Lecture 33: Genetic Implications of Breast Cancer

Question 1

What are the risk factors for breast cancer?

Answer 1

1. age
2. family history
3. reproductive factors (late pregnancy/no full term pregnancy)
4. alcohol
5. lifestyle
6. benign breast cancer

Question 2

What are the causes of hereditary breast cancer?

Answer 2

1. BRCA1 = 20-40%
2. BRCA2 = 10-30%
3. TP53 = 1%
   
   • high penetrance
   • Li-Fraumeni syndrome
4. PTEN = 1%
5. Undiscovered genes = 30-70%

Question 3

What is the purpose of BRCA1/2?

Answer 3

Repairs DSB

Question 4

What are the characteristics of BRCA1?

Answer 4

Tumor suppressor gene on chromosome 17
Autosomal dominant transmission
Protein has role in genomic stability, homologous DNA repair
Many different mutations seen

Question 5

What is the population most at risk for BRCA1/2?

Answer 5

1 in 40 ashkenazi jews have BRCA1 and BRCA2 mutations

Question 6

What cancers does BRCA1 predispose a woman for?

Answer 6

1. primary breast 60-80% cumulative risk with 12.5% invasive risk
2. second breast
3. ovary 30-45%
4. pancreas (2-3%)
5. other cancer (slight global increase)

Question 7

What cancers does BRCA2 predispose woman for?

Answer 7

Breast, second breast and ovary the same as BRCA1
Melanoma = 3-5%
Pancreas = 3-5%

Question 8

What does BRCA1 mutation predispose men for?

Answer 8

1. breast (1-5%)
2. prostate (just does it earlier)
3. pancreas

Question 9

What does BRCA2 mutation predispose women for?

Answer 9

1. male breast 5-10%
2. bad prostate 15-25
3. melanoma 3-5
4. pancreas 3-5
   MUCH WORSE FOR DUDES

Question 10

Who do you refer for genetic testing?

Answer 10

1. breast and ovarian in a single lineage
2. breast cancer <40
3. male breast cancer
4. 2 or more women in a single lineage with breast cancer under age 50
5. Ashkenazi jewish with breast or ovarian cancer
6. triple negative breast cancer under age 50

Question 11

What is triple-negative breast cancer?

Answer 11

Breast cancer that does not express any of the following genes for

1. Estrogen receptor (ER)
2. Progesterone Receptor (PR)
3. Her2/neu

Question 12

What is the takehome for this lecture?

Answer 12

Test the people in the lineage that HAVE the diagnosis FIRST
-this is so that it will give you what the mutation is
Genetic testing = $4000
Saves money if you find the gene that is deleterious…so then you only need to test for that one deleterious gene that is $400

Question 13

What is the clinical management plan for BRCA mutation-positive patient?

Answer 13

1. Possible testing for other adult relatives
   i. increased surveillance
   ii. Lifestyle changes
   iii. chemo-prevention
   iv. prophylactic surgery

Question 14

What is the overall management of BRCA1/2 mutation cariers?

Answer 14

Breast cancer risk reduced by

i. mammogram and MRI starting at age 25
ii. oophorectomy
iii. SERM chemoprevention
iv. mastectomy

Question 15

Are true negatives (no bad genes for cancer) really at lower risk for breast cancer?

Answer 15

Yes

Domchek et al.

Question 16

How do you reduce ovarian cancer risk?

Answer 16

i. salpingo-oophorectomy after birth
ii. screening until child bearing
iii. OCP

Question 17

What is RRSO? Significance?

Answer 17

Risk reducing salpingo-oophrectomy

Significantly reduces the risk of breast and ovarian cancer

Question 18

What is a salpingo-oophrectomy?

Answer 18

Removal of both the OVARY and the adjoining FALLOPIAN tube

Main treatment method for BRCA1 patients

Question 19

What is PARP?

Answer 19

Poly ADP Ribose Polymerases
Repairs SSB break
PARP inhibitor used for BRCA1/2 mutations
Because it makes it so that PARP doesn’t repair the breaks…you let the defective BRCA1 and 2 try to repair it
But this will lead to cytotoxicity of the breast cancer

Question 20

Does type of chemotherapy matter?

Answer 20

Yes

BRCA1 and 2 do not react the same to carboplatin and docetaxel