~5-10% of all cancer cases have a strong hereditary component with significant increased risk for close relatives ~15-20% of cancer cases are “familial” with clustering of cases and probable multifactorial causation ~75% of all cancers are sporadic with minimal inherited component and slight to negligible increased risk for relatives
Accounts for about 5-10% of all cases of breast and ovarian cancer ~50-70% of HBOC cases associated with mutations in the tumor suppressor genes BRCA1 or BRCA2 Genetic testing for BRCA1 and BRCA2 mutations is available to women whose family history meet “hereditary breast cancer” criteria. Important to test affected family member first.
13% of Ashkenazi Jewish women with “sporadic” breast CA <50 24% of Ashkenazi Jewish women with ovarian CA
Chemoprevention Tamoxifen - up to 45% reduction in BrCA risk in BRCA2 carriers (?in BRCA1 carriers) Oral Contraceptives – 50% reduction in ovarian CA Prophylactic bilateral mastectomy May reduce breast CA risk up to 90% Prophylactic bilateral oophorectomy May reduce risk for ovarian CA by 50-90% studies need validation May reduce risk for breast CA by 50% - studies also need validation
Cowden Syndrome– <1% of all BrCA Multiple lesions of the skin and mucosa (acral keratoses, papillomas, trichilemmomas), breast, thyroid and endometrial lesions/cancer, GI hamartomas, truncal lipomas, macrocephaly Li-Fraumeni – <1% of all BrCA Very early onset cancers: sarcoma, breast, leukemia, osteosarcoma, melanoma, colon, pancreas, brain, adrenal cortex Peutz-Jeghers - <1% of all BrCA Multiple early-onset GI hamartomas, mucocutaneous hyperpigmentation, cancers: breast, testes, ovaries, GI-tract
Type of primary cancer(s) in each affected relative Age of disease onset in each affected relative earlier onset generally confers higher risk for close relatives Cancer status in 1 st and 2 nd degree relatives (often discounted) Other medical findings associated with hereditary cancer syndromes: i.e. thyroid findings, benign breast disease, lipomas, uterine fibroids, skin findings, etc. Cancer status in both sides of the family (paternal family history often overlooked when assessing risk of “female” cancers)
Identifies the chance of detecting a BRCA1 or BRCA2 mutation in women with a family history of early-onset breast and/or breast and ovarian cancer Based on the age of diagnosis, total number of affected 1 st and 2 nd degree relatives Separate risk tables for persons of Ashkenazi Jewish ancestry Limitations: Based on non-validated clinical data sent in with samples Does not include relatives with breast cancer >50 years Does not capture other breast cancer syndromes www.myriad.com
2 or more 1 st degree, or one 1 st and one 2 nd degree relative in the same lineage with breast cancer <50 yrs or two or more 1 st degree relatives of the patient’s father Insurance coverage: Some insurers and some plans will cover cancer genetic risk assessment/cancer genetic counseling. Others will not. More difficult to obtain coverage for unaffected person with a family history than an affected person. Pre-authorization recommended. Pre-authorization for cancer genetic testing is important as tests are expensive. The genetic counselor will facilitate the pre-auth for testing if indicated and if patient decides to have testing. Insurance discrimination – needs to be discussed before insurer is contacted regarding coverage.
Gail Model: 5 year risk of 1.1%; lifetime risk of 18.8% Claus Model: Lifetime risk of 18.8% based on mother, age 58 and maternal aunt, age 65 Myriad table – risk of BRCA1/2 mutation: 2.9% risk of mutation based on family history (no one with breast <50 or ovarian cancer) Pedigree analysis: no indications of other breast cancer syndromes
Again, it is important for patient to check own insurance policy to see if genetics referral is covered. Some patients will not want their insurance notified of a genetics referral because of concerns about insurance discrimination.
Familial Cancer Risk Assessment: Breast and Ovarian Cancer Genetics and Primary Care
Goal: Classification Who needs what? Family Hx Assessment Personalized prevention recommendations Referral for genetic evaluation with personalized prevention recommendations Standard prevention recommendations Intervention Average Moderate (“Familial”) High/Genetic Risk Classification