Genetic testing, counselling Gynaecological cancers

1. Testing, genetic counseling and its
implication in gynaecological
cancers
Dr. Namrata Das
Junior Resident
Radiotherapy and Oncology
Moderator: Dr. C. K. Das

2. Overview
• Genetic counseling
What is genetic counseling?
Whom to test?
How to test?
What are it’s implications?
• Genetic counseling in carcinoma ovary
HBOC
• Genetic counseling in carcinoma
endometrium
Lynch Syndrome
• Li-Fraumeni Syndrome
• Cowden Syndrome
• PGIMER Experience and Workflow

5. • Mutations associated
with increased risk of
cancer
• High penetrance
phenotype
• Germline mutation
• Transmission to offspring
from mother or father
• Early onset
• Autosomal dominant
• Occur more frequently
in a family
• No typical inheritance
pattern
• Age of onset variable
• Maybe chance
clustering/ genetic
variation in low
penetrance genes/
shared environment/
combination
HEREDITARY CANCERS FAMILIAL CANCER

6. Genetic Counseling
What is genetic counseling?
Whom to test?
How to test?
What are it’s implications?

7. Genetic Counseling
Process by which patients, families and clinicians are informed about the
inheritance pattern, genetic and genomic basis of traits and clinical
disorders.
Covers four main aspects:
1.Diagnostics
1.Management
and preventive
measures
Risk calculation 1.Support

8. Areas requiring genetic counseling
• Prenatal and preconception
• Paediatrics: with/suspected genetic conditions and family
• Cancer genetics
• Cardiovascular
• Infertility, artificial reproduction, pre-implantation genetics
• Neurogenetics, psychiatric genetics

9. Genetic counseling in India
Clinicians –
gynaecologists, paediatricians, oncologists
APC PGIMER,AIIMS New Delhi, SGPGI Lucknow – provides DM degrees in
Clinical genetics
Genetic counsellor
USA, Canada: genetic counsellors possess a MS degree in genetic
counseling
Training courses and genetic counseling programmes are now available in
India in a few institutes

10. Cancer genetic counseling
It is a communication
process between a health
care professional and an
individual concerning
cancer occurrence and risk
in his or her family
Genetic
assessment
Medical
assessment
Psychological
assessment
Information
and
counseling
regarding
intervention

11. Pre-test
counseling
Genetic Risk
Assessment,
testing
Post-test
counseling
Precounseling
Information
Family History
Focused
physical
Examination
Risk
Assessment
DNA Testing
Options of
Surveillance,
Risk
Reduction and
Tailored
Treatment
Follow-Up

12. INFORMED CONSENT
Pre-Conception and Pre-Natal
Diagnostic Techniques Act, 1994
Two pre-requisites

13. Pre-Testing Assessment
PATIENT
NEEDS AND
CONCERNS
Knowledge of
genetic testing
for cancer risk,
including
benefis, risks
and limitations
Goals for
cancer family
risk
assessment
DETAILED
MEDICAL AND
SURGICAL
HISTORY
Carcinogen exposure (eg,
history of radiation
therapy)
Personal cancer history
(eg, age, histology,
laterality)
History of salpingo-
oophorectomy
Previous breast biopsies
and pathology results
Hormone or oral
contraceptive use
Reproductive history
DETAILED
FAMILY
HISTORY
Expanded
pedigree:
three
generations
FOCUSED
PHYSICAL
EXAM

14. Family History
Points to be noted:
1. Types of cancer
2. Bilaterality
3. Age at diagnosis
4. History of
chemoprevention and/or risk-
reducing surgery
5. Prior genetic testing
results for patient and their
family members and
pathology reports of primary
cancers

15. Focused Physical Exam
Trichilemmoma
Multiple hamartoma
COWDEN SYNDROME

16. Criteria for further genetic risk evaluation
Any age with known pathogenic
variant in a cancer susceptibility
gene in family/ tumour tissue
Any age, diagnosed with:
1. Ovarian cancer
2. Pancreatic cancer
3. Metastatic prostate cancer
4. Breast/prostate cancer in Ashkenazi
Jewish population
Breast cancer diagnosed:
1. <= 50 years
2. TNBC diagnosed <= 60 years
3. Two breast primaries
4. Close relative with breast cancer <= 50 years/
invasive ovarian cancer/ male breast cancer/pancreatic
cancer/high grade (>7 GS) prostate cancer
5. >= 2 blood relatives with breast cancer at any age
>= 3 members: breast cancer,
sarcoma, adrenocortical
carcinoma, brain tumour,
leukemia
>=3 members: colon cancer,
endometrial cancer, thyroid
cancer, kidney cancer,
dermatological manifestations,
macrocephaly, hamartomatous
polyps of GIT
Breast cancer, GI malignancy,
hamartomatous polyp, ovarian
sex chord tumour, childhood
skin pigmentation

17. Pre-test
counseling
Genetic Risk
Assessment,
testing
Post-test
counseling
Precounseling
Information
Family History
Focused
physical
Examination
Risk
Assessment
DNA Testing
Options of
Surveillance,
Risk
Reduction and
Tailored
Treatment
Follow-Up
GENETIC RISK ASSESSMENT GENETIC TESTING

18. Post-test counseling
• Results along with their significance and impact and
recommended medical management options
• Interpretation of results in context of personal and family
history
• Informing and testing at-risk family members
• Available resources such as disease specific support groups
and research studies

19. Genetic Counseling
What is genetic counseling?
Whom to test?
How to test?
What are it’s implications?

20. WORLD
INDIA

21. Female Lifetime Risk of Cancer
• Ovarian Cancer: General population-1.4%/One first-degree relative-4.2%
• Breast Cancer: General population-12.4%/One first-degree relative-24%
• Endometrial Cancer-2.6%

22. Gynecologic Genetic Cancer Syndromes
Hereditary Breast Ovary Cancer Syndrome
Lynch Syndrome
Cowden Syndrome
Li-Fraumeni Syndrome
Peutz-Jeghers Syndrome
Gorlin Syndrome
10-15%

23. 1. Early age of onset Carcinoma breast
2. Multiple family members on the same side of the
pedigree with the same cancer
< 50 years for breast, colon,
uterine cancer
3. Clustering of cancers in the family known to be
caused by a single gene mutation
Breast/ovarian/pancreatic
Colon/uterine/ovarian
Colon/desmoid tumours/osteoma
4. Multiple primary cancers in the same patient Breast/ovarian cancer
5. Ethnicity Ashkenazi Jews
6. Unusual presentation of cancer/tumour Breast cancer in male
Medullary carcinoma thyroid
7. Pathology TNBC

24. Genetic Counseling
What is genetic counseling?
Whom to test?
How to test?
What are it’s implications?

25. Blood, saliva Tumour tissue

26. Single vs Multigene Panel Testing

27. Genetic testing approach:
•Family with cancers highly associated with a particular
cancer susceptibility gene: test youngest (at
diagnosis), bilateral disseminated disease, multiple
primary cancers
•Risk to relatives: advise about possible inherited
cancer risk of relatives
•Reproductive organs: pre-implantation genetic
diagnosis

28. Genetic Counseling
What is genetic counseling?
Whom to test?
How to test?
What are it’s implications?
Carcinoma ovary Carcinoma endometrium

29. Factor Relative Risk
Hx of Breast Cancer
None 1.0
1st Degree Relative 2.1
Personal History 10
Hx of Ovarian Cancer
None 1.0
One 1st Degree Relative 3.1
>2 1st Degree Relatives 4-15
Hereditary Cancer Syndrome 12-30
Genetic Counseling in carcinoma ovary

30. Molecular profiling of Serous Ca Ovary

31. BRCA1/2 Characteristics

32. BRCA mutation cancer risks
Cancer General
Population
BRCA1 BRCA2
Breast 12% 40-80% 40-70%
Ovarian 1% 24-40% 11-18%
Male Breast 0.1% 1-2% 5-10%
Prostate 15-18% <30% 39%
Pancreatic 0.5% 1-3% 2-7%

33. Hereditary Breast Ovary Cancer Syndrome

34. BRCA family tree

35. BRCA1/2 Testing criteria
Age <= 45 years
Age (45-50 years): additional
breast primary/ >=1 blood
relative with breast cancer/ >=
1 blood relative with high grade
prostate cancer
Any age:
- >=1 relative with breast cancer diagnosed
<=50 years
- Ovarian cancer
-male breast cancer
- Metastatic prostate cancer
- Pancreatic cancer
<= 60 years with TNBC
Personal History of
male breast cancer
Personal history of
pancreatic cancer
Personal history of
metastatic prostate
cancer
Personal history of high grade
prostate cancer (>= 7 GS) with
- >= 1 relative with ovarian,
pancreatic, metastatic prostate at any
age
- Breast cancer < 50 years
- Ashkenazi Jewish ancestry
BRCA1/2 pathogenic/likely
pathogenic variant detected
by tumour profiling in
absence of germline testing
Regardless of family
history, BRCA testing
to determine eligibility
for targeted treatment
An individual not meeting
above criteria but with >= 1
first and second degree
relative meeting any of the
above criteria
Personal history of breast cancer + one of following:

36. BRCA testing :PCR

37. BRCA Testing Sanger sequencing
Disadvantage:
• Time consuming
• Labour intensive
• Cannot detect copy
number variation –
deletion, duplication

38. BRCA Testing MLPA
Detects Copy
Number Variations
(CNVs):
duplications,
deletions

39. Genetics Test: NGS

40. Types of results from genetic testing

41. Breast and Ovarian Cancer Management Based
on Genetic Test Results
Gene Breast Cancer Risk and Management Ovarian Cancer Risk and
Management
Other Cancer modification
BRCA1 Increased risk Increased risk Prostate Cancer
BRCA2 Increased risk Increased risk Pancreas, prostate,
melanoma
ATM Increased risk
• Screening
• Risk reducing mastectomy (RRM):
insufficient evidence
Potential increase in risk,
insufficient evidence for Risk
Reducing Salpingo-
oophorectomy (RRSO)
BRIP1 Unknown Increased: consider RRSO at
45-50 years
Mismatch
repair genes
Unknown Increased Colon, uterine, others
RAD51C,
RAD51D
Unknown Increased: consider RRSO at
45-50 years
STK11 Increased Increased risk of non-
epithelian ovarian cancer

42. Summary of BRCA Testing

43. Genetic Counseling
What is genetic counseling?
Whom to test?
How to test?
What are it’s implications?

44. BRCA PATHOGENIC/LIKELY PATHOGENIC MANAGEMENT
Prevention
Breast screening
-Clinical breast exam: 25 years, 6-12 monthly
- Age 25 – 29 years annual breast MRI
- Age 30-75 years: Annual mammogram with
consideration of tomosynthesis and breast MRI
Discuss Risk Reducing Mastectomy (RRM)
Discuss Risk Reducing Salpingo-
Oophorectomy (RRSO)
Drugs: Oral contraceptives, tamoxifen
Treatment
Breast :Olaparib/talazoparib
Ovary:
Treatment: 3rd line Olaparib
Treatment: 4th line Niraparib HRD+
Maintenance: 1st line Olaparib
Men
Risk to
relatives
- Clinical
breast
examination from 35
years
- 45 years: Prostate
screening (BRCA2)
Recommend
genetic
counseling
and ttesting
for at risk
relatives

45. Risk Reduction Startergy in BRCA mutation

46. Ca endometrium
Relative Risk
Relative Risks are calculated by dividing
the likelihood of developing cancer for
people exposed to a particular risk
factor, by the likelihood of developing
cancer for people not exposed to this
risk factor.

47. Genetics of Ca Endometrium

48. Genetics of Ca Endometrium: TransPORTEC
Classification

49. Lynch syndrome : cancer risks
General Population Risk Lynch syndrome
Colorectal 5.5% 40-80%
Uterine 2.7% 25-60%
Stomach <1% 1-13%
Ovarian 1.6% 1-24%
• Most common inherited CRC
• Increased risk of CRC, endometrial cancer
Also at increased risk:
Small intestine, biliary system (pancreas, liver, bile duct), brain, skin, and urinary tract
(kidneys, ureters, bladder, urethra)

50. Elevated HNPCC Risk: Amsterdam Criteria II
3 – 2 – 1 rule:
• Three or more relatives with histologically verified Lynch syndrome
associated cancers, one of whom is a first degree relative of the other two
and FAP has been excluded
• Lynch syndrome associated cancers involving at least two generations
• One or more diagnosed before the age of 50 years
• Sensitivity: 22%, specificity: 98%
• Lynch syndrome associated cancers: CRC, Ca endometrium, small bowel,
transitional cell carcinoma of ureter or renal pelvis

51. Lynch family tree

52. Management strategy of Lynch syndrome

53. Li – Fraumeni tumour spectrum
Soft tissue sarcoma,
osteosarcoma
CNS tumour
CNS tumour
Adrenocortical
carcinoma
p53

54. Li-Fraumeni syndrome
Combination of an individual diagnosed age <
45 years with a sarcoma
CLASSIC LI-FRAUMENI SYNDROME (LFS)
CRITERIA
A first degree relative diagnosed age < 45 years
with cancer
Additional first or second degree relative in the
same lineage with cancer diagnosed < 45 years
ir a sarcoma at any age
CHOMPRET CRITERIA
Individual with LFS spectrum tumour AND
1st/2nd degree relative with aforementioned
tumours before age 56 years
Individual with multiple tumours two of which
belong to LFS spectrum with initial tumour
occurring before 46 years
Individual with adrenocortical carcinoma or
choroid plexus carcinoma or RMS of embryonal
anaplastic type at any age, regardless of family
history
OR
OR

55. MANAGEMENT
Prevention
Breast screening
-Clinical breast exam: 20 years, 6-12
monthly
- Age 20 – 29 years annual breast MRI
- Age 30-75 years: Annual mammogram
with consideration of tomosynthesis and
breast MRI
Discuss Risk Reducing Mastectomy (RRM)
Other cancer risk
6-12 months: comprehensive
physical and neurological
assessment
Colonoscopy, UGIE: every 2-5
years starting at 25 years or 5
years before earliest known
colon cancer

56. Cowden syndrome
• Occur due to germline mutations
of PTEN gene
• High risk of breast and
endometrial cancer
Management:
• Option of RRM
• Endometrial cancer screening

57. Issues in Cancer Genetic Screening
1. Psychological Issues
2. Presymptomatic Screening in
Children
- screen only when benefit is
absolute

58. Issues in Cancer Genetic Screening
3. Confidentiality
4. Insurance and Discrimination Issues
5. Reproductive Issues

59. PGIMER Experience

60. Conclusion

61. References
• Chapter 36, Genetic Counseling. Cancer, 10th edition. DeVita,
Hellman, Rosenberg.
• NCCN Guidelines 2019: Genetic/Familial High Risk Assessment

62. Thank you

63. Lifetime risk of cancer
• Lifetime risk of cancer is an
estimate of a person’s chances of
being diagnosed with cancer at
some point during their lifetime.
• Usually expressed as the odds of
developing cancer (1 in X), as a
percentage, or as the number of
people diagnosed per 100 people
• Methods: (1) Cumulative risk, (2)
Current probability, (3) Adjusted
for multiple primaries