Clinical options for mutations of BRCA 1/2 genes. Ioannis Th. Natsiopoulos Breast surgeon

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1 Clinical options for mutations of BRCA 1/2 genes Ioannis Th. Natsiopoulos Breast surgeon

2 The detection of a BRCA mutation is not diagnosis of a disease; it is genetic information and risk assessment

3 Indications for genetic test in a patient Breast ca at an age < 50 Triple-negative breast ca Two primary breast ca Breast ca at any age plus one of the following: * > 1 close relative with breast cancer at an age < 50 * > 1 close relative with ovarian cancer at any age * > 2 close relatives with breast cancer or/and pancreatic cancer at any age * high-risk groups Combination of breast ca with one of the following or more: thyroid ca, sarcoma, adrenal gland ca, endometrial ca, pancreatic ca, brain tumors, diffuse stomach ca, skin manifestations and/or macrocephaly, or leukemia/lymphoma on the same side of the family (especially at a young age) Ovarian ca Breast ca in men

4 Indications for genetic test in a healthy person with family history > 2 primary breast ca either in one or in two persons on the same side of the family (either the mother's or the father's) > 1 ovarian ca on the same side of the family (either the mother's or the father's) 1 st or 2 nd degree relative with breast ca at an age < 45 Combination of breast ca with one or more of the following : thyroid ca, sarcoma, adrenal gland ca, endometrial ca, pancreatic ca, brain tumors, diffuse stomach ca, skin manifestations and/or macrocephaly, or leukemia/lymphoma on the same side of the family (especially at a young age) Existence of a known pathogenic mutation in the family Breast ca in men

5 Breast cancer 56-84% Second primary breast cancer 40-60% Ovarian cancer 36-63% Increased risk for other forms of cancer: Colorectal cancer: 10-15% Male breast cancer: 1-5% Pancreatic cancer: 2-3%

6 BRCA2-Associate cancer forms: Risk during lifetime Breast cancer: (60-80%) Ovarian cancer: (10-27%) Breast cancer: (5-10%) Increased risk for cancer occurrence: Prostate cancer: 15-25% Pancreatic cancer: 3-5% Melanoma: 3-5%

7 Mortality in BRCA (+) population until the age of 70 (without any screening and any intervention aiming at risk reduction) Cause of death BRCA-1 BRCA-2 General population Breast cancer 19% 10% 1.2% Ovarian cancer 17% 6% 0.5% Other cause 11% 13% 14.2% Total 47% 29% 16%

8 Option after detection of BRCA mutation Intensive screening (aiming at early diagnosis of the disease) Risk reduction - Surgical methods - Pharmacological methods (?)

9 Intensive screening Breast Annual mammography and ultrasonography Annual magnetic resonance tomography (until the age of 50?) Ovaries Transvaginal ultrasound 2-3 times annually CA times annually Breast cancer screening increases survival rates in BRCA carriers but ovarian cancer screening does not offer much

10 Surgery to reduce the risk Prophylactic salpingo-oophorectomy Prophylactic mastectomy - Simple mastectomy + breast reconstruction - Skin sparing mastectomy + breast reconstruction - Nipple sparing mastectomy (?) Prophylactic mastectomy is usually accompanied by a sentinel lymph node biopsy (SNB) because the chances of discovering subclinical cancer are about 5%

11 Drugs to reduce the risk of breast cancer Tamoxifen Until today there is no research showing that the risk in BRCA mutation carriers can be reduced with drug administration, with a possible exception being the BRCA-2 carriers

12 Intensive screening It reduces deaths caused by breast cancer through earlier diagnosis It is not a surgical, irreversible method It does not reduce the risk of cancer occurrence Diagnoses most cancers when they are >10 mm Frequently gives false positive results, leading to an equal number of unnecessary biopsies High cost and psychological stress for the examined persons

13 Prophylactic salpingo-oophorectomy It reduces the risk of ovarian cancer by up to 85% It reduces the risk of a 1st breast cancer by up to 50%, if performed before the age of 50 (the benefit for BRCA-2 carriers is considerable) It significantly increases survival rates It does not seem to reduce the risk of development of a 2nd breast cancer It doubles the risk of cardiovascular episodes It increases the risk of osteoporosis-related fractures by 50% It is irreversible, which is important for women who have not given birth yet

14 Prophylactic mastectomy It reduces the risk of breast cancer development by more than 90% It increases survival rates very much It does not affect reproduction There are many available breast reconstruction methods Despite the different breast reconstruction methods, it remains an amputating procedure The reconstructed breast is often not aesthetically pleasing The reconstructed nipple is not an "operating" nipple

15 Skin sparing mastectomy (without nipple reconstruction)

16 Skin sparing mastectomy (without nipple reconstruction)

17 Skin sparing mastectomy (with nipple reconstruction)

18 Skin sparing mastectomy (with nipple reconstruction)

19 Effectiveness of strategies for risk reduction (Survival until the age of 70) Intervention General population BRCA-1 BRCA-2 None 84% 53% 71% PSO(40) - 68% 77% PSO(50) - 61% 75% PM(25) - 66% 79% PM(40) - 64% 78% IBS - 59% 75% PM(25)+PSO(40) - 79% 83% IBS(25-39)+PSO(40)+PM(40) - 77% 82 IBS(25-69)+PSO(40) - 74% 80% PSO: PROPHYLACTIC SALPINGO-OOPHORECTOMY PM: PROPHYLACTIC MASTECTOMY IBS: INTENSIVE BREAST SCREENING

20 Factors affecting the selection of a strategy The type of mutation (BRCA-1, BRCA- 2) The carrier's family status The carrier's wishes The age at which the mutation is detected Whether the mutation is detected in a patient or a healthy person

21 Genetic counseling is a complex procedure and requires that the counselor has the necessary knowledge and experience. The selection of the strategy to be followed is not standard, the same or clear in all cases it is a completely personal matter.

22 You have a BRCA mutation. You will have a prophylactic mastectomy and oophorectomy!!!! Otherwise you will die of cancer!!!!!

23 Learn... What it means to have a BRCA mutation Your personal risk Your personal choices The pros and cons of your choices

24 ...and make up your mind All decisions based on complete and correct information are correct.

25 Thank you