Knowing and understanding your inherited genetics is important for ovarian and uterine cancer patients. Dr. Melissa Frey, gynecologic oncologist at Weill Cornell Medicine, discusses how genetic factors affect women with ovarian and uterine cancer and influence treatment decisions, with a particular focus on BRCA1 & 2 and Lynch Syndrome.
This webinar was being put on in partnership with FORCE.
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All in the Family: Hereditary Risk for Gynecologic Cancer
1. All in the Family
How genes affect gynecologic cancer risk
January 2021
Melissa Frey M.D.
Assistant Professor
Division of Gynecologic Oncology
Weill Cornell Medicine
Obstetrics and Gynecology
2. Research support
• NIH/NCATS Grant # KL2-TR-002385
• Invitae
• Ambry
Introduction
• Gynecologic oncologist at Weill Cornell Medicine
• Clinical care (surgery/chemotherapy) for women with all gynecologic
cancers
• Clinical and research focus on genetics and cancer
4. Definitions for hereditary cancer
• Cells are the building blocks of the body – they make up all of the organ’s
and tissues
• Every cell contains DNA (deoxyribonuecleic acid)
• Hereditary material
• The code for building and maintaining cells
• Sections of DNA are called genes
• Instructions for the cells
• Many genes together form chromosomes
• People inherit 2 pairs of chromones (23 from their mother and 23 from their father)
5. DNA, Genes, Chromosomes, Cells
ACGTAATTCCGGAAATTAAAGTTCAGGA
A
DN
A
Genes ACGTAATTCCGGAAATTAAAGTTCAGGAACGGAAATTAAAGCGGAAATTAAAGTT
Chromosome
s
A
C
G
T
A
T
T
A
C
G
G
T
G
T
A
T
G
G
G
A
C
G
G
T
Cells
Nucleus
7. How are genes passed in families?
23 pairs of
chromosomes
8. How are genes passed in families?
23 pairs of
chromosomes
9. How are genes passed in families?
23 pairs of
chromosomes
10. How are genes passed in families?
23 pairs of
chromosomes
11. How are genes passed in families?
23 pairs of
chromosomes
BRCA mutation
BRCA mutation
BRCA mutation BRCA mutation
1. BRCA can be inherited
from mother or father
2. Just 1 copy 🡪 cancer risk
13. BRCA1/2 Cancer Risk
Breast cancer
>60%
Ovarian cancer
BRCA1 – 40-60%
BRCA2 – 15-30%
Pancreatic cancer
BRCA1 - < 5 %
BRCA2 – 5-10%
Melanoma
Prostate cancer
14. For a woman with ovarian cancer, what do we learn by
finding a BRCA1/2 mutations?
Treatment implications PARP inhibitors
Risk of other cancers Breast, Melanoma, Pancreas
Risk for family members First degree relatives (50% risk)
15. What are options for BRCA1/2 cancer risk reduction?
Breast cancer
Mammogram / MRI
Risk-reducing mastectomy
Risk-reducing medical therapy
16. BRCA1/2 BREAST cancer risk reduction
Age Intervention
25y Clinical breast exam ever 6-12 months
25-29y Breast MRI every 12 months
30-75y Mammogram and breast MRI every 12 months
Discuss option of risk-reducing mastectomy
Discuss option of chemoprevention (Tamoxifen)
17. What are options for BRCA1/2 cancer risk reduction?
Breast cancer
Mammogram / MRI
Risk-reducing mastectomy
Risk-reducing medical therapy
Ovarian cancer
Risk-reducing salpingo-
oophorectomy
Oral contraceptive pills
18. BRCA1/2 OVARIAN cancer risk reduction
35-40y
Risk-reducing salpingo-oophorectomy
(Reasonable to wait until 40-45y in BRCA2)
Age Intervention
30-35y Consider transvaginal sonogram + serum CA125
Oral contraceptive pills
Discuss option for hysterectomy
Salpingectomy (however…alone is not standard of care)
23. What are options for BRCA1/2 cancer risk reduction?
Breast cancer
Mammogram / MRI
Risk-reducing mastectomy
Risk-reducing medical therapy
Ovarian cancer
Risk-reducing salpingo-
oophorectomy
Oral contraceptive pills
Pancreatic cancer
MRCP / MRI
Endoscopic ultrasound
Melanoma
Dermatologic exam
Ophthalmology exam
25. Lynch syndrome
• Colorectal cancer – 50-60%
• Endometrial cancer – 30-60%
• Ovarian cancer – 4-40%
• Breast cancer – 10-18%
• Gastric (stomach cancer) – 5-9%
• Pancreatic cancer – 6%
• Prostate cancer – 4-11%
• Bladder cancer – 2-13%
• Biliary tract cancer – 2-4%
• Kidney cancer – 0-30%
• Brain cancer – 1-2%
MLH1
MSH2
MSH6
PMS2
EPCAM
26. For a woman with ovarian cancer, what do we learn by
finding a Lynch syndrome mutation?
Treatment implications Immunotherapy
Risk of other cancers Colon, uterine
Risk for family members First degree relatives (50% risk)
27. What are options for Lynch syndrome cancer risk
reduction?
Uterine / ovarian cancer
Pelvic ultrasound
Endometrial biopsy
Risk-reducing surgery
(hysterectomy, bilateral
salpingo-oophorectomy)
Pancreatic cancer
MRCP / MRI
Endoscopic ultrasound
Skin cancer
Dermatologic exam
Gastrointestinal cancer
Colonoscopy
Endoscopy
32. Which genes can cause breast cancer?
BRCA1
BRCA2
ATM
BARD1
BRIP1
CDH1
CHEK2
NF1
PALB2
PTEN
MSH6
PMS2
NBN
RAD51C
RAD51D
STK11
TP53
Uncertain risk
33. For women with ovarian cancer, what are the
implications of genetic testing?
Ovarian cancer
Clarify cause of cancer
Targeted therapy
Risk of other cancers
BRCA1
mutation
34. For women with ovarian cancer, what are the
implications of genetic testing?
Ovarian cancer
Clarify cause of cancer
Targeted therapy
Risk of other cancers
BRCA1
mutation
CASCADE TESTING
35. Cascade genetic testing
cas·cade
a process whereby something, typically information or knowledge, is
successively passed on
Cancer cascade testing – offering relatives
(who are also at risk for carrying the
mutation) the option for genetic assessment
36. Ideal use of genetic testing and cascade testing
Ovarian cancer
Targeted therapy (PARP inhibitor)
Prevention of other cancers
Relatives
Genetic testing
(Cascade)
Relatives with
BRCA1/2 mutation
Cancer prevention!
BRCA1 mutation
<30 % of relatives get tested
37. Why do <30% of family members complete genetic
testing?
Ovarian cancer
BRCA1 mutation
Prepare/recover
from surgery
Prepare for
chemotherapy
Navigate time off
from work
Financial toxicity
of cancer
Cope with cancer
diagnosis
Consider risk for
other cancers
Burden on
the patient
Contact relatives to disclose
her cancer diagnosis and
genetic mutation
Explain complex genetics
Assist relatives in getting
genetic testing
CASCADE
38. Cascade testing
• Research at Weill Cornell evaluating clinician-facilitated cascade
testing
• Telephone genetic counseling for relatives
• Option for genetic testing with a mailed saliva kit
• Goals
• 1. Transfer burden of cascade testing from the newly diagnosed
patient to the clinical team
• 2. Prioritize the convenience of relatives
42. Why is it critical to identify women with
BRCA1/2 mutations and Lynch
syndrome?
What are the population-based
implications?
43. Breast cancer
Numbers of cases (2020)
Number of deaths (2020)
% of cases due to inherited conditions
# of cases that could have been
prevented / detected earlier with
screening
Ovarian cancer
21,750
13,940
20%
4,350
Uterine cancer
65,620
12,590
3%
1968
276,480
42,170
10%
27,648
44. Breast cancer
Numbers of cases (2020)
Number of deaths (2020)
% of cases due to inherited conditions
# of cases that could have been
prevented / detected earlier with
screening
Ovarian cancer
21,750
13,940
20%
4,350
Uterine cancer
65,620
12,590
3%
1968
276,480
42,170
10%
27,648
~ 34,000
cancers
49. History of commercial genetic testing
1995
Myriad 1996 - 2013 Multiple companies
BRCA1
1996
BRCA2
2006
BART
Development of next
generation
sequencing
(multigene panel
testing)
2010
Supreme Court
invalidated single
gene patent
2013
50. Repeating genetic testing
•Yes, sometimes repeat genetic testing is indicated
• Based on changes in technology
• Based on changes in family history
• Based on changes in knowledge of genetic syndromes
•Genetic assessment by an oncologist or genetic
counselor is critical!
51. Summary
• Inherited mutations account for about 20-25% of ovarian cancers
• Information about a genetic mutation has many health implications
• Cancer treatment
• Risk for other cancers
• Risk for cancer among relatives
• Genetic testing is complex and dynamic
• Sometimes repeat genetic testing is warranted
• For those with mutations, communication with family members is
critical (and something the medical team should facilitate)