Genetic Connections to Breast
Cancer
Susan R. Capasso EdD, MS, CGC
February 14, 2023
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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.
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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.
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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
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