What Percentage of Cancer is Considered to be Hereditary? 60-85% of cancer is thought to be sporadic 10-30% of cancer is thought to be familial 5-10% of cancer is thought to be hereditary

ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing Most Cancer Susceptibility Genes Are Dominant With Incomplete Penetrance ASCO Penetrance is often incomplete May appear to “skip” generations Individuals inherit altered cancer susceptibility gene, not cancer Normal Carrier, affected with cancer Susceptible Carrier Sporadic cancer Basic Genetics 31

Factors that Influence the Cancer Pattern within a Family Penetrance Gender Environment Genotype Risk-Reduction Early death Modifier genes

Causes of Hereditary Susceptibility to Breast Cancer ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing Causes of Hereditary Susceptibility to Breast Cancer Contribution to Hereditary Breast Cancer 20%–40% 10%–30% <1% 30%–70% Gene BRCA1 BRCA2 TP53 PTEN Undiscovered genes ASCO Breast and Ovarian Cancer 4

Hereditary Breast and Ovarian Cancer: BRCA1 Breast cancer 50%-85% Second primary breast cancer 40%-60% Ovarian cancer 20%-60% Autosomal Dominant Transmission Precise Risk for Male Breast Cancer Unclear Increased Risk for Prostate Cancer? Adapted from ASCO

Hereditary Breast and Ovarian Cancer: BRCA2 breast cancer (50%-85%) male breast cancer (6%) ovarian cancer (10%-20%) Autosomal Dominant Transmission Increased risk of prostate, laryngeal, melanoma and pancreas cancers Adapted from ASCO

Features Suggestive of BRCA1 or BRCA2 Mutations Multiple cases of early onset breast cancer Ovarian cancer (with family history of breast or ovarian cancer) Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi Jewish heritage Male breast cancer ASCO

BRCA 1 or 2-Linked Hereditary Breast and Ovarian Cancer? 92 Breast, dx 45 d. 89 Prostate dx.75 Non-carrier Ovary, dx 59 d. 62 Breast, dx 59 Breast, dx 73 68 71 BRCA1 or 2-mutation carrier Affected with cancer Breast, dx 36 36 Adapted from ASCO

BRCA1 and BRCA2 in the Ashkenazi Jewish Population 1 in 40 Individuals of Ashkenazi Jewish descent has a BRCA1 or BRCA2 Mutation BRCA1 185delAG Prevalence = ~1% 5382insC Prevalence = ~0.15% BRCA2 6174delT Prevalence = ~1.5% Adapted from ASCO

Detecting Mutations in BRCA1 and BRCA2 Test Comments Cost Full gene sequencing Detects coding region mutations $2,975 3-mutation panel Targets three mutations most common in Ashkenazi Jews $415 Single site Targets family mutation $350

Ideally, Begin Testing With an Affected Person Breast Ca, 42 Test first, if possible Ovarian Ca, 38 d.45 Breast Ca, 65 Person seeking counseling (proband) If a mutation is found in an affected person, testing will be more informative for other family members ASCO 15

Interpreting a Negative Result No identified mutation in family Family with known mutation Breast Ca, 52 Breast Ca, 52 Ovarian Ca, 45 Breast Ca, 47 Ovarian Ca, 45 Breast Ca, 47 BRCA1 + 37 BRCA1 - 37 BRCA1 - Inconclusive True negative ASCO 20

Clinical Management of BRCA Mutation-Positive Patient Positive BRCA1 or BRCA2 test result Possible testing for other adult relatives Increased surveillance Lifestyle changes Chemo- prevention Prophylactic surgery ASCO

Clinical Management of BRCA Mutation-Negative Patient Negative BRCA1 and BRCA2 test result Member of family w/ known BRCA1 or BRCA2 mutation? NO YES Emphasize risk of unidentified familial mutation Emphasize risk of sporadic cancer Encourage adherence to population screening guidelines Provide individualized risk-management plan ASCO

Benefits, Risks, and Limitations of BRCA Testing Identifies high-risk individuals Identifies non-carriers in families with a known mutation Allows early detection and prevention strategies May relieve anxiety (positive or negative) Risks and Limitations Does not detect all mutations Continued risk of sporadic cancer Efficacy of interventions unproven Variant of uncertain significance May result in psychosocial or economic harm Adapted from ASCO

Genetic Predisposition Testing Is a Multi-Step Process Provide post-test counseling and follow-up Disclose results Select and offer test Provide informed consent Provide pretest counseling Identify at-risk patients ASCO 2

Case Discussions What are the ethical issues? Beneficence Nonmaleficence Autonomy Right to know Right not to know Justice What are the counselor’s duties? Duty to warn Duty to recontact How might the issues be resolved?

[ Ashkenazi Jewish ] 93 Breast dx. 61 40 39 Proband is 61 AJ with breast cancer. She is overwhelmed by her diagnosis when she comes for genetic counseling. She decides not to pursue genetic testing because she can’t cope with too much new information at one time. Some time later the daughter independently presents seeking counseling. The daughter’s results will be relevant to mom. Jennifer said that ethically, since she was no longer caring for the mothr, she regarded the daughter as her patient of obligation. (In Baltimore she could refer the daughter to another caregiver; but not in many areas). In the end, the daughter tested negative for the three most common Ashkenazic mutations. Breast dx. 61 40 39

[ Ashkenazi Jewish ] 93 Breast dx. 61 Breast dx. 40 40 39 Two months later, her daughter calls with a new diagnosis of breast cancer. She wants to undergo genetic testing to guide her treatment (a positive result will dictate a full mastectomy). If she tests positive, she will “inform on” her mother. What do you do? Which family member is your patient? Breast dx. 61 Breast dx. 40 40 39

Breast dx. 43 BRCA1/2 NMF NMF - no mutation found Patient has genetic testing and is BRCA1/2 NMF. She cancels two appoints for disclosure. You are concerned that she is afraid to receive positive results. Do you call her with the NMF results?

3 = Pancreas Cancer The proband is concerned about her family history of pancreas cancer. You look at the history and realize that you recognize this family.

3 3 3 BRCA2 + 3 = Pancreas Cancer An affected family member was found to have a BRCA2 mutation, but the next of kin refuses to receive the results. What responsibility do you have to maintain confidentiality? 3 = Pancreas Cancer

3 Breast dx. 51 Breast dx. 42 “BRCA1 +” Two sisters come to your clinic seeking genetic testing because a third sister apparently has a BRCA1 mutation. After further investigation, you believe that the sister lied about her genetic testing in order to get insurance to pay for a prophylactic mastectomy. How do you provide appropriate information to her sisters without calling her sister a liar? How do you keep them from viewing a NMF result as a “true negative”? “BRCA1 +”

Ovarian dx. ? Breast dx. 63 Breast dx. 59 Breast dx. 57 Breast dx. 47 The proband’s mother was found to have a BRCA2 mutation. The proband elects to have genetic testing and is a “true negative”. 29 30

Ovarian dx. ? Breast dx. 63 Breast dx. 59 Breast dx. 57 Breast dx. 47 BRCA2 + Her sister accompanies her to the disclosure visit and wants genetic testing. You are concerned that the sister is not emotionally stable enough to receive positive results. Do you “let” her get testing? 29 30 BRCA2 -

P Breast dx. 30s Ovary dx. 40s Breast dx. 20s Ovary dx. 60s 39 68 [ Polish Jewish ] The proband is pregnant and has found a breast lump. She wants genetic testing, and says she’ll test her fetus is she is positive.

[ Polish Jewish ] Breast dx. 30s 68 Breast dx. 20s Ovary dx. 60s She is found to have a BRCA1 mutation, and still wants to test the fetus. How do you handle the case? 39 BRCA1 + P