1. Hereditary Cancer Predisposition: Updates in Genetic Testing
Darcy Thull, MS
Certified Genetic Counselor
UPMC Cancer Genetics Program
2017

2. Disclosure
I have no relevant financial relationships to disclose

3. Cancer
Sporadic/Shared Factors
~90%
5-10%
Hereditary Susceptibility

4. 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

5. 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)

6. DNA

7. BRCA Genetic Testing Timeline
Identification of BRCA1/2 genes
Commercial sequencing at Myriad Genetics
Detects ~85% of gene mutations
2002 BRCA1 5-site rearrangement testing
Increases detection rate by a few percentage points
2006 BRCA1/2 Rearrangement testing (BART) started
Special cases only
2012 (October 12) BRCA1/2 sequencing and rearrangement (BART) testing becomes standard on all samples
Myriad Gene Patent for BRCA1/2 overturned 6/2013
--History Matters--
Patients tested prior to October 12, 2012 may need additional BRCA1/2 testing to ensure a mutation is not present

8. 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

9. When should BRCA testing be considered?
This will become more important when we talk about the Angelina Jolie effect
Most health insurance carriers follow NCCN guidelines for testing coverage—some exceptions

10. Breast Cancer Case Three generations of women
br ca dx50
Three generations of women
Early-onset breast cancer
Ovarian cancer
Small family

11. BRCA Test Results--2004
Still concerned about a hereditary cancer predisposition

12. Breast Cancer Case—Patient Returns 2008
br ca dx50
Three generations of women
Early-onset breast cancer
Ovarian cancer
Small family
BRCA deletion/duplication studies completed (BART)

13. BRCA Deletion/Duplication Results
New Nomenclature
Pathogenic Variant= Mutation

14. Implications of Identifying a Mutation
br ca dx50
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

15. Clinical Management: Mutation-Positive Patient
Testing for other adult relatives
Increased
surveillance
Medication to lower risk
Preventive
surgery
Treatment options

16. 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

17. Cancer Gene Panel High-Risk Genes Moderate-Risk Genes Newer Genes
Well studied
Lifetime risk of cancer >50%
May be related to more than 1 type of cancer
Guidelines for screening and prevention established
Lifetime risk of developing breast cancer 24-49%
Guidelines for screening available
Guidelines for prevention not established
Not as well studied
Data based on small numbers of patients
Cancer risks not yet determined
May increase risks for breast and other cancers
Guidelines for care not established

18. Possible Genetic Test Results
Pathogenic Variant Detected or
Positive Result
Increased Cancer Risks
Apply Management Guidelines if available
Test other family members if actionable
No Pathogenic Variant Detected or
Negative Result
Assess result based on family history
Screen based on family history No genetic testing for unaffected family members
Variant of Uncertain Significance (VUS)
Subtle DNA change
Unknown if benign variant (normal) or disease causing
Follow based on family history
More info may become available

19. Another reason to consider updated/additional genetic testing is a change in personal or cancer family history (new diagnoses)

20. 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

21. 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

22. Questions?