5. Breast Cancer

Question 1

What factors complicate the diagnosis of HBOC?

Answer 1

Incomplete penetrance

High prevalence of sporadic breast cancer

Phenocopies - different members of a family develop different types of cancer

Question 2

What is the major role of BRCA1 and BRCA2?

Answer 2

TSGs

Homologous recombination repair of DSBs and nucleotide excision repair

BRCA1 forms complex with BARD1, co-localises with BRCA2/RAD51 at sites of DNA damage.

BRCA2 mediates homologous recombination repair

Question 3

What is the clinical consequence of HBOC?

Answer 3

Increased risk of early onset breast, ovarian, pancreatic, prostate cancer and melanoma

Question 4

How are VUSs in BRCA1/2 investigated?

Answer 4

1. Segregation
2. Test tumour DNA - in most BRCA1/2 related tumours the WT allele is deleted (LOH) - indicates the germline variant is pathogenic

Question 5

What other roles do BRCA1/2 have?

Answer 5

BRCA1 - pathways controlling cell cycle progression, checkpoint control

BRCA2 - DNA synthesis, transcribed in late G1 phase, raised in S phase

Question 6

What proportion of HBOC cases are caused by BRCA1 and BRCA2?

Answer 6

66% BRCA1
34% BRCA2

Question 7

Which cancer predisposition syndromes confer an increased risk of breast cancer?

Answer 7

Li Fraumeni (TP53)

Peutz-Jeghers (STK11)

Cowden syndrome (PTEN)

NF1

Nijmegen breakage syndrome (NBN)

Question 8

What other genes confer predisposition to breast cancer?

Answer 8

ATM
CHEK2
PALB2
RAD51C
RAD51D

R208 Inherited breast cancer and ovarian cancer

Question 9

What is the consequence of identifying a mutation in a moderate risk gene?

Answer 9

In a family with a high risk FH, the mutation may not account for all of the risk in the family

Question 10

When are PARP inhibitors used?

Answer 10

1. Ovarian, fallopian tube or peritoneal high-grade serous carcinoma
2. BRCA1/2 positive (germline or somatic) or HRD positive
3. Responded to 1st line platinum based chemo

Question 11

How do PARP inhibitors work?

Answer 11

Poly (ADP-ribose) polymerase inhibitors

PARP protein repairs single strand breaks via BER pathway

PARPi lead to accumulation of unrepaired single-strand breaks that result in the collapse of replication forks during DNA replication –> lead to double-strand breaks

HRD cancer cells cannot repair the DSBs -> genomic instability & cell death

Synthetic lethality of tumour cells with impaired HRD

Question 12

What is the name of the PARP inhibitor recommended by NICE?

Answer 12

Olaparib

Question 13

What is the purpose of HRD testing?

Answer 13

Identify patients who with HRD who would benefit from PARP inhibitors

HRD present in approx half of ovarian cancers

But HR pathway gene mutations other than BRCA1 and BRCA2 are rare, and it is unclear if they are connected to HRD

Question 14

How is HRD tested for?

Answer 14

Myriad myChoice assay in US or shallow WGS

Tests for
1. tBRCA1/2 variants (somatic & germline)
2. Genomic instability score based on: LOH, telomeric allelic imbalance (TAI) and large-scale state transitions (LST)

Question 15

What is triple negative breast cancer?

Answer 15

Breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2)

Therefore not sensitive to endocrine therapy or HER2 treatment

Often seen in patients with BRCA1 mutations

Question 16

How is triple negative breast cancer characterised clinically?

Answer 16

Highly invasive, high metastatic potential, prone to relapse, and poor prognosis.

Question 17

What is the risk of cancer associated with BRCA1/2 mutations?

Answer 17

Breast - Up to ~70% by age 70 for breast cancer, compared to 12% in general pop

Ovarian - ~40% for BRCA1, ~20% for BRCA2 compared to 1-2%

Question 18

How does homologous recombination repair work?

Answer 18

Repairs DSBs using sister chromatid during G2 phase (after chromosome duplication)

Single strand of sister chromatid acts as template for repair