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Genetic Connections to Breast
Cancer
Susan R. Capasso EdD, MS, CGC
February 14, 2023
1
Learning Objectives
By the end of this session, attendees will be able to:
• Understand the importance of developing a collaborative
partnership of non-genetics and genetics experts to address
the growing number of patients at risk for hereditary breast
cancer.
• Emphasize the importance of obtaining an accurate family
history with continual updates.
• Discuss the benefits and limitations of Next Generation
Sequencing Panel Tests.
2
Delivery of Hereditary Cancer Care
• Today, there are many healthcare providers
who participate in the delivery of cancer risk
assessment and testing.
• A collaborative healthcare team composed of
non-genetics and genetics experts is ideal to
address the growing number of patients at
risk for hereditary breast cancer.
Genetic
Counselors
Have played an integral role in the
delivery of care in oncology for
many years.
.
What is the
Role of a
Genetic
Counselor
in
Oncology?
• Referrals may be done to a genetic
counselor by a physician or another
member of the medical team to discuss
family history and genetic risks, or
before or after having genetic testing.
• Genetic Counselors help patients
understand:
– Their genetic risks based on their
family history.
– Their genetic risks for certain
cancers or other diseases.
– Whether genetic testing might be
right for them.
– What the results of genetic tests
may mean for them and their family.
Cancer
Most cancers occur in people who
do not have a strong family history
of that specific cancer: SPORADIC
Some families have more of the
same kind or related kinds of
cancer than expected in the general
population with no specific pattern
of inheritance, likely caused by a
combination of genetic and
environmental factors: FAMILIAL
Hereditary
Cancer
• Those individuals in which
cancer is passed down
generation through
generation by inheriting
pathogenic variants:
HEREDITARY
• Only 5-10% cancers
BRCA Genes
• Dr. Mary-Claire King
• BRCA1 gene
discovered in 1994
• BRCA2 gene
discovered in 1995
• Hereditary Breast
and Ovarian Cancer
Hereditary
Cancer
Determining which families have
cancer related to an inherited
gene mutation is important since
the cancer risks in hereditary
cancer families are much higher
than the general population.
Following published guidelines for
increased surveillance,
chemoprevention and preventive
surgeries cancer risks have been
reduced in many individuals with
inherited cancer predispositions.
Family
History
Obtaining a three
generation pedigree is a
very powerful tool
including:
– Type of cancer
– Age of diagnosis
– Ethnicity
– Results of any cancer
testing in any relative
Hereditary Risk
• Recognizing a patient’s hereditary risk may
identify:
– risks for certain cancers
– treatment options
– at-risk family members
– long-term management
Genetic
Red Flags
• Family history of multiple affected
relatives
• Condition in the less often affected
sex
• A known mutation in a cancer
susceptibility gene
• Earlier age at onset of disease than
expected
• Multiple primary tumors in the
same person
• Bilateral disease
• Non-cancer findings suggestive of a
syndrome
• Ethnic predisposition
• Consanguinity
• Autosomal dominant inheritance
pattern
Autosomal Dominant
Inheritance pattern
Pathogenic
Variants
• Patients who have an increased
risk for cancer may have
germline testing using a saliva
or blood sample to identify
pathogenic variants
• In addition, a genomic tumor
test(somatic testing) may
identify that a patient has a
hereditary cancer syndrome.
Goal of Genomic Tumor Testing
• Identify biomarkers that have
predictive or therapeutic
significance for an active
cancer.
• Some of the DNA variants detected
are relevant for therapeutic
decisions can also be associated
with hereditary cancer risks
(e.g., BRCA1, BRCA2).
Recognize associated cancers
in HBOC
Lifetime cancer risks associated with
HBOC
Cancer Type
BRCA1 BRCA2 General
Population
Breast >60% >60% 12.3%
Male Breast 1.2% 7-8% 0.1%
Ovarian 39-58% 13-29% 1.6%
Pancreatic ≤5% 5-10% 1.6%
Prostate Increased* 15-20%* 12%
Melanoma No increase Increased 2.3%
*prostate cancer risks for BRCA1/2 carriers by age 65
Prevalence of HBOC
• About 5-10% of breast cancer and 10-15% of ovarian
cancers are attributed to HBOC.
• An estimated 1 in 333-500 individuals in the general
population have a disease-causing BRCA1 or BRCA2
mutation.
• About 1 in 40 individuals of Ashkenazi Jewish ancestry carry
a BRCA1 or BRCA2 mutation.
• Tend to develop cancer at an earlier age than the general
population.
18
Criteria for referral
• A known mutation in a cancer susceptibility gene
• Ovarian cancer
• Male breast cancer
• Pancreatic cancer
• Prostate cancer
• Breast cancer diagnosed ≤ 45
• Breast cancer diagnosed > 45 with family history of
related cancers
• Triple negative breast cancer diagnosed at any age
• Two primary tumors in the breast
• Ashkenazi Jewish ancestry and breast cancer at any
age
• BRCA1/2 mutation identified in tumor profiling
Other genes that Contribute to Breast
and Ovarian Cancer
• Other hereditary cancer syndromes that
increase the risk for breast cancer
– Cowden syndrome: PTEN
– Li-Fraumeni syndrome: TP53
• The presentation of these syndromes in a
family may overlap with HBOC
• But can have characteristic features
• Other moderate genes risk genes
Multigene
Panel
Testing
Genetic Testing has expanded due
to new technology utilizing Next
Generation Sequencing (NGS)
technology which allows for rapid
and inexpensive analysis of large
chunks of the genome
Multigene NGS panels allow
simultaneous sequencing of many
genes associated with a specific
family cancer phenotype or
multiple phenotypes
Identification
of Carriers of
Pathogenic
Variants
Important to identify patients at
risk for other breast cancer
syndromes. Multi-gene panels
are increasingly recommended
For example TP53, PALB2, PTEN
Knowledge of these other genes
can influence radiation therapy
and chemotherapy decisions
Benefits of
Multi-Gene
Panel Testing
for Breast
Cancer Risk
Provides better diagnostic yield
compared with a limited BRCA1/2
genetic test for patients at risk for
hereditary breast cancer or
individuals diagnosed with breast
cancer.
In a retrospective comparison of
multiple genetic tests there was no
difference between the multi-gene
panel test and the limited BRCA1/2
test in the detection of potentially
harmful BRCA pathogenic variants.
Multigene
Panel
Testing
Includes
“intermediate”
penetrant genes
of unclear action
Should be offered
in the context of
professional
expertise with pre
& post test
counseling.
More cost
effective and time
effective than
sequential testing
Can reveal more
than one
pathogenic
mutation
Risks of
Multigene
Testing
Results can be complicated to
interpret
Testing may find gene mutations
that show a moderate or
uncertain risk of cancer
It may be hard to know what
you should do with the results
Positive
Test Result
• If identified:
– Increased risk for certain types of
cancer
– Different mutations are linked to
increased risks for different types of
cancers
– The risks may differ for the different
mutations
– Some are very high, others less but
– Still more than the general public
Positive
Test
Result
May be offered special or more frequent
cancer screening exams to find any
cancers that develop as early as possible:
dependent on the specific mutated genes
Originally there were concerns that some
mutations on multi-gene panels have no
clear guidelines about the best screening
exams to use or how often
NCCN guidelines are increasing
Prophylactic
Surgery • Patients may be offered certain types of
surgeries that may help reduce risk of
developing cancer
– Most commonly mastectomy,
oophorectomy and hysterectomy
Family
members
If an individual is positive for a genetic
mutation then family members may
also carry this same mutation
1st degree relatives at 50% risk to have
inherited same mutation, 2nd degree
relatives 25%, 3rd degree relatives
12.5%
A genetic counselor can help identify
who in the family is at risk of having
the mutation, who should be tested
and when they should be tested
Negative
Test
Result
You could have a pathogenic
variant in a gene but technology
not there yet.
Some types of cancer may occur
in several people in a family
without being caused by a
genetic mutation.
There may be a pathogenic
variant in other members of your
family but you did not inherit it.
Variant of
Uncertain
Significance
(VUS)
Seen in affected and not affected
These are single nucleotide DNA
polymorphisms that are neither
confirmed benign nor pathogenic
Rates are going down and there
are ACMG guidelines and lab data
available
VUSs
• More are found in individuals
with non-European ancestry who
have been historically
underrepresented in genomic
research.
• The classification of a variant
– benign, uncertain, or
pathogenic – can change over
time as labs generate more data
about specific variants.
• In some cases, a VUS may be
reclassified as "actionable" as
new data is obtained.
Established Models
• The risk of developing breast cancer can be
calculated utilizing various models
– Tyrer-Cuzick
– Gail
– Claus
• These typically have short-term and long-term
cancer risk estimates
• Other factors that can increase risk include such
factors as family history, reproductive history, and
number of biopsies.
Resources and References
• American College of Obstetricians and Gynecologists (2019) Committee Opinion
#793: Hereditary Cancer Syndromes and Risk Assessment
• American Society of Clinical Oncology(2020) Hereditary Breast and Ovarian
Cancer
• Berliner J.et al(2021). Risk Assessment and Genetic Counseling for Hereditary
Breast and Ovarian Cancer Syndromes-Practice Resource of the National Society
of Genetic Counselors
• Jackson Laboratories Hereditary Cancer Modules
• National Comprehensive Cancer Network(v.1.2022): Genetic/Familial High- Risk
Assessment: Breast, Ovarian and Pancreatic
37

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Genetic Connections to Breast Cancer - February 14, 2023

  • 1. Genetic Connections to Breast Cancer Susan R. Capasso EdD, MS, CGC February 14, 2023 1
  • 2. Learning Objectives By the end of this session, attendees will be able to: • Understand the importance of developing a collaborative partnership of non-genetics and genetics experts to address the growing number of patients at risk for hereditary breast cancer. • Emphasize the importance of obtaining an accurate family history with continual updates. • Discuss the benefits and limitations of Next Generation Sequencing Panel Tests. 2
  • 3. Delivery of Hereditary Cancer Care • Today, there are many healthcare providers who participate in the delivery of cancer risk assessment and testing. • A collaborative healthcare team composed of non-genetics and genetics experts is ideal to address the growing number of patients at risk for hereditary breast cancer.
  • 4. Genetic Counselors Have played an integral role in the delivery of care in oncology for many years. .
  • 5. What is the Role of a Genetic Counselor in Oncology? • Referrals may be done to a genetic counselor by a physician or another member of the medical team to discuss family history and genetic risks, or before or after having genetic testing. • Genetic Counselors help patients understand: – Their genetic risks based on their family history. – Their genetic risks for certain cancers or other diseases. – Whether genetic testing might be right for them. – What the results of genetic tests may mean for them and their family.
  • 6. Cancer Most cancers occur in people who do not have a strong family history of that specific cancer: SPORADIC Some families have more of the same kind or related kinds of cancer than expected in the general population with no specific pattern of inheritance, likely caused by a combination of genetic and environmental factors: FAMILIAL
  • 7. Hereditary Cancer • Those individuals in which cancer is passed down generation through generation by inheriting pathogenic variants: HEREDITARY • Only 5-10% cancers
  • 8. BRCA Genes • Dr. Mary-Claire King • BRCA1 gene discovered in 1994 • BRCA2 gene discovered in 1995 • Hereditary Breast and Ovarian Cancer
  • 9. Hereditary Cancer Determining which families have cancer related to an inherited gene mutation is important since the cancer risks in hereditary cancer families are much higher than the general population. Following published guidelines for increased surveillance, chemoprevention and preventive surgeries cancer risks have been reduced in many individuals with inherited cancer predispositions.
  • 10. Family History Obtaining a three generation pedigree is a very powerful tool including: – Type of cancer – Age of diagnosis – Ethnicity – Results of any cancer testing in any relative
  • 11. Hereditary Risk • Recognizing a patient’s hereditary risk may identify: – risks for certain cancers – treatment options – at-risk family members – long-term management
  • 12. Genetic Red Flags • Family history of multiple affected relatives • Condition in the less often affected sex • A known mutation in a cancer susceptibility gene • Earlier age at onset of disease than expected • Multiple primary tumors in the same person • Bilateral disease • Non-cancer findings suggestive of a syndrome • Ethnic predisposition • Consanguinity • Autosomal dominant inheritance pattern
  • 14. Pathogenic Variants • Patients who have an increased risk for cancer may have germline testing using a saliva or blood sample to identify pathogenic variants • In addition, a genomic tumor test(somatic testing) may identify that a patient has a hereditary cancer syndrome.
  • 15. Goal of Genomic Tumor Testing • Identify biomarkers that have predictive or therapeutic significance for an active cancer. • Some of the DNA variants detected are relevant for therapeutic decisions can also be associated with hereditary cancer risks (e.g., BRCA1, BRCA2).
  • 17. Lifetime cancer risks associated with HBOC Cancer Type BRCA1 BRCA2 General Population Breast >60% >60% 12.3% Male Breast 1.2% 7-8% 0.1% Ovarian 39-58% 13-29% 1.6% Pancreatic ≤5% 5-10% 1.6% Prostate Increased* 15-20%* 12% Melanoma No increase Increased 2.3% *prostate cancer risks for BRCA1/2 carriers by age 65
  • 18. Prevalence of HBOC • About 5-10% of breast cancer and 10-15% of ovarian cancers are attributed to HBOC. • An estimated 1 in 333-500 individuals in the general population have a disease-causing BRCA1 or BRCA2 mutation. • About 1 in 40 individuals of Ashkenazi Jewish ancestry carry a BRCA1 or BRCA2 mutation. • Tend to develop cancer at an earlier age than the general population. 18
  • 19. Criteria for referral • A known mutation in a cancer susceptibility gene • Ovarian cancer • Male breast cancer • Pancreatic cancer • Prostate cancer • Breast cancer diagnosed ≤ 45 • Breast cancer diagnosed > 45 with family history of related cancers • Triple negative breast cancer diagnosed at any age • Two primary tumors in the breast • Ashkenazi Jewish ancestry and breast cancer at any age • BRCA1/2 mutation identified in tumor profiling
  • 20. Other genes that Contribute to Breast and Ovarian Cancer • Other hereditary cancer syndromes that increase the risk for breast cancer – Cowden syndrome: PTEN – Li-Fraumeni syndrome: TP53 • The presentation of these syndromes in a family may overlap with HBOC • But can have characteristic features • Other moderate genes risk genes
  • 21. Multigene Panel Testing Genetic Testing has expanded due to new technology utilizing Next Generation Sequencing (NGS) technology which allows for rapid and inexpensive analysis of large chunks of the genome Multigene NGS panels allow simultaneous sequencing of many genes associated with a specific family cancer phenotype or multiple phenotypes
  • 22. Identification of Carriers of Pathogenic Variants Important to identify patients at risk for other breast cancer syndromes. Multi-gene panels are increasingly recommended For example TP53, PALB2, PTEN Knowledge of these other genes can influence radiation therapy and chemotherapy decisions
  • 23. Benefits of Multi-Gene Panel Testing for Breast Cancer Risk Provides better diagnostic yield compared with a limited BRCA1/2 genetic test for patients at risk for hereditary breast cancer or individuals diagnosed with breast cancer. In a retrospective comparison of multiple genetic tests there was no difference between the multi-gene panel test and the limited BRCA1/2 test in the detection of potentially harmful BRCA pathogenic variants.
  • 24. Multigene Panel Testing Includes “intermediate” penetrant genes of unclear action Should be offered in the context of professional expertise with pre & post test counseling. More cost effective and time effective than sequential testing Can reveal more than one pathogenic mutation
  • 25. Risks of Multigene Testing Results can be complicated to interpret Testing may find gene mutations that show a moderate or uncertain risk of cancer It may be hard to know what you should do with the results
  • 26.
  • 27.
  • 28.
  • 29. Positive Test Result • If identified: – Increased risk for certain types of cancer – Different mutations are linked to increased risks for different types of cancers – The risks may differ for the different mutations – Some are very high, others less but – Still more than the general public
  • 30. Positive Test Result May be offered special or more frequent cancer screening exams to find any cancers that develop as early as possible: dependent on the specific mutated genes Originally there were concerns that some mutations on multi-gene panels have no clear guidelines about the best screening exams to use or how often NCCN guidelines are increasing
  • 31. Prophylactic Surgery • Patients may be offered certain types of surgeries that may help reduce risk of developing cancer – Most commonly mastectomy, oophorectomy and hysterectomy
  • 32. Family members If an individual is positive for a genetic mutation then family members may also carry this same mutation 1st degree relatives at 50% risk to have inherited same mutation, 2nd degree relatives 25%, 3rd degree relatives 12.5% A genetic counselor can help identify who in the family is at risk of having the mutation, who should be tested and when they should be tested
  • 33. Negative Test Result You could have a pathogenic variant in a gene but technology not there yet. Some types of cancer may occur in several people in a family without being caused by a genetic mutation. There may be a pathogenic variant in other members of your family but you did not inherit it.
  • 34. Variant of Uncertain Significance (VUS) Seen in affected and not affected These are single nucleotide DNA polymorphisms that are neither confirmed benign nor pathogenic Rates are going down and there are ACMG guidelines and lab data available
  • 35. VUSs • More are found in individuals with non-European ancestry who have been historically underrepresented in genomic research. • The classification of a variant – benign, uncertain, or pathogenic – can change over time as labs generate more data about specific variants. • In some cases, a VUS may be reclassified as "actionable" as new data is obtained.
  • 36. Established Models • The risk of developing breast cancer can be calculated utilizing various models – Tyrer-Cuzick – Gail – Claus • These typically have short-term and long-term cancer risk estimates • Other factors that can increase risk include such factors as family history, reproductive history, and number of biopsies.
  • 37. Resources and References • American College of Obstetricians and Gynecologists (2019) Committee Opinion #793: Hereditary Cancer Syndromes and Risk Assessment • American Society of Clinical Oncology(2020) Hereditary Breast and Ovarian Cancer • Berliner J.et al(2021). Risk Assessment and Genetic Counseling for Hereditary Breast and Ovarian Cancer Syndromes-Practice Resource of the National Society of Genetic Counselors • Jackson Laboratories Hereditary Cancer Modules • National Comprehensive Cancer Network(v.1.2022): Genetic/Familial High- Risk Assessment: Breast, Ovarian and Pancreatic 37

Editor's Notes

  1. Nccn guidelines
  2. Powerful tool but needs to be updated In addition to the National Comprehensive Cancer Network (NCCN) guidelines for identifying patients appropriate for genetic testing there are numerous assessment tools including those online.
  3. : Autosomal dominant inheritance Affected individuals in every generation Any child of an affected individual has a 50% chance of inheriting the trait; unaffected family members do not pass it to their children Males and females equally likely to be affected (although there may be sex-limited expression, such as with ovarian cancer)
  4. Multiple genes can contribute to the breast/ovarian cancer phenotype or other phenotypes Higher mutation detection rate reduces the number of families with uninformative results Increase the number of patients who can be provided tailored surveillance, risk reduction options and testing of at risk family members
  5. TP53 Li Fraumeni rare inherited disease that greatly increases one’s risk for developing cancer during their lifetime LFS develop multiple cancers and multiple tumors often in childhood or as young adults osteosarcoma, breast, brain, acute leukemia, adrenal cortical tumors, melanoma Wilms tumor of the kidney had stomach colon, pancreas
  6. By analyzing additional clinically actionable genes, we see that a population of 1951 breast cancer patients would benefit from an increase in mutation detection by ~46%. There are significant number of mutation carriers that would be missed and therefore, undermanaged. Patients associated with hereditary colon cancer or ovarian cancer are also expected to see a similar increase in mutation detection with additional genes analyzed.
  7. Risks and Benefits of Genetic Testing Genetic Testing can have emotional effects especially if a mutation is found It can impact other family members Some may not want to know
  8. To
  9. Those found to have the gene but who currently do not have cancer may choose prophylactic surgery
  10. Whether affected or not
  11. Familial Cancer
  12. Some patients are quite concerned because they want to know do I have a mutation or not Seen in affected and not