19.06.05 Breast cancer

Question 1

What is breast cancer

Answer 1

Heterogenous group of neoplasms originating from the epithelial cells lining the milk ducts

Question 2

Is BC the most common cancer for women in the UK

Answer 2

Yes. 31% of new cancer cases in females (2009)

Question 3

What is the estimated lifetime risk of BC in UK women

Answer 3

1 in 8 (1 in 29 will die of it)

Question 4

What are risk factors for BC

Answer 4

Reproductive behaviour, weight gain, alcohol consumption, use of HRT, family history of BC

Question 5

What proportion of BC is due to hereditary factors

Answer 5

27% (although only 5% due to highly penetrant autosomal dominant inherited mutations)

Question 6

When is BC due to BRCA1/2 suspected

Answer 6

• If early disease onset (under 50yrs)
• Two or more breast primaries
• BC and ovarian cancer in a single individual
• BC and OC in close (first, second, third degree) relatives from same side of family
• At risk populations (Ashkenazi Jewish)
• Family member has BRCA1.2 variant
• Male BC

Question 7

What complicates diagnosis

Answer 7

• Incomplete pentrance
• High prevalence of sporadic BC
• Different cancers in individuals of the same family (phenocopies)

Question 8

Example of probability models to determine likelihood of a family having BRCA1/2 variants

Answer 8

Myriad II, BOADICEA

Question 9

What is NICE guidance for prior risk of BRCA mutation to access genetic testing

Answer 9

10% (was 20%)

Question 10

What are BRCA1 and 2 genes

Answer 10

Tumour suppressor genes

Question 11

What are mutations in BRCA associated with

Answer 11

• Early onset breast cancer
• increased risk of ovarian, pancreatic and other cancers
• 5-7% of all BCs
• 50-80% lifetime risk of BC, 30-50% for ovarian c.

Question 12

Function of BRCA1 and 2

Answer 12

• Form dimers that localise to sites of DNA damage and mediate homologous recombination repair of double stranded DNA breaks
• BRCA1-BARD1
• BRCA2-RAD51
• BRCA1 also regulates cell cycle progression

Question 13

What proportion of variants are large dels/dups, rearrangements

Answer 13

• BRCA1= 15-27% (has more Alu repeats, hence larger proportion)
• BRCA2= 6%

Question 14

If a VUS is seen, what subsequent studies can be done to aid interpretation

Answer 14

• Co-segregation studies (need to take into account phenocopies and incomplete penetrance)
• Tumour DNA analysis for LOH (loss of heterozygosity). If the wild type allele is lost and there is LOH, variant is more likely to be pathogenic

Question 15

Is prenatal testing or testing of minors offered

Answer 15

No

Question 16

Surgical treatments available and risk reduction

Answer 16

• Bilateral prophylactic mastectomy reduces BC risk by 90%.

- Bilateral prophylactic oophorectomy reduces ovarian cancer risk by 53%.

Question 17

Chemoprevention. What is Tamoxifen

Answer 17

-Tamoxifen (oestrogen receptor (OR) antagonist). 10-24% of BRCA1 and 65-79% of BRCA2 associate BC are OR positive

Question 18

Chemoprevention. What is PARP inhibitors

Answer 18

• PARP1 is an enzyme that repairs single-strand DNA breaks by BER.
• Inhibition of PARP1 leads to formation of double strand breaks
• BRCA1/2 null cells cannot repair ds breaks thus leads to apoptosis of cells.

Question 19

What proportion of genetic predisposition to familial BC remains unexplained

Answer 19

50%. Likely due to the combined effect of several genetic variants.

Question 20

Rare intermediate-penetrance BC susceptibility accounts for what percentage of familial risk

Answer 20

2.3%. Genes such as ATM, CHEk2, PALB2, RAD50 and RECQL

Question 21

Why are intermediate penetrance genes not tested in BRCA1/2 negative patients

Answer 21

• Clinical consequences are not clear
• No clinical decisions can be made on their absence/ presence
• More likely to detect VUSs