Women with ovarian cancer joined Julie Larson, LCSW, guest speaker Dr. Kathryn Pennington of UW Medicine, and peers via video or phone to discuss genetics and ovarian cancer.

1. Understanding
Genetics and
Ovarian Cancer
Kathryn Pennington, MD
Gynecologic Oncology
Assistant Professor
University of Washington, Seattle, WA
September 9, 2020

2. Disclosures
None

3. Overview
Genetics 101
How knowing your own genetic status is
important for family members
How genetics influences treatment of your
ovarian cancer
• Lots of info about PARP inhibitors!

4. Why is genetic testing
important?
Influences prognosis and treatment options for
ovarian cancer
Inherited mutations:
• May influence screening recommendations for
other cancers (e.g. breast cancer risk)
• Identification of risk to family members

5. Genetics 101
What is a gene?
• A portion of your DNA that makes a
protein (e.g. BRCA1 gene makes a
BRCA1 protein)
What is a mutation?
• A change in the sequence of the DNA that
makes the protein not work

6. What causes hereditary or
inherited ovarian cancer?
Mutations in certain genes such as:
• BRCA1, BRCA2 (MOST COMMON)
• BRIP1, RAD51C, RAD51D, others
• MLH1, MSH2, MSH6

7. Why do inherited mutations
increase the risk of cancer?
Most ovarian cancer risk genes are involved
in DNA repair
When DNA repair is not effective, cells
accumulate mutations that can lead to cancer

8. How do you inherit a
mutation?
Mom’s Chr 17 Dad’s Chr 17
Daughter’s
Chr 17
Daughter has 50%
chance of inheriting
mutated gene
Only takes one
mutated copy to
have risk
mutation

9. How do you inherit a
mutation?
Mom’s Chr 17 Dad’s Chr 17
Daughter’s
Chr 17
Daughter has 50%
chance of inheriting
mutated gene

10. Other things to consider
Not everyone with a mutation will
actually get cancer
Why? It’s likely a complex blend of other
inherited factors and environmental
exposures
Can mutations “skip” people in the
family?
BRCA1( - )
Mom Dad Aunt
Daughter Son
Could these kids have the BRCA1 mutation?

11. Ovarian cancer patients have a
high rate of inherited mutations
 15% with inherited
mutations in BRCA1 and
BRCA2
 4% with inherited
mutations in other genes
associated with ovarian
cancer risk
Norquist et al, JAMA Oncology 2016
1915 women with ovarian cancer
BRCA1
10%
BRCA2
5%
Other
genes
4%No
mutation

12. What about mutations in
genes other than BRCA1
and BRCA2?

13. Genes other than BRCA1 and BRCA2
20% of mutations in ovarian cancer
patients are in genes other than BRCA1 or
BRCA2
BRCA1
BRCA2
BRIP1
PALB2
RAD51D
RAD51C MMR BARD1
Mutation carriers

14. What genetic testing options
are available?
Single site
Ashkenazi Jewish
3-site
“Single” gene
(usually BRCA1
and BRCA2)
Gene panel
testing

15. Recommendations for genetic testing
NCCN guidelines:
ALL women with epithelial ovarian cancer
should have genetic testing
• 1/3 of mutation carriers have no significant
family history
• 1/3 of mutation carriers are over age 60 at
diagnosis

16. Why is genetic testing
important?
Influences prognosis and treatment options for
ovarian cancer
Inherited (germline) mutations:
• May influence screening recommendations for
other cancers (e.g. breast cancer risk)
• Identification of risk to family members

17. What about my family?
What if my daughter inherited my mutation?

18. The likelihood of developing breast
and/or ovarian cancer in persons
with BRCA1 or BRCA2 mutations
 “Ovarian” includes ovarian, fallopian tube, and primary
peritoneal cancer
44% risk by 80
(36 – 53%)
17% risk by 80
(11 – 25%)
Kuchenbaecker et al, JAMA 2017
Breast Ovary

19. What steps can a person
take to manage their
ovarian cancer risk?
Knowledge is power
Understand the risk, understand
the timing, and make
connections with a team that
can help
Chemoprevention
Birth control pills
Surgery

20. For your family:
identifying others at risk
BRCA1 mutation

21. For your family:
identifying others at risk
BRCA1 mutation
50% 50%
50% 50% 50% 50% 50%
• Each 1st degree relative has a 50% chance of inheriting the
mutation

22. For your family:
identifying others at risk
Cascade testing
Each one recommended to have
testing for specific familial mutation

23. “Meryl” –
Genetic testing
Has a germline (inherited) BRCA1 mutation
Her daughters:
• “Stephanie” has the BRCA1 mutation – she has an
increased risk of breast and ovarian cancer
 many strategies for risk-reduction
• “Alice” tested negative– does NOT have an increased
risk of breast or ovarian cancer

24. Why is genetic testing
important?
Influences prognosis and treatment
options for ovarian cancer
Inherited (germline) mutations:
• May influence screening recommendations for
other cancers (e.g. breast cancer risk)
• Identification of risk to family members

25. Types of genetic testing
Germline testing
 Test for INHERITED
mutations
• Blood test
• Cheek swab
Inherited mutations
Somatic (tumor) testing
 Test for mutations that
spontaneously arose in the
tumor (did not inherit)
• Biopsy
Acquired mutations

26. Overall survival
BRCA2
BRCA1
Other HR Mutation
No Mutation
Months on study
Norquist et al, Clinical Cancer Research, 2018
For women with ovarian cancer – mutation status
impacts prognosis

27. How does genetic testing
influence the treatment of
ovarian cancer?
PARP inhibitors!
Can sometimes be used to treat:
• Recurrent ovarian cancer
• Newly-diagnosed ovarian cancer

28. What is a PARP inhibitor?
• PARP inhibitors: olaparib (LYNPARZA®),
niraparib (ZEJULA®), rucaparib (RUBRACA®)
• Oral drug – taken once or twice a day
• Especially effective for cancers with BRCA1 or
BRCA2 mutation
– Some cancers without BRCA1/2 mutations may
also respond
• Common side effects: fatigue,
nausea/vomiting, decreased blood
counts

29. Indications for PARP
inhibitor therapy
Recurrent ovarian cancer
• Monotherapy
• Maintenance therapy
Newly-diagnosed ovarian cancer

30. Indications for PARP
inhibitor therapy
Recurrent ovarian cancer
• Monotherapy
• Maintenance therapy
Newly-diagnosed ovarian cancer

31. PARP inhibitor as
monotherapy in recurrent
ovarian cancer
FDA approvals:
• Olaparib: germline BRCA1/2 mutation, at
least two prior chemotherapies
• Rucaparib: germline or somatic BRCA1/2
mutation, at least one prior chemotherapy
Gelmon et al, Lancet Oncology, 2011
Swisher et al, Lancet Oncology, 2017

32. Indications for PARP
inhibitor therapy
Recurrent ovarian cancer
• Monotherapy
• Maintenance therapy
Newly-diagnosed ovarian cancer

33. Maintenance therapy
What is it?
• Treatment that is given after chemotherapy
• Given to continue/maintain the good results
of a prior treatment
• Goal: to delay the time before a new
recurrence or progression of existing
disease occurs

34. Platinum-sensitive recurrence:
Carboplatin doublet
Bevacizumab (AVASTIN®) maintenanceBevacizumab (AVASTIN®)
Carboplatin doublet PARP inhibitor maintenance
Carboplatin doubletCarboplatin doublet
MAINTENANCE THERAPY OPTIONS:
(e.g. olaparib, rucaparib, or niraparib)

35. Landmark trials in PARP inhibitor
maintenance therapy after platinum-
sensitive recurrence
PARP inhibitor maintenance after
chemotherapy delays the time to next
recurrence
• Especially effective in BRCA1/2 mutations
Study 19
HR: 0.18
Ledermann, Lancet Onc
2014
HR: 0.30
SOLO2 NOVA
HR: 0.27
Mirza, NEJM 2017 Coleman, Lancet 2017
HR: 0.23
ARIEL3
Pujade-Laurain, Lancet
Onc 2017

36. What should you know about
maintenance therapy?
How will you feel?
• There can still be side effects
What is the potential benefit?
Blood work, office visits - things that
remind you of your cancer diagnosis
What are your priorities?
• Being able to travel, work?
• Time off chemo?
• Symptom-free?

37. Hypothetical maintenance
situations and “benefit”
Pretend we have a crystal ball:
• After finishing chemo: cancer unfortunately
will come back in 1 year
• If maintenance drug A is taken after
finishing chemo: cancer won’t come back
until 3 years
Maintenance therapy delayed
recurrence by two extra years!
= 2-year “benefit”

38. Hypothetical maintenance
situations, how to think
about “benefit”
Maintenance drug A after chemo (vs chemo
alone): 2-year “benefit”
Maintenance drug B after chemo (vs chemo
alone): 3-MONTH “benefit”
Mild side effects from drug A, you generally feel well. Worth it?
Severe side effects from drug A, you feel terrible, can’t enjoy life. You feel
worse than when you were taking chemo! Worth it?
No side effects from drug B at all! Worth it?
Moderate side effects from drug B. Worth it?

39. Benefit of PARPi maintenance
therapy in platinum-sensitive
recurrence:
BRCA1/2 mutation (germline or
somatic): on average, 11-16 month
benefit
No BRCA1/2 mutation: ~4-5 month
benefit

40. Indications for PARP
inhibitor therapy
Recurrent ovarian cancer
• Monotherapy
• Maintenance therapy
Newly-diagnosed ovarian cancer
(maintenance therapy)

41. SOLO-1 trial: maintenance olaparib
after primary treatment for BRCA1/2-
mutated ovarian cancer
Moore et al, NEJM 2018
• Median PFS with
olaparib not yet
reached
• 70% lower risk of
cancer progression
or death
• HR 0.28, p<0.001
Carboplatin + paclitaxel PARP inhibitor maintenance x 2 years

43. How many ovarian cancers
have BRCA1 or BRCA2 mutations?
~15% germline (inherited) BRCA1/2 mutations
~5% somatic (tumor) BRCA1/2 mutations
We must not miss any of these mutations!
If your germline testing was negative, ask your
doctor if your tumor has been tested!

44. PRIMA trial: maintenance niraparib after
primary treatment for ovarian cancer
(BRCA1/2 mutation not required)
Gonzalez-Martin et al, NEJM 2019
Carboplatin + paclitaxel PARP inhibitor maintenance x 3 years
• Niraparib effective
for all individuals
with ovarian cancer
• BUT much more
effective for those
with mutations in
BRCA1/2 or “HRD”

46. If my tumor doesn’t have a
BRCA1/2 mutation, can I still
benefit from a PARP inhibitor?
Yes, but it’s complicated…
The amount of benefit may be less, and
its harder to predict
Cells with homologous recombination
deficiency are
more likely to respond to PARP inhibitors
(NEW CONCEPT!)

47. Homologous
recombination deficiency
Homologous recombination = an
important way to repair DNA
Causes of homologous
recombination deficiency:
• BRCA1 and BRCA2 mutations
(germline or somatic)
• Mutations in some other homologous
recombination genes
• A few other causes, which don’t
require mutations

48. How do we measure
homologous
recombination deficiency?
“HRD assay” – test can be done on your tumor
Warning: this test is imperfect.
The assay looks for indirect changes in the tumor.
It doesn’t actually measure homologous
recombination deficiency.
HRD was here

49. How does HRD test help?
Predicting the benefit of niraparib
maintenance therapy in newly-diagnosed
ovarian cancer
BRCA1/2 mutation (germline or
somatic): on average, 11-month benefit
No BRCA1/2 mutation, but “HRD”
positive: similar, 11-month benefit
No BRCA1/2 mutation, and “HRD”
negative: 3-month benefit

50. Newly-diagnosed ovarian
cancer
Carboplatin + paclitaxel
Bevacizumab (AVASTIN®) maintenanceBevacizumab (AVASTIN®)
Carboplatin + paclitaxel PARP inhibitor maintenance
Carboplatin doublet
Carboplatin + paclitaxel
MAINTENANCE THERAPY OPTIONS:

51. How to pick a maintenance
therapy?
BRCA1/2 mutation (germline or
somatic): Olaparib maintenance x 2 yrs
No BRCA1/2 mutation, but “HRD”
positive: Niraparib maintenance x 3
years (11-month benefit)
No BRCA1/2 mutation, “HRD” negative:
• Niraparib: 3-month benefit
• Bevacizumab: 3-month benefit
Have a conversation about side effects
and the pros and cons of each

52. Ideal genetic testing to
guide treatment decisions
Germline testing: panel of all known
ovarian cancer genes (not just BRCA1/2)
Tumor testing: can be helpful if germline
testing was negative
• BRCA1/2 at minimum
• HRD test – may be helpful if BRCA1/2
negative

53. Questions??