Overview of Cancer Genetics The Role of Cancer Genetics in Precision Medicine April 17, 2018 / May 1, 2018 Vanessa Manso / Matthew Share, MS Licensed / Certified Genetic Counselor William G. Rohrer Cancer Genetics Program

Objectives Identify the best practices for referring patients for genetic counseling Discuss the key components of genetic assessment and testing Describe current approaches to genetic testing for hereditary cancer syndromes Identify potential benefits and limitations of the multigene panel testing approach for hereditary cancer Discuss the implications, risks, and benefits of genetic testing for the individual and their family Recognize key features of major genetic syndromes

Most Cancers are Sporadic Environmental exposures / random chance Familial (~20%) Shared environmental exposures Similar genetic background Hereditary (~10%) Inherited genetic mutation  increased risk Image from http://publications.nigms.nih.gov/thenewgenetics/chapter1.html

Family History Features Suggestive of Hereditary Cancer Syndromes Cancer in 2+ relatives Multiple generations Same side of the family Younger age @ cancer diagnosis Multiple primary cancers Includes bilateral Less common cancer types Ovarian cancer Breast cancer in a man Paraganglioma Medullary thyroid cancer Absence of typical environmental risk factors Cancer with certain pathologic characteristics “Triple negative” breast cancer Cancer cells with genetic instability or abnormal staining Ancestry w/ higher incidence of mutations in hereditary cancer syndrome genes Ashkenazi Jewish ancestry & BRCA1, BRCA2 Blood relative(s) with a known mutation

Sporadic Familial Hereditary Bilateral Breast @71 Breast @41 & 52

Key Components of Genetic Assessment and Testing Medical & family history obtained / assessed Education regarding hereditary cancer Informed consent: explain clinical and familial implications of genetic testing and other diagnostic studies Healthy tissue sample (blood, saliva, cheek cells) obtained if proceeding with testing https://www.nsgc.org/p/cm/ld/fid=18#scope

Genetic Testing Practices Syndrome- or gene-specific testing (1990’s-present) Typically single gene or single syndrome testing i.e. BRCA1 / BRCA2; Lynch syndrome; CDH1; etc. Single-site testing for a known mutation Multi-gene testing (“panel testing”; 2013-present) Variable number of genes tested Pan-cancer versus targeted cancer gene panels Panel based on level of known cancer risk High / moderate / “increased” risk levels http://www.cancer.gov/about-cancer/causes-prevention/genetics/risk-assessment-pdq#link/_1320

The Majority of Breast Cancers Do Not Have an Identifiable Germline Mutation

The Majority of Ovarian Cancers Do Not Have an Identifiable Germline Mutation

When to Refer for Further Genetic Risk Evaluation: Breast & Ovarian Breast cancer diagnosed ≤ 50 years Ashkenazi Jewish ancestry and breast/ovarian (or pancreatic) cancer Triple negative breast cancer ≤ 60 Multiple primary cancers Breast cancer in a male Ovarian cancer at any age Family history and/or known familial mutation NCCN version 1.2018 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

http://www. breastlink http://www.breastlink.com/wp-content/uploads/2015/04/Nimmi-S-Kapoor-MD-Genetic-Testing-American-Society-Breast-Surgeons.pdf

Hereditary Breast Cancer Genes High Risk Moderate Risk Increased Risk BRCA1 ATM BARD1 BRCA2 CHEK2 BRIP1 CDH1 PALB2 NBN PTEN   RAD50 STK11 RAD51C TP53 RAD51D others… Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) **possible increased risk of breast cancer for carriers**

The Majority of Colorectal Cancers Do Not Have an Identifiable Germline Mutation

When to Refer for Further Genetic Risk Evaluation: Colorectal Cancer (CRC) CRC diagnosed ≤ 50 Amsterdam and Bethesda Criteria Lynch screen: IHC/MSI Lifetime polyp count Family history Known familial mutation NCCN version 3.2017 “Genetic/Familial High Risk Assessment: Colorectal”; www.nccn.org

Hereditary CRC Syndromes Lynch syndrome (Hereditary nonpolyposis colorectal cancer)- MLH1, MSH2, MSH6, PMS2, EPCAM Colon, uterine, stomach, other cancer risks Familial adenomatous polyposis (FAP)- APC Colon polyps (100+) Extracolonic findings: CHRPE, extra teeth, desmoids MUTYH-associated polyposis (MAP)- MUTYH Colon polyps (0-100), duodenal cancer, duodenal polyps NCCN version 3.2017 “Genetic/Familial High Risk Assessment: Colorectal”; www.nccn.org

Hereditary Gastric Cancer Syndromes Hereditary diffuse gastric cancer: CDH1 (possibly CTNNA1) Gastric cancer (up to 70-80%); lobular breast cancer (40-50%) Gastric cancer: Lynch syndrome, Juvenile polyposis syndrome (BMPR1A, SMAD4), Peutz-Jeghers syndrome (STK11), APC Gastrointestinal stromal tumor (GIST): KIT, NF1, PDGFRA, SDHA/B/C/D https://www.cancer.net/cancer-types/hereditary-diffuse-gastric-cancer NCCN version 5.2017 “Gastric Cancer”; www.nccn.org

Potential Benefits of Multi-Gene Testing (versus traditional sequential gene testing) Higher mutation detection rate especially for patients who do not meet specific personal or family history criteria Lower likelihood of “uninformative” negative results Often more cost- and time-efficient May find a mutation in more than one gene NCCN version 1.2018 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

Considerations of Multi-Gene Testing Which test (# genes?) or laboratory to choose? Increased risk for variant result Faster / cheaper ≠ better Limited data re: cancer risks associated with some genes Potential lack of clear medical management guidelines for mutation carriers Challenges in making medical management recommendations if a patient carries mutations in multiple genes Potential added TAT for larger panels NCCN version 1.2018 “Genetic/Familial High Risk Assessment: Breast and Ovarian”; www.nccn.org

Possible Results of Genetic Testing Positive “Mutation” “Pathogenic variant” “Deleterious variant” “Likely pathogenic/deleterious variant” Negative Variant of uncertain/unknown significance

Pathogenic mutation Slide for professional use from Myriad Genetic Laboratories https://new.myriadpro.com/products/myriad-myrisk/patient-education/ Use of this image does not imply endorsement.

Positive Test Result Cancer risk(s) increased due to pathogenic hereditary gene mutation Cancer treatment decisions (if applicable) Result may influence surgical decisions, chemotherapy options, clinical trial eligibility Cancer screening and risk reduction options Additional imaging? More frequent clinical exams? Surgery? Chemoprevention? Lifestyle changes? Information for the family A “diagnosis” for the family Testing of relatives with / without cancer for the known mutation May or may not influence clinical care and management

Negative/Uncertain Test Result Cancer risk(s) may still be increased based on personal risk factors and/or family history Cancer treatment decisions (if applicable) Not impacted by result Cancer screening and risk reduction options Based on personal and family history Information for the family A negative/variant result does not eliminate the possibility of hereditary cancer in the family Other family members may still wish to consider genetic testing

What is a Variant of Uncertain Significance? Alteration in a gene with limited and/or conflicting evidence regarding pathogenicity Classification system AA biochemical similarities Presence/absence in healthy individuals Presence in individuals with X-related cancers Prediction algorithms: PolyPhen and SIFT Internal data *Occasional variant classification studies through laboratory*

Emerging Evidence Testing Single nucleotide polymorphisms (SNP) Small single-base changes in the genetic code that collectively may increase cancer risk Polygenic risk score combined with risk models to calculate new risk estimate Considerations: How to use results clinically is not yet clear Labs will not re calculate score as information changes Some opt out, others opt in, rapidly evolving field

Tumor vs. Germline Testing One is not a substitute for the other! Tumor genetic testing may detect a mutation that is also in the germline A tumor “mutation” might be considered a germline “variant of uncertain significance” May do germline testing to follow up on a mutation found via tumor testing dependent on the gene and the personal / family history targeted to the mutation or to include full gene analysis +/- other genes

Slide for professional use from Myriad Genetic Laboratories https://new.myriadpro.com/products/myriad-myrisk/patient-education/ Use of this image does not imply endorsement.

DTC testing- 23andMe https://www.23andme.com/dna-health-ancestry/

DTC testing- 23andMe No physician order necessary Consumers “opt-in” to receive this part of result Not relevant result for general population (non-AJ) Not full BRCA1/BRCA2 analysis No other hereditary breast cancer genes studied Positive* result Negative result - concerns may lead to false sense of security re: cancer risk may deter individuals from seeking clinical genetic evaluation

Summary Several reasons for a patient to be referred to genetics Personal diagnosis, family history, screening tests, less common cancer types The scope of testing can vary Genetic testing is negative more often than not Identification of a genetic syndrome / mutation can have major impact on patients and families

Case #1 Prostate @ 43 Breast @ 72 BRCA2: breast (male and female), ovarian, prostate, pancreatic, melanoma 43 45 38 40 Single site testing: BRCA2- Single site testing: BRCA2+ Single site testing: BRCA2+ Breast @ 42 9-gene breast cancer panel: BRCA2+ 20 18 Single site testing: BRCA2+ Single site testing: BRCA2- Ancestry: Maternal- SE Asian, Paternal- Irish, non-Jewish

Case #2 Prostate @ 72 Colon @49 Ovarian @60 MLH1: colon, uterine, gastric, ovarian, pancreatic, etc. 62 59 58 57 52 Uterine @52 Colon @48 & 58 Single site testing: MLH1+ Colon @45 Genetic testing 2014 9 gene gyn cancer panel: MLH1+ 34 28 6 Single site testing: MLH1+ Single site testing: MLH1- Ancestry: African, non-Jewish 32

Case #3 63 CDH1: diffuse gastric cancer, lobular breast cancer, signet ring colon cancer Lobular breast @ 51 23 31 20 Single site testing: CDH1+ Gastric @23 Signet ring features Single site testing: CDH1+ Genetic Testing: CDH1+ P Ancestry: Maternal & Paternal- Irish, Non-Jewish

Cancer Genetics Program Practice Locations 2 Cooper Plaza, Camden 900 Centennial Blvd, Voorhees 100 Salem Drive, Willingboro Locations for Inspira patients: Vineland, Mickleton, Mullica Hill

Cancer Genetics Program Team Oncologists Generosa Grana, MD (Program Director) Christina Brus, MD Alexandre Hageboutros, MD A. Kamel Abou Hussein, MD Pallav Mehta, MD Jamin Morrison, MD Kumar Rajagopalan, MD Kanu Sharan, MD Robert Somer, MD Christian Squillante, MD Preeti Sudheendra, MD Advanced Practice Nurses (APNs) Jennifer Bonafiglia, APN-C Phyllis Duda, APN-C Kristi Kennedy, APN-C Helen Nichter, APN-C Evelyn Robles-Rodriguez, APN-C Genetic Counselors Brooke Levin, MS, LCGC Vanessa Manso, MS, LCGC Kristin Mattie, MS, LCGC Matthew Share, MS, LCGC Jennie Stone, MS, LCGC Program Staff Manager Evelyn Robles-Rodriguez, RN, MSN, APN, AOCN Administrative Coordinator Brandi Ford, CCMA, AAS (Camden) Medical Assistant Myra Salcedo, RMA (Camden)

Cancer Genetics Program Genetic Counselors L to R: Kristin Mattie, Vanessa Manso, Matthew Share, Jennie Stone, Brooke Levin