Download Hereditary Cancer Predisposition

Hereditary Cancer Predisposition:
Updates in Genetic Testing
Darcy Thull, MS
Certified Genetic Counselor
UPMC Cancer Genetics Program
2017
Disclosure
• I have no relevant financial relationships to disclose
2
Cancer
Sporadic/Shared
Factors
~90%
5-10%
Hereditary
Susceptibility
Types of Genetic Testing
Germline Studies
Genomic Tumor Studies
• Evaluation of a blood
or saliva specimen to
identify inherited
genetic mutations
• Aid in determining
treatment
• OncotypeTM (breast)
• May enable
personalized therapy
that is targeted to a
specific gene pathway
•
EGFR mutations (lung)
• Can sometimes identify
hereditary cancer
predispositions
Genome Medicine/Precision Medicine
• The use of knowledge from genetic testing of tumor
(somatic) or germline to direct a patient’s cancer care
• Next Generation Sequencing (NGS) the ability to analyze
multiple genes or DNA fragments simultaneously-- faster
and at less cost (gene panels)
DNA
BRCA Genetic Testing Timeline
• 1994-95
Identification of BRCA1/2 genes
– Commercial sequencing at Myriad Genetics
– Detects ~85% of gene mutations
•
•
•
•
--History Matters-2002 BRCA1 5-site rearrangement testing
Patients tested prior to
– Increases detection rate by a few percentage points
October 12, 2012 may
2006 BRCA1/2 Rearrangement testing (BART) started
need additional
– Special cases only
BRCA1/2
testing
to
2012 (October 12) BRCA1/2 sequencing and rearrangement
ensurestandard
a mutation
(BART) testing becomes
on all is
samples
present
Myriad Gene Patent fornot
BRCA1/2
overturned 6/2013
Features of Hereditary Cancer Syndromes
• Multiple family members with
the same or related types of
cancer across several
generations (Autosomal
Dominant inheritance)
• Young age at diagnosis
(under 45)
• Individuals with multiple
separate cancer diagnosis
• Uncommon cancers (male
breast, ovary)
• Suggestive Tumor studies
(TNBC <60, MMR deficient
colon tumors)
• Ethnicity
When should BRCA testing be considered?
Most health insurance carriers follow NCCN
guidelines for testing coverage—some
exceptions
9
Breast Cancer Case
63
76
57
45
50
ov ca dx 45
br ca dx 47
79
50
29
childbir th
78
48
BSO 3 5
br ca dx50
br ca dx 45
48
•
•
•
•
60
45
br ca dx 48
Three generations of women
Early-onset breast cancer
Ovarian cancer
Small family
75
BRCA Test Results--2004
Still concerned about a hereditary cancer predisposition
Breast Cancer Case—Patient Returns 2008
63
76
57
45
50
ov ca dx 45
br ca dx 47
79
78
BSO 3 5
60
29
childbir th
48
75
br ca dx 45
br ca dx50
50
•
•
•
•
48
45
br ca dx 48
Three generations of women
Early-onset breast cancer
Ovarian cancer
Small family
BRCA
deletion/duplication
studies completed
(BART)
BRCA Deletion/Duplication Results
New Nomenclature
Pathogenic Variant=
Mutation
Implications of Identifying a Mutation
63
76
57
45
50
ov ca dx 45
br ca dx 47
79
50
60
29
childbirth
78
48
BSO 3 5
br ca dx 45
48
br ca dx 48
45
br ca dx50
75
BRCA2 Cancer Risks (lifetime)
• 60% Breast Cancer Risk (Avg)
• 30-40% Second Breast Cancer
• 16-27% Ovary Cancer Risk
• 5% Pancreas Cancer
• 39% Prostate Cancer
• 5% Melanoma
Clinical Management: Mutation-Positive Patient
Mutation Positive
Testing for other adult
relatives
Increased
surveillance
Medication
to lower risk
Preventive
surgery
Treatment
options
No more BRCA Patents and NGS
• Multi-gene cancer panels become clinically available
• Many laboratories offer hereditary breast cancer panels
which include analysis of BRCA1/2 and other genes
• Panels vary in number and types of genes included
Cancer Gene Panel
High-Risk
Genes
Moderate-Risk
Genes
Newer Genes
• Well studied
• Well studied
• Not as well studied
• Lifetime risk of
cancer >50%
• Lifetime risk of
developing breast
cancer 24-49%
• Data based on
small numbers of
patients
• May be related to
more than 1 type of
cancer
• Guidelines for
screening and
prevention
established
• Guidelines for
screening available
• Guidelines for
prevention not
established
• Cancer risks not yet
determined
• May increase risks
for breast and other
cancers
• Guidelines for care
not established
Possible Genetic Test Results
Pathogenic Variant
Detected
or
Positive Result
•
•
•
•
No Pathogenic
Variant Detected
or
Negative Result
Variant of
Uncertain
Significance (VUS)
•
•
•
•
•
Increased Cancer Risks
Apply Management
Guidelines if available
Test other family members
if actionable
Assess result based on family
history
Screen based on family
history
No genetic testing for
unaffected family members
Subtle DNA change
Unknown if benign variant
(normal) or disease causing
Follow based on family history
More info may become available
Unknown
BRCA1/2
Other
Genes
Another reason to consider updated/additional genetic testing is
a change in personal or cancer family history (new diagnoses)
19
Issues to Consider with Panels
• They may not provide an answer (no mutations
detected)
• The likelihood of a VUS is higher since multiple genes
are being analyzed
• May not be completely covered by insurance due to lack
of evidence for management
• There may not be sufficient information to comment on
specific cancer risks related to a mutation in a “newer”
gene
Summary
• Testing technology changes and updated testing may be a
consideration
• Personal and family cancer histories change and additional
testing may be considered
• NGS multigene panels provide additional information, but
not all pathogenic variants (mutations) identified will result in
a change in clinical management (new genes)
• Testing more genes means there is a greater chance to
identify a VUS
• Testing not be completely covered by insurance due to lack
of evidence regarding medical interventions for some genes
evaluated
Questions?