1. Shiva Sharma SHO to Professor Redmond

2.  Introduction  Increased risk groups  Consideration of genetic testing  Management of patients with mutation  Follow-up

3.  Lifetime average risk 1 in 8  Approximately 184,450 breast cancer cases in USA  5-10% due to high penetrance gene carrying patients  Breast Cancer gene first identified 1990  BRCA 1/2 mutations found to be 1 in 250-500  Increased prevalence in some ethnic groups  Specific screening consideration given to those classified as increased risk  Tailored treatment options for inherited risk groups

4.  Risk factor: variable increasing the chances of developing breast cancer from the average population  Major risk factors – double the risk  Minor risk factors – risk between 1.0-2.0

5.  BRCA 1/2, PTEN, Tp53  Tumour suppressor genes coding for DNA repair  Accounts for 5-10% breast cancers  Young age of diagnosis  Aim is to recognise individuals early to reduce morbidity/mortality

6.  Characteristic history  Large number affected family  Young age of diagnosis  Multiple cancers in one person  Uncommon cancers  Common cancers at younger age

7.  Tumour suppressor gene  85% lifetime risk of Breast cancer  Found in 45% of families with multiple cases  90% of families with both breast and ovarian cancer  Frequency 1/250-500  More common in Ashkenazi Jewish population  20-25% of cases where woman <30 found to be carriers

9.  Major risk factors significantly increase risk  Once an major risk is identified minor factors add little

12. 1. Average Risk – the general population 2. Moderate Risk – increased risk for age group, but less than 5x 3. High Risk – 5-10x  LCIS, ADH, ALH  First degree relatives without mutation 4. Very High Risk - >10x  High penetrance gene mutation  Chest wall irradiation prior to 30

13.  Accepted national screening programs  40 in USA  50 in UK and Ireland  Annual mammography and examination  Chemoprevention not indicated

14.  Screening as in the average risk group  Patients should be acquainted with chemo preventative drugs

15.  Annual mammography  Semi-annual breast exam  Premenopausal – Tamoxifen  Postmenopausal – Tamoxifen or raloxifene

16.  Woman with strong family history without BRCA mutation  MRI with annual mammography  Screening 10years before youngest diagnosed family member or 40  Twice yearly breast exam  Consider chemoprevention

17.  History of irradiation  Annual mammography starting 5-10years after treatment  Annual MRI consideration  Semi-annual exam  Consideration for chemoprevention and risk reduction surgery

18.  BRCA 1/2, PTEN, Tp53 mutations highly penetrant genes  Genetic testing in children only for suspected p53 mutation  BRCA mutation testing not before 25

19.  Guidelines for consideration of testing 1. Early age of onset 2. Multiple affected family members  2+ relatives diagnosed <50  2+ ovarian cancer 3. Multiple primary cancers including breast and ovarian in 1 patient 4. Male breast cancer

20. 5. Medullary and triple negative breast cancers more likely to be BRCA 6. Ashkenazi Jewish descent or other ethnic groups with known mutations 7. 1 st and 2 nd degree relatives with breast cancer 8. Family history prostate, thyroid sarcoma, endometrial, adrenocortical, brain, pancreatic cancer

21.  Testing for known mutations  If negative, then move on to full sequence testing  Issue with Variation of Unknown Significance  Recommend careful surveillance

22.  Careful lifetime follow-up  +/- chemoprevention  +/- risk reduction surgery

23.  Semi-annual exam  Annual mammography and annual MRI offset by 6months

24.  Bilateral total mastectomy +/- reconstruction  95% effective  Timing of surgery should be offered to patients in late 30’s, but before 50  Axillary SNB  Pre-op MRI, if negative, biopsy not indicated

25.  Prophylactic oophorectomy  50% reduction in Breast cancer in BRCA patients  HRT can still be used for symptomatic relief

26.  Life time follow up for BRCA mutations  Gynaecology follow up with pelvic examination annually  Continued follow-up even if prophylactic mastectomy and oophorectomy performed

27.  Genetic testing is a valuable investigation  Patient interest  Informing patients  Tailored treatment and follow-up