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

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 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

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? 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

Breast Cancer Case Three generations of women br ca dx50 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 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)

BRCA Deletion/Duplication Results New Nomenclature Pathogenic Variant= Mutation

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

Clinical Management: Mutation-Positive Patient 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 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

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

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

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?