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 Aid in determining

treatment
or saliva specimen to OncotypeTM (breast)
identify inherited May enable
genetic mutations 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 patients 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
Special cases only
need additional

BRCA1/2 testing to
2012 (October 12) BRCA1/2 sequencing and rearrangement
ensurestandard
(BART) testing becomes a mutationon all is
samples
Myriad Gene Patent fornot present
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 coveragesome
exceptions 9
Breast Cancer Case

63 57 45 50 60 29

ov ca dx 45 br ca dx 47 childbir th

76 79 78 48 75

BSO 3 5 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 Test Results--2004

Still concerned about a hereditary cancer predisposition

Breast Cancer CasePatient Returns 2008

63 57 45 50 60 29

ov ca dx 45 br ca dx 47 childbir th

76 79 78 48 75

BSO 3 5 br ca dx 45

br ca dx50

50 48 45

br ca dx 48

Three generations of women

Early-onset breast cancer BRCA
Ovarian cancer deletion/duplication
Small family studies completed
(BART)
BRCA Deletion/Duplication Results

New Nomenclature
Pathogenic Variant=
Mutation
Implications of Identifying a Mutation

63 57 45 50 60 29

ov ca dx 45 br ca dx 47 childbirth

76 79 78 48 75
br ca dx50
BSO 3 5 br ca dx 45

BRCA2 Cancer Risks (lifetime)

60% Breast Cancer Risk (Avg)
30-40% Second Breast Cancer
50 48 45 16-27% Ovary Cancer Risk
br ca dx 48 5% Pancreas Cancer
39% Prostate Cancer
5% Melanoma
Clinical Management: Mutation-Positive Patient

Mutation Positive

Testing for other adult

relatives

Increased Medication Preventive Treatment

surveillance to lower risk surgery 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 Moderate-Risk Newer Genes

Genes Genes
Well studied Well studied Not as well studied

Lifetime risk of Lifetime risk of Data based on

cancer >50% developing breast small numbers of
cancer 24-49% patients
May be related to
more than 1 type of Cancer risks not yet
cancer Guidelines for determined
screening available
Guidelines for May increase risks
screening and Guidelines for for breast and other
prevention prevention not cancers
established established
Guidelines for care
not established
Possible Genetic Test Results

Pathogenic Variant Increased Cancer Risks

Apply Management
Detected Guidelines if available
or Test other family members
if actionable
Positive Result
Assess result based on family
No Pathogenic history
Variant Detected Screen based on family
history
or No genetic testing for
Negative Result unaffected family members

Variant of Subtle DNA change

Uncertain Unknown if benign variant
(normal) or disease causing
Significance (VUS) 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?