling and Beyond.

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1 HBOC Syndrome A review of BRCA 1/2 testing, Cancer Risk Assessment, Counseling and Beyond. Conni Murphy, ARNP Cancer Risk Assessment and Genetics Program Jupiter Medical Center Learning Objectives Identify persons at risk for HBOC Syndrome. Interpret a three generation pedigree for HBOC risks. Recognize the availability of NCCN guidelines for testing criteria of HBOC. Explore NCCN guidelines for chemoprevention and surgical management in persons with BRCA 1/ 2 mutations. State limitations of the Gail Risk Model. Describe the differences between the IBIS, Gail and BRCA PRO risk models for cancer risk assessment. Develop a surveillance plan utilizing NCCN guidelines for persons with elevated cancer risks. Impact of HBOC in Your Practice Approximately 10% of all breast and ovarian cancers are hereditary Mutations in BRCA1 and BRCA2 dramatically increase the risks for breast and ovarian cancer Specific medical management options are available to reduce cancer risks

2 Hereditary Breast and Ovarian Cancer Most cases caused by a BRCA1 or BRCA2 mutation Other genes 7-10% BRCA1 BRCA2 Sporadic Hereditary AJHG 1998;62: JCO 2002;20: 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: Family History Considerations One-half of BRCA carriers inherit the mutation from their father Ovarian cancer is a very important indicator Early onset breast cancer is more important than the number of affected family members

Prevalence of BRCA Mutations www.myriadtests.

3 Prevalence of BRCA Mutations Prevalence of Mutations in Ashkenazi Jewish Individuals BRCA Gene Mutations Increase Cancer Risk» BRCA Mutation General Population Breast Cancer up to 87% 8% Ovarian Cancer up to 44% <1% Male Breast Cancer up to 8% 0.05% 2 nd Primary Breast up to 64% up to 11% Pancreatic Cancer up to 7% <1% Prostate Cancer up to 20% 13%

4 To Test or Not to Test? What About Risk Assessment? Obtain a 3 generation pedigree Determine if genetic testing is appropriate Counsel re: testing and outcomes Perform a Cancer Risk Assessment Documentation- utilize basic elements of informed consent ASCO or NCCN Test Options Comprehensive BRACAnalysis BRACAnalysis rearrangement testing (BART) Multisite 3 BRACAnalysis (187delAG, 5385insC, 6174delT- founder mutations) Single Site BRACAnalysis- for a known mutation Myriad Lab verifies insurance benefits and only contacts the patient if cost is >$375. out of pocket. 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:

5 Interpreting Test Results Positive for a deleterious mutation No mutation detected Mutation previously identified in the family- informative No known mutation in the family- less informative Genetic variant of uncertain significance- VUS Positive for a Deleterious Mutation BRCA-associated cancer risks 50% chance for first degree relatives to have the same mutation (Autosomal Dominant Inheritance) Children Siblings Parents Test relatives for identified familial mutation No Mutation Detected True Negative - Negative for known mutation in the family - General population cancer risks, despite family history- consider cancer risk assessment No known mutation in the family - Negative rules out most causes of HBOC - Manage based on personal and family cancer history

6 Genetic Variant of Uncertain Significance Clinical significance not yet known Manage based on personal and family cancer history May be further clarified by testing of specified family members molecular or functional analysis population studies Genetic Testing Benefits Allows for individualized medical management Accurate risk assessment Covered by insurance Alleviates uncertainty and anxiety Limitations Positives and true negatives are most informative results Genetic testing for BRCA1 and BRCA2 does not identify all causes of HBOC Genetic Discrimination Myth versus Reality Federal and state laws prohibit the use of genetic information as a pre-existing condition Genetic Information Nondiscrimination Act (GINA) of protects your eligibility for health insurance, premiums, contributions and terms of coverage GINA does not apply to life, disability or long term care insurance The majority of states have additional laws No well-documented cases of genetic discrimination. AJHG 2000;66:

7 Documentation ASCO,NAPBC and NCCN guidelines Collect relevant information to assess personal and family history. Provide information on the specific genetic mutation being tested, including the range of risk and how test results can impact care. Review possible test outcomes. Perform a psychosocial assessment. Discuss the impact to patient and blood relatives. Perform a cancer risk assessment. Provide information on risk of mutation and specific cancers associated with the mutation. Review the concepts of inheritance patterns, variability and penetrance. Provide disclosure of results, significance and impact of the results, medical management options, informing relatives, future contact practices, clinical trials, and available resources. A Review of the Process Set threshold for testing 3 to 4 generation pedigree Testing is or is not appropriate Informed Consent Cancer risk assessment Review results using the basic elements of pre and post test counseling- NCCN, ASCO and NAPBC Document, Document, Document Results are Negative forbrca 1/2 deleterious mutations- Now what? Cancer Risk Assessment and risk reduction counseling are imperative for persons with suspected HBOC syndrome. Equally important is the recognition of persons at High Risk for breast or ovarian cancer due to a strong family medical history of such cancers, or a history of LCIS /ADH, or prior Thoracic Radiation (<30y). When persons opt out of testing or test negative, appropriate risk models and individualized counseling should be performed.

8 NCI/Gail Risk Model Unaffected women age > 35 Excludes women with LCIS, DCIS and paternal hx Does not include age of onset for breast cancer Does not include male breast cancer, bilateral breast cancer or ovarian cancer Includes up to 2 affected first degree relatives only Provides 5 year and lifetime risk for breast cancer 5 year risk is used to assess appropriateness of chemoprevention strategies Tyrer-Cuzick/ IBIS Unaffected patients only (no breast cancer or DCIS) Excludes male breast cancer Includes women with ADH and LCIS Includes previous genetic test results Is included in the ACS guidelines for risk assessment to determine the appropriateness of annual MRI Commonly used to assess cancer risk after BRCA testing- aides with surveillance and treatment plans Provides mutation risk and cancer risk BRCA PRO (Berry Model) Used for affected and unaffected patients (breast and ovarian cancer) Considers first and second degree relatives and age at diagnosis Provides mutation risk for BRCA 1 and BRCA 2 Provides breast and ovarian cancer risk assessment (five year and lifetime)

9 NCCN Guidelines If the NCI/Gail Risk Model reveals > 1.7% 5 year risk for breast cancer, the patient is a potential candidate for chemoprevention strategieshormonal/endocrine therapies. If a risk model such as Tyrer-Cuzick/IBIS or BRCA PRO reveal a > 20% lifetime risk- the patient should be counseled re: risk reduction strategies and increased surveillance- including annual breast MRI alternating with annual mammography. Managing Cancer Risk These interventions may apply to BRCA mutation carriers and High Risk Patients The Goal is Improved Outcomes Surveillance Chemoprevention Prophylactic surgery JAMA 2000;283: Surveillance for Breast Cancer Procedure Age to begin Frequency Breast self awareness Clinical breast exam Mammography- Consider Tomosynthesis MRI Breast Ultrasound yrs Monthly yrs 6 months to a year yrs Yearly Age 25 or ten years prior to the youngest dx Currently in clinical trials Yearly JAMA 1997; 277: Cancer 2004;100: NEJM 2004;351:

10 Medical Management in Male BRCA Carriers Breast Site Procedure Clinical breast exam Frequency Yearly Breast self-exam Monthly Prostate Mammography Prostate-specific antigen testing Digital rectal exam Based on Clinical Findings Yearly Yearly JCO 2004;22: Chemoprevention of Breast Cancer tamoxifen Affected BRCA carriers: 75% decrease for contralateral breast cancer Unaffected BRCA2 carriers: 62% decrease Unaffected high-risk: 45% decrease Lancet 2000;356: JAMA 2001;286: JNCI 1998; 90: Tamoxifen for Risk Reduction 20 mg daily for 5 years- with ALH 86% risk reduction, 49% for high risk. Limited data on greater than five years use. Has been used in pre and post menopausal women. Increases risk for DVT/emboli, cataracts, endo ca. Routine EMB in absence of sx is not recommended. Caution with SSRI s they reduce the active metabolite of tamoxifen. Effexor and Celexa have minimal impact.

11 Other Risk Reduction Agents Raloxifene (Evista)- Postmenopausal women only, age > 35. Less efficacious than tamoxifen, but may be better tolerated. Exemestane or other aromatase inhibitors- ongoing clinical trials for prevention of contralateral breast cancer. Prophylactic Mastectomy Greater than 90% breast cancer risk reduction in BRCA carriers Total (simple) mastectomy more effective than subcutaneous mastectomy Ongoing studies re: nipple and areolar sparing surgery NEJM 2001;345: JNCI 2001;93: JCO 2004;22: Surveillance for Ovarian Cancer CA-125 Pelvic exams Transvaginal ultrasound Additional screening techniques under investigation due to limited efficacy of current options

12 Chemoprevention of Ovarian Cancer Oral Contraceptives 60% risk reduction for ovarian cancer In BRCA carriers > 6 years usage Additional research needed to clarify risk reduction NEJM 1998; 339:424-8 NEJM 2001;345: JNCI 2002;94: Prophylactic Oophorectomy ~96% ovarian cancer risk reduction in BRCA carriers Can reduce breast cancer risk by up to 68%. Recommend bilateral salpingo-oophorectomy (BSO) after childbearing is complete or by age 40. Risk Reducing Prophylactic BSO includes peritoneal washings and microdissection of specimens. NEJM 2002;346:

13 Tyrer-Cuzick/IBIS Risk Model IBIS Risk Assessment BRCA PRO Risk Model

BRCA PRO Pedigree #1 Presented for risk assessment, NOT testing 39 y. female, menarche age 12, G3P2012, first live birth age 35, premenopausal, OCP x 6 yr, No HRT, breast fed x 1 yr.

14 BRCA PRO Pedigree #1 Presented for risk assessment, NOT testing 39 y. female, menarche age 12, G3P2012, first live birth age 35, premenopausal, OCP x 6 yr, No HRT, breast fed x 1 yr. Mother- breast and ovarian ca 60y, BRCA neg (?) M. Aunt VUS- reclassified as polymorphism (?) MGF- prostate ca 70y GM Aunt- breast ca 35y MGM- ovarian ca 70y GMGM- ovarian ca 50y Father-prostate ca 69 P. 1 st cousin breast ca 58 Pedigree #1 1. Obtain test results of mother and m.aunt 2. If we can not verify results, patient does meet NCCN criteria for testing due to maternal lineage, she does not meet NCCN criteria for paternal lineage. However, patient declines testing. 3. Perform a risk assessment: IBIS lifetime breast cancer risk 24.59%. 4. Mutation risk: IBIS-4.1%, Myriad-5.3%, BRCA PRO 8.4%

15 BRCA PRO

16 Pedigree #2 52 y. female, originally presents with 89y mother to have mother tested to aide in medical decision making of offspring Mother does not meet medicare criteria for testing Due to cost, proband changed to daughter who meets NCCN criteria for testing due to ovarian ca maternal or paternal lineage (second degree relatives) Pedigree #2 Age 52 H/O ADH at age 44 Menarche age 12, menopause age 50, No HRT G2P2, did not breast feed Can not use Gail risk model due to ADH IBIS model reveals lifetime risk 60.2% Consider med/onc eval: chemoprevention and MRI, may also consider Prophylactic Mastectomy. In Summary Interpret your pedigree Know your risk models Whether or not you test for HBOC, offer cancer risk assessment Utilize ASCO and NCCN guidelines for testing and counseling Document thoroughly

17 Our Services At our breast center of excellence, we use NCCN guidelines as a threshold for testing and counseling. Every patient is offered a cancer risk assessment. Once the patient s consent or referral is obtained, they will receive an individualized cancer risk assessment and risk reduction counseling. We offer a surveillance plan based on NCCN guidelines. For High Risk Patients- referrals are given for consultations on chemoprevention and risk reducing surgeries (under the direction of the referring HCP).

Does Cancer Run in Your Family?

Does Cancer Run in Your Family? A Patient s Guide to Hereditary Breast and Ovarian Cancer Syndrome What is Hereditary Cancer? Most cancers occur in people who do not have a strong family history of that