exploiting tumour biology

Question 1

What is the standard treatment for post-menopausal women with ER+ BC

Answer 1

If adjuvant therapy is required, aromatase inhibitors should be given first (e.g. anastrozole, exemestane)

Question 2

What type of cancer are PARPi usually used?

Answer 2

TNBC

Question 3

Why do targeted treatments fail?

Answer 3

1. Change in target/target environment (e.g. PD-1)
2. Drug metabolism difference (P-glycoprotein efflux)
3. Tumour heterogeneity (difference between primary tumour and metastases)

Question 4

Why does resistance to ER+ therapies occur?

Answer 4

This occurs due to an increased activation of the PI3K/MTOR pathway (can use mTOR inhibitors such as everolimus).

Question 5

Is Tamoxifen a targeted therapy?

Answer 5

Yes

Question 6

What causes DNA damage?

Answer 6

1. ROS and Nitrogen species
2. Oestrogen, cholesterol
3. UV light
4. Chemotherapy
5. Cigarette smoke

Question 7

What are the 5 DNA damage repair pathways?

Answer 7

1. Mismatch Repair
2. Nucleotide Excision Repair
3. Base Excision Repair
4. Homologous Recombination Repair
5. Non-Homologous End Joining

Question 8

How is PARP-1 altered in tumour cells?

Answer 8

Overexpression of PARP-1 is reported in some cancers, as PARP-1 is attracted to zinc fingers to the site of damage where it becomes polymerised, producing a negative charge and recruiting damage repair proteins.

Question 9

Why is PARPi use not recommended with some chemotherapy?

Answer 9

Myelosuppression has been reported therefore combining with other myelosuppressive agents is not recommended. Can be used with radiotherapy instead.

Question 10

What DNA damage repair mechanisms are altered in ovarian cancer?

Answer 10

Half of all high grade serous ovarian cancer have faults in HRR, usually via BRCA-1/2 mutations.

Question 11

Why are PARPi effective in ovarian cancer?

Answer 11

DNA damage causes single strand breaks which are repaired by BER. PARPi prevent BER from occurring, therefore SSB persists and is converted to a double strand break during tumour DNA replication. If HRR is deficient (which is the case for BRCA-1/2 mutated tumours), the double strand break is unprepared, leading to genomic instability and cell death.

Question 12

What are the clinical results of PARPi?

Answer 12

Phase III trial assessing BRCA mutated patients with high grade serous ovarian cancer. They had the last line of chemotherapy, therefore is not curable. With olaparib (PARPi) patients achieved 19.1 months progression free survival, compared to placebo which was just 5.5 months PFS. Approval in July 2019.

Question 13

Are there any indications for getting a good response to Olaparib?

Answer 13

Usually have a response to platinum therapies is promising. Also BRCA-1/2 mutated tumours usually do better.

Question 14

What is next for PARPi?

Answer 14

Should be combined with other agents to cause increased effect. Can we induce a BRCA-1/2 mutated phenotype to treat other hard to treat tumours?

Question 15

How does PARPi resistance occur?

Answer 15

1. Cancers may restore HRR function.
2. Upregulation of P-gp
3. Reactivation of functional BRCA