Recent trends in molecular testing and maintenance target therapies in ovarian cancer TOG 2023

Question 1

Ovarian cancer accounts for what proportion of cancer-related mortailirt in UK?

Answer 1

5%

Question 2

Overall 5 year survival of ovarian cancer

Answer 2

43%

Question 3

In high grade serious carcinoma what proportion is due to
1) BRCA 1
2) BRCA 2

Answer 3

1) BRCA 1 9%
2) BRCA 2 8%
3) Somatic BRCA1/2 3%

Question 4

Following surgical cytoreduction and platinum based chemotherapy, what proportion of ovarian cancer will relapse?

Answer 4

70%

Question 5

What proportion of epithelial ovarian carcinomas are high grade serous?

Answer 5

70%

Question 6

What proportion of HGSC prevent in stage III/IV (+ve LN, mets)

Answer 6

80%

Question 7

What proportion of HGSC originate from fimbrial epithelium?

Answer 7

70%

Question 8

Most common mutation in HGSC cancers?

Answer 8

TP53 - 96%
BRCA1/2 20%

Question 9

BRCA1/2 show superior sensitivity to which treatments

Answer 9

Platinum based chemo and PARPi (PARP inhibitors)

Question 10

What proportion of HGSC have mutated to aberration of 1+ gene in homologous recombination repair HRR?

Answer 10

> 50%

Question 11

Differences in nonhomologous end-joining NHEJ and Homologous recombination repair (HRR)

Answer 11

NHEJ - faster, higher error, performed at any time of cell cycle

HRR - precise, error free DNA repair pathway, G2 or S phase of cell cycle uses sister chromatic as a template for repair

Question 12

How can homologous recombination deficiency occur?

Answer 12

Loss of canton either by epigeentics or genes encoding for HRR

In these events cell resorts to less efficient NHEJ pathway - inevitable genomic instability

Question 13

How do PARPs support DNA repair?

Answer 13

PARP-1 supports DNA repair via the BER pathway; it replaces missed bases by directing DNA polymerase-b to thesite of DNA damage.

Identifies replication fork interruptions and modifies critical proteins in the HRR DNA repair pathway

Negative feedback to NHEJ pathway

Question 14

Is inhibition to genetic lack or PARP more cytotoxic?

Answer 14

Inhibition

Question 15

Examples of PARPi

Answer 15

Olaparib, niraparib and rucaparib

Question 16

How is PARPi used in treatment of ovarian cancer?

Answer 16

1st line: After response to chemo, continues up to 2 years

Relapse: PARPi continued until disease progression

Question 17

Common SE with PARPi

Answer 17

GI upset & diarrhoea
Abdo pain
Haematological upset - anaemia, thrombocytopenia (niraparib), neutropenia
Fatigue
Deranged LFT (rucaparib)

Question 18

HRD testing is available to which patients in UK

Answer 18

New Dx Stage III/IV, high grade non mutinous for 1st line Tx

Question 19

In recurrent platinum sensitive HGSC, is increased survival seen with PARPi for BCRA1/2 and non-BCRA1/2

Answer 19

Prolonged survival for both but longer medians in BCRA1/2

Question 20

NICE has approved olaparib and niraparib for..

Answer 20

olaparib -platinum-sensitive relapsing high-grade epithelial (includingserous) ovarian cancer with BRCA1/2mut.

niraparib - regardless of BRCA1/2 mutations

Question 21

Is disease free survival seen in platinum sensitive cancer with PARPi?

Answer 21

No

Question 22

Risk of secondary malignancies with PARPi?

Answer 22

Higher risk myelodysplatic syndrome and acute myeloid leukaemia.