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Genetics of Breast Cancer

Genetics of Breast Cancer

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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>

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