Genetics of Breast Cancer


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Genetics of Breast Cancer

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  • panel-due to inbreeding and increased frequency of these mutations. Founder due to migration, inbreeding due to cultrual/society isolation Go to sequencing if once you remove their ash jew heritage, they still fulfill the >5% risk of carrying a mutation Minimize writing—take out if you consider them not ashk jews etc
  • Again minimize writign once ikknow it
  • chec,k on the 10-20%, get infor for breast cancer risk per year etc
  • (BRCA2 cancers do not have characteristic histopathology)
  • Slide 9: Managing Hereditary Cancer Risk A discussion of the likelihood of carrying a mutation and the associated risks of cancer should occur in the context of available medical interventions to address those risks. The benefits and limitations of increased surveillance, chemoprevention, and prophylactic surgery should each be considered for women with hereditary risk. Over the past few years, numerous published studies have documented the efficacy of various medical management options in reducing cancer risk among carriers of a BRCA1 or BRCA2 mutation. References : 1. Frank TS, et al. Sequence analysis of BRCA1 and BRCA2 : correlation of mutations with family history and ovarian cancer risk. JCO 1998;16:2417-2425. 2. The Breast Cancer Linkage Consortium: Cancer Risks in BRCA2 Mutation Carriers. JNCI 1999;15:1310-1316. 3. Verhoog LC, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1 . Lancet 1998;351:316-321. 4. Verhoog LC, et al. Survival in hereditary breast cancer associated with germline mutations of BRCA2 . JCO 1999;17:3396-3402. 5. Schrag D, et al. Life expectancy gains from cancer prevention strategies for women with breast cancer and BRCA1 or BRCA2 mutations. JAMA 2000;283:617-624. 6. Narod SA, Offit K. Prevention and Management of Hereditary Breast Cancer. J Clin Oncol . 2005 Mar 10; 23(8):1656-63.
  • Ca 125 high false positive rate
  • Age 50 years for general population, high risk is 45 years old
  • It is known that tamoxifen reduces risk of an unaffected woman developing cancer if her risks are high who is under age 50 yrs best, but reduces risk of estrogen + tumors, not estrogen -. That is why unaffected BRCA1 carriers did not show decrease.
  • In young women can do tah-bso to be able to give hrt for prolonged periods without increased risk of uterine ca due to tam or unapposed estrogen Find out specifics about how long to use tamoxifen etc—2 years for a benefit etc Affected BRCA carriers: 50% decrease for contralateral breast cancer Unaffected BRCA2 carriers: 62% decrease Unaffected high-risk: 45% decrease
  • Genetics of Breast Cancer

    1. 1. Genetics of Breast Cancer Reem Saadeh, MD Clinical Geneticist Sibley Memorial Hospital October 3, 2009
    2. 2. <ul><ul><ul><li>Genetics of hereditary breast cancer </li></ul></ul></ul><ul><ul><ul><li>When to suspect someone may have hereditary breast cancer </li></ul></ul></ul><ul><ul><ul><li>When to consider genetic testing </li></ul></ul></ul><ul><ul><ul><li>Interpreting test results </li></ul></ul></ul><ul><ul><ul><li>Cancer risks associated hereditary breast cancer </li></ul></ul></ul><ul><ul><ul><li>Use of genetic test results in medical management </li></ul></ul></ul><ul><ul><ul><li>Relevant health insurance issues </li></ul></ul></ul>Goals
    3. 3. Sporadic Breast Cancer <ul><li>Of all cases of breast cancer: </li></ul><ul><ul><li>~ 90% are sporadic </li></ul></ul><ul><ul><ul><li>Risk Factors include: </li></ul></ul></ul><ul><ul><ul><ul><li>Menarche <12 years old </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Menopause >55 years old </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Nulliparity or first child >30 years old </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Atypical hyperplasia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Alcohol use in excess >3 drinks/day, obesity </li></ul></ul></ul></ul><ul><li>Lifetime risk for sporadic </li></ul><ul><ul><li>Breast cancer: 6-12% </li></ul></ul><ul><ul><li>Ovarian cancer 1-2% </li></ul></ul><ul><ul><li>Prostate cancer: 15% </li></ul></ul>
    4. 4. Red Flags for Hereditary Breast Cancer <ul><li>Of all cases of breast cancer: </li></ul><ul><ul><li>5-10% are hereditary </li></ul></ul><ul><li>Breast cancer with onset <50 years old </li></ul><ul><li>B/L breast cancer </li></ul><ul><li>Ovarian cancer at any age </li></ul><ul><li>Male with breast cancer </li></ul><ul><li>Multiple family members with early onset breast cancer </li></ul><ul><li>Ashkenazi Jewish ancestry with breast cancer </li></ul><ul><li>Multiple affected generations. </li></ul>
    5. 5. BRCA1 and BRCA2 <ul><ul><li>BRCA1 and BRCA2 </li></ul></ul><ul><ul><ul><li>Mutations in these two genes account for 30-50% of hereditary breast cancer. </li></ul></ul></ul><ul><ul><ul><li>There is a significant portion of hereditary breast cancer that is unexplained </li></ul></ul></ul><ul><ul><li>Hereditary Breast Ovarian Cancer Syndrome (HBOC) </li></ul></ul><ul><ul><ul><li>Increased risk of breast, ovarian, prostate, pancreatic, melanoma and others </li></ul></ul></ul><ul><ul><li>Incidence of BRCA1/2 mutations </li></ul></ul><ul><ul><ul><li>0.2% of population carry BRCA1/2 mutations </li></ul></ul></ul><ul><ul><ul><li>2% of Ashkenazi Jews carry BRCA1/2 mutations </li></ul></ul></ul>
    6. 6. Autosomal Dominant Inheritance Important to note that affected in this case only means that individual has one non working gene.
    7. 7. Evaluating the Family History <ul><li>Helpful to obtain information about the person’s siblings, children, parents, aunts/uncles and grandparents. </li></ul><ul><li>Current age or cause and age at death </li></ul><ul><li>Cancer screening and prophylactic or treatment surgical procedures that may decrease risk of another cancer </li></ul><ul><li>Types of cancer-abdominal cancer, did that mean ovarian. </li></ul><ul><li>2nd cancers, primary vs metastasis </li></ul>
    8. 8. Guidelines for testing patients <ul><li>Physicians and genetic counselors are able to process the family and personal cancer history of an individual and determine what their likelihood risk is to have a BRCA1 or BRCA2 mutation and therefore to offer testing. </li></ul><ul><li>Genetic risk assessment is APPROPRIATE for patients with greater than approximately 5%-10% chance of having an inherited a mutation in BRCA1 or BRCA2. </li></ul><ul><li>Genetic risk assessment is RECOMMENDED for patients with greater than approximately 20%-25% chance of having an inherited a mutation in BRCA1 or BRCA2. </li></ul>
    9. 9. Testing Process <ul><li>Blood sample. </li></ul><ul><li>Only done at Myriad Genetic Laboratories in Salt Lake City </li></ul><ul><li>Sequencing of BRCA1/2 </li></ul><ul><li>Multisite/Jewish panel: 3 founder mutations </li></ul><ul><ul><li>BRCA1: 187delAG, 5385insC </li></ul></ul><ul><ul><li>BRCA2: 6174delT </li></ul></ul>
    10. 10. Fees <ul><li>Myriad reports that >94% of patients test fees for BRCA1/2 are covered by >90% of insurance companies including Medicare </li></ul><ul><ul><ul><li>Comprehensive: $3120 </li></ul></ul></ul><ul><ul><ul><li>3 mutation: $535 </li></ul></ul></ul><ul><ul><ul><li>Single site: $440 </li></ul></ul></ul><ul><ul><li>Payment options </li></ul></ul><ul><ul><ul><li>Can be guaranteed no more than 10% ($375) of test is out of pocket </li></ul></ul></ul><ul><ul><ul><li>Payment plan is available that is affordable to the patient </li></ul></ul></ul>
    11. 11. Results <ul><ul><li>+ mutation </li></ul></ul><ul><ul><li>- mutation </li></ul></ul><ul><ul><ul><li>First one to be tested: </li></ul></ul></ul><ul><ul><ul><ul><li>Not detected by current sequencing methods </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Due to alteration in different gene </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Nonhereditary breast cancer </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Breast cancer risk: depends on patient’s personal/family/Gail </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Ovarian cancer risk: if first or second degree relative with ovarian cancer risk is 5-10%, otherwise, risk is general population risk </li></ul></ul></ul></ul><ul><ul><ul><li>True negative </li></ul></ul></ul><ul><ul><ul><ul><li>General population risk </li></ul></ul></ul></ul><ul><ul><li>Inconclusive (~10%)-variant of uncertain significance </li></ul></ul>
    12. 12. Reveiw of Risks <ul><li>BRCA1 cancer risks </li></ul><ul><ul><li>Breast ca: 50-85% </li></ul></ul><ul><ul><li>Ovarian ca: 25-50% </li></ul></ul><ul><ul><li>Prostate ca: ~8% </li></ul></ul><ul><li>BRCA1 vs BRCA2 breast cancer tumors more likely to be </li></ul><ul><ul><li>Medullary </li></ul></ul><ul><ul><li>have increased histology grade </li></ul></ul><ul><ul><li>estrogen negative </li></ul></ul><ul><ul><li>progesterone negative </li></ul></ul><ul><ul><li>HER2/NEU negative </li></ul></ul><ul><li>BRCA2 </li></ul><ul><ul><li>Breast ca: 50-85% </li></ul></ul><ul><ul><li>Ovarian cancer 15-27% </li></ul></ul><ul><ul><li>Prostate ca: 7%-20% </li></ul></ul><ul><ul><li>Male breast ca: 5-6% </li></ul></ul><ul><ul><li>Pancreas, melanoma 2-4% </li></ul></ul><ul><ul><li>Stomach, laryngeal, gallbladder/bile duct, esophagus, fallopian tube </li></ul></ul><ul><li>Ovarian cancers with + mutation are usually </li></ul><ul><ul><li>Epithelial and high grade serous </li></ul></ul><ul><ul><li>Average age of onset 40-60 in BRCA1, 50-70 in BRCA2 </li></ul></ul>
    13. 13. Managing Hereditary Cancer Risk <ul><ul><ul><ul><li>Improved outcomes with proven medical interventions </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Surveillance </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Chemoprevention </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Prophylactic surgery </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Treatment of cancer in individuals with BRCA1 or BRCA2 related tumors is similar to that of sporadic forms of these cancers. </li></ul></ul></ul></ul>JAMA 2000;283:617-24
    14. 14. Surveillance <ul><li>Surveillance-begins at age 25 years </li></ul><ul><ul><li>Self breast exam q 1 mo </li></ul></ul><ul><ul><li>Physician breast exam q 4-6 mo </li></ul></ul><ul><ul><li>Mammograms q 1 yr </li></ul></ul><ul><ul><li>Breast MRI q 1 yr </li></ul></ul><ul><ul><li>Ovarian transvaginal u/s q 6-12 mo </li></ul></ul><ul><ul><li>CA-125 –blood marker of ovarian ca q 6-12 mo </li></ul></ul>
    15. 15. Issues for Men <ul><li>Breast: </li></ul><ul><ul><li>Breast self exam—monthly </li></ul></ul><ul><ul><li>Clinician breast exam—yearly </li></ul></ul><ul><ul><li>Mammogram based on clinical findings </li></ul></ul><ul><li>Prostate </li></ul><ul><ul><li>Prostate specific antigen—yearly </li></ul></ul><ul><ul><li>Digital rectal examination—yearly </li></ul></ul><ul><ul><li>Begins same age as general population </li></ul></ul>
    16. 16. Chemoprevention <ul><li>Hormone related medications </li></ul><ul><ul><li>Tamoxifen, aromatase inhibitors reduces risk in those unaffected women and those with estrogen + tumors </li></ul></ul><ul><li>Oral contraceptives </li></ul><ul><ul><li>Can have a significant risk reduction of ovarian cancer but benefits being sorted out. </li></ul></ul><ul><li>Data is insufficient to make recommendations regarding HRT for women with BRCA1 or BRCA2 mutations. </li></ul>
    17. 17. Prophylactic Surgery <ul><li>Breast: </li></ul><ul><ul><li>Bilateral mastectomies reduce risk by >90% </li></ul></ul><ul><li>Ovaries </li></ul><ul><ul><li>Prophylactic oopherectomies reduces ovarian cancer risk by >95% </li></ul></ul><ul><ul><ul><li>Recommended after child bearing or 35-40 years. </li></ul></ul></ul>
    18. 18. Insurance discrimination <ul><li>HIPAA </li></ul><ul><li>GINA –Genetic Information Nondiscrimination Act </li></ul><ul><ul><li>Prohibits the use of an individual’s genetic information in the setting of eligibility or premium or contribution amounts by both group and individual health insurers.  </li></ul></ul><ul><ul><li>Prohibits health insurers from requesting or requiring an individual to take a genetic test. </li></ul></ul><ul><ul><li>Prohibits use of an individual’s genetic information by employers in employment decisions such as hiring, firing, job assignments, and promotions. </li></ul></ul><ul><ul><li>Prohibits employers from requesting, requiring, or purchasing genetic information about an individual employee or family member. </li></ul></ul>
    19. 19. The Patient’s Decision <ul><li>Why get tested: </li></ul><ul><ul><li>Increased knowledge </li></ul></ul><ul><ul><li>Health care decisions regarding breast and ovarian cancer treatment and prevention </li></ul></ul><ul><ul><ul><li>Lumpectomy vs prophylactic mastectomy </li></ul></ul></ul><ul><ul><ul><li>Removal of ovaries </li></ul></ul></ul><ul><ul><li>Information for relatives </li></ul></ul><ul><ul><li>Emotional benefits </li></ul></ul><ul><li>Why not get tested: </li></ul><ul><ul><li>Emotional implications </li></ul></ul><ul><ul><li>Difficulties interpreting test results </li></ul></ul><ul><ul><li>Family information </li></ul></ul>
    20. 20. In Summary <ul><li>Hereditary breast cancer accounts for 5-10% of all breast cancer of which 40-50% are attributable to mutations in BRCA1/2. </li></ul><ul><li>Patients with “red flags” benefit from genetic counseling which then determines appropriateness of testing. </li></ul><ul><li>Patients with a positive mutation benefit from increased surveillance, chemoprevention and/or surgical intervention. </li></ul><ul><li>Legislation protects against genetic discrimination. </li></ul>
    21. 21. <ul><li>Thank you! </li></ul><ul><li>Reem Saadeh, MD </li></ul><ul><li>202-370-6546 </li></ul><ul><li>[email_address] </li></ul>