Robert Nathan Slotnick MD PhD FACOG FACMG (FF) Perinatologist and Director Medical Genetics

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1 THE GENETICS OF CANCER: How Therapy and Surveillance Are Changing Robert Nathan Slotnick MD PhD FACOG FACMG (FF) Perinatologist and Director Medical Genetics Perinatal Assoc. of N. NV 1500 E. 2 nd St Suite 108 Reno, NV (p) (f) Objectives Review of the genetics of cancer Discuss the approach & management of the most common hereditary cancer syndromes Hereditary Breast & Ovarian Cancer syndrome (HBOC) Polyposis syndromes (FAP, AFAP, MAP, & Peutz Jeghers) Hereditary Non-Polyposis Colorectal Cancer (HNPCC) aka Lynch Syndrome At end be able to identify the features of the above conditions, know when to initiate referral, and appreciate the changes in medical management and its purpose in early detection and/or prevention of cancer What s new: cancer of unknown origin, panels, cancer genotyping, genetic directed cancer therapeutics 1

Genetics of Cancer Cancer is due to a mutation of a gene within a specific cell in the body The damaged cell reproduces into multiple damaged cells which then accumulate into a tumor Therefore, all

2 Genetics of Cancer Cancer is due to a mutation of a gene within a specific cell in the body The damaged cell reproduces into multiple damaged cells which then accumulate into a tumor Therefore, all cancers are genetic but NOT all cancer is hereditary In every sense, then, CANCER IS A GENETIC DISEASE Cancer Etiologies Sporadic cancer (60%) By chance Environmental insults & aging damages the DNA within a given cell Familial cancer (30%) Multifactorial Several genes (not typically known) in combination with several environmental factors These multiple factors will tend to be shared by family members thereby moderately increasing risk Hereditary cancer (10%) Cancer that develops due to the person INHERITING a single gene that is mutated The mutated gene is in every cell of the body & dramatically increase the risk to develop cancer over the lifetime Genes have roles in certain parts of the body & therefore a mistake will increase the risk of not just any cancer but cancer in the corresponding area Because the predisposition is inherited, environment & age play less of a role & cancer typically develops earlier than usual 2

Genetics of Cancer Hereditary Breast Cancer Syndromes Hereditary Breast & Ovarian Cancer Syndrome (HBOC) Breast <50, ovarian, male breast, pancreatic, melanoma & prostate <50 Cowden Syndrome PTEN

3 Genetics of Cancer Hereditary Breast Cancer Syndromes Hereditary Breast & Ovarian Cancer Syndrome (HBOC) Breast <50, ovarian, male breast, pancreatic, melanoma & prostate <50 Cowden Syndrome PTEN gene Both malignant and benign tumors of the breasts, uterus, thyroid, and skin; benign macrocephaly Li Fraumeni p53 gene Young breast cancer (20s), childhood adrenocortical tumors, sarcomas, leukemia, etc 3

Family History of HBOC Hereditary Sporadic Ov, 52 Br, 63 Br, 71 Br, 42 Br, 45 Breast cancer before age 50 Ovarian cancer at any age Male Breast Caner Bilateral Breast Cancer Ashkenazi ancestry

4 Family History of HBOC Hereditary Sporadic Ov, 52 Br, 63 Br, 71 Br, 42 Br, 45 Breast cancer before age 50 Ovarian cancer at any age Male Breast Caner Bilateral Breast Cancer Ashkenazi ancestry None of the breast cancer is diagnosed before age 50 No ovarian cancer No clear pattern on one side of family or other New Engl J Med 2000;342: Hereditary Breast & Ovarian Cancer Syndrome 4

56%-87% Ovarian Cancer Lifetime Population

5 BRCA1/2 Mutations Increase the Risk of Early-Onset Breast Cancer By age 40 By age 50 Lifetime Population Risk 0.5% 2% 12% Hereditary Risk 10%-20% 33%-50% 56%-87% BRCA1/2 Mutations Increase the Risk of Ovarian Cancer Lifetime Population Risk 1.8% Hereditary Risk ~44% (BRCA1) 27% (BRCA2) 5

6 BRCA1/2 Mutations Increase the Risk of a Second Primary Breast Cancer First 5 yrs from dx Lifetime Population Risk 5% 11% 40%-62% Hereditary Risk 12%-20% Beyond Females, Breasts, & Ovaries Cancer Site General Pop BRCA Risk Risk Male Breast <1% 7% Prostate 15% 20% Melanoma 1% 2-4% Pancreatic 1% 2-4% 6

7 Inheritance of Hereditary Cancer Syndromes Father with a mutation on one chromosome Each child has a ½ or 50% chance of inheriting the same mutation Inheritance Who is at risk? But it s not just about the patient s children.. 7

8 NCCN Guidelines for Medical Management- Breast Cancer Screening Screening Age to Begin Frequency Goal Self Exams 18 Monthly Early detection Clinical exams 25 Annually Early detection Mammograms w/ MRI 25 Annually (6 mos apart) Early detection NCCN Guidelines for Medical Management- Ovarian Cancer Screening Screening Ages Frequency Goal Pelvic Exams 25 to 35 Annually Early detection Transvaginal ultrasound 25 to 35 Annually Early detection CA to 35 Annually Early detection 8

9 NCCN Guidelines for Medical Management- Breast & Ovarian Cancer Chemoprevention Cancer Chemoprevention Age to Begin Goal Breast Tamoxifen Variable Reduces risk by 50% Ovarian Oral contraceptives Variable Reduces risk by 60% NCCN Guidelines for Medical Management Breast & Ovarian Cancer Surgical Prevention Cancer Surgery Age to Begin Goal Breast Bilateral Mastectomy Variable Reduces risk by 90% Breast Ovarian Bilateral Salpino Oophorectomy Bilateral Salpino Oophorectomy Reduces risk by 50% Reduces risk by 96% 9

10 Referral for Genetic Counseling for Hereditary Breast Cancer Anyone with a personal and/or family history on EITHER side of the family of: Breast Cancer: Diagnosed < age 50 In 2 or more close relatives Bilateral breast cancer or multiple primary breast cancer diagnoses Male breast cancer Triple Negative Disease (ER -, PR -, Her-2 - ) Breast and Ovarian Cancer: Both cancers in the same woman One of each cancer diagnosed in two close relatives Ovarian Cancer: In 2 or more close relatives Anyone with Ashkenazi Jewish ancestry and a family history of ovarian cancer at any age and/or breast cancer diagnosed < 60 Anyone with a personal and/or family history suggestive of one of the more rare genetic syndromes associated with increased breast cancer risk Breast, thyroid, uterine Breast, sarcomas, brain tumors, and childhood tumors/leukemias Panels and where we are now Myriad s gene patenting technology: single gene and expensive Microarray technology allow multiple genes tested at once: less expensive Many companies; 83 different genes for cancer risk and cheaper coc 10

11 Multigene Testing in Cancer 11

12 History Patient had genetic counseling and based on the PennII model, the patient had a 59% chance to have a mutation in either BRCA1 or BRCA2 Patient elected for full sequencing and rearrangement studies of BRCA1 and BRCA2 which were negative, NO MUTATION DETECTED Based on a significant risk for a hereditary breast and ovarian cancer syndrome in this family, patient elected the OvaNext panel at Ambry Genetics OvaNext Panel OvaNext is a next generation sequencing panel that simultaneously analyzes 19 genes that contribute to increased risk for breast, ovarian, and/or uterine cancers Genes include: ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MRE11 A, MSH2,MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, STK11, and TP53 There is also a BreastNext panel which has all of the above minus the Lynch syndrome genes 12

Results The patient was found to have a germline deleterious mutation in the RAD51C gene RAD51C RAD51C along with BARD1, BRIP1, MRE11A, NBN, and RAD50 are genes involved in the Fanconi anemia (FA)

13 Results The patient was found to have a germline deleterious mutation in the RAD51C gene RAD51C RAD51C along with BARD1, BRIP1, MRE11A, NBN, and RAD50 are genes involved in the Fanconi anemia (FA) BRCA pathway, which is critical for DNA repair by homologous recombination and interact in vivo with BRCA1 and/or BRCA2 Mutations in RAD51C is expected to increase the risk of breast cancer 3 fold with a lifetime risk of breast cancer of ~36% and a 5.88 RR with an up to an 11% risk of ovarian cancer Breast & Ovarian Cancer Risks for the General Population vs. RAD51C vs. BRCA1/BRCA2 13

Hereditary Colorectal Cancer Syndromes Polyposis Familial Adenomatous Polyposis (FAP) Turcot & Gardner syndrome Attenuated Familial Adenomatous Polyposis (AFAP) Peutz Jeghers Syndrome: Colon, breast,

primarily on clinical findings Familial Adenomatous Polyposis (FAP) 100-1000s of colon polyps Autosomal dominant caused by mutations in the APC gene -20-30% of cases are de novo, proband will be 1st

14 Hereditary Colorectal Cancer Syndromes Polyposis Familial Adenomatous Polyposis (FAP) Turcot & Gardner syndrome Attenuated Familial Adenomatous Polyposis (AFAP) Peutz Jeghers Syndrome: Colon, breast, ovarian, pancreatic, sex cord tumors, gastric, mucocutaneous pigmentation MYH Associated Polyposis (MAP) AR polyposis (~55 polyps); increased risk of colon ca; age of onset Diagnosis relies primarily on clinical findings Familial Adenomatous Polyposis (FAP) s of colon polyps Autosomal dominant caused by mutations in the APC gene % of cases are de novo, proband will be 1st affected individual in family Risk of developing: -Adenomas ~100%: avg age of onset 16 yr -Colon cancer ~100%: avg age of dx. 39 yrs Risks for extracolonic tumors: upper GI, desmoid, osteoma, thyroid, brain, hepatoblastoma, etc CHRPE (congenital hypertrophy of the retinal pigment epithelium) 14

15 Variants of FAP Turcot syndrome: polyposis & CNS tumors (medulloblastoma) Gardner syndrome: polyposis, osteomas, & soft tissue tumors Attenuated Familial Adenomatous Polyposis (AFAP): -Have between colonic polyps (~10+) -More proximally located polyps -Colorectal cancer risks ~80-100% -Diagnosis of colon cancer at a later age than FAP (50-55y) -Autosomal dominant (APC gene) but 20-30% of cases will be 1 st affected in individual in family Screening for APC Mutation Carriers Sigmoidoscopy at 10-12y Annually Colonoscopy once polyps are detected Annually until polyp burden requires colectomy Upper endoscopy or esophagogastroduodenoscopy (EGD) at detection or at age 25 Every 1-3 years Post colectomy endoscopy of remaining rectum or pouch 6mo to 3y depending on # of polyps on previous exam Physical exam and consideration of ultrasound for thyroid risk at 10-12y Annually 15

16 Management for APC Carriers Polypectomy as needed Preventive removal of the colon and rectum Timing based on number/size of polyps Chemoprevention To reduce # of polyps in any remaining rectum Nonsteroidal anti-inflammatory drugs (NSAIDs) = regression of adenomas & decreased # of polyps requiring ablation in remaining rectum Molecular Genetic Testing for Polyposis While polyposis syndromes can be diagnosed clinically, genetic testing to find the disease causing mutation is very important as it allows diagnosis for at risk, currently unaffected, family members Determines who does and who does not need screening Save children from undergoing colonoscopy and other inconvenient tests Reduces costs Confirm diagnosis of FAP or AFAP in people w/ equivocal findings (e.g., <100 adenomatous polyps) 16

17 Who Should Be Referred for Counseling and/or Testing? Anyone with: ->10-20 adenomas -At-risk based on family history Start testing with affected relative if possible Can test minors because cancer screening starts in childhood Hereditary Non-Polyposis Colorectal Cancer (HNPCC) aka Lynch Syndrome Clinical picture is autosomal dominant family history of colon cancer and/or other HNPCC tumors Risks are also increased for: endometrial, ovary, pancreas, stomach, ureter & renal pelvis, small bowel, biliary tract, sebaceous skin tumors, & brain cancers Younger age at onset (recent data shows avg age at dx changed from 45 to 61 new, less penetrant, genes have been discovered) 90% of colon cancers are rightsided NOT predominated by polyps aka nonpolyposis 17

Etiology of Lynch Syndrome Lynch syndrome is caused by mutations in 1 of 4 different mismatch repair genes: MLH1, MSH2, MSH6, & PMS2 During normal cell division, DNA mutations may occur causing

18 Etiology of Lynch Syndrome Lynch syndrome is caused by mutations in 1 of 4 different mismatch repair genes: MLH1, MSH2, MSH6, & PMS2 During normal cell division, DNA mutations may occur causing mismatches in the code These errors are corrected by the mismatch repair genes If a mismatch repair gene is dysfunctional, mutations will accumulate and cancer develops These mismatches can be seen in the microsatellite region of DNA Therefore, >90% of Lynch syndrome tumors are microsatellite instable (MSI-H) whereas only 15% of sporadic tumors are Hallmark pathological feature of Lynch syndrome Cancer Cancer Risks General Population Risk HNPCC Risks Mean Age of Onset Colon 5.5% 80% 44 years (Now 61!) Endometrium 2.7% 20%-60% 46 years Stomach <1% 11%-19% 56 years Ovary 1.6% 9%-12% 42.5 years Hepatobiliary tract <1% 2%-7% Not reported Urinary tract <1% 4%-5% ~55 years Small bowel <1% 1%-4% 49 years Brain/central nervous system <1% 1%-3% ~50 years 18

19 Lynch Syndrome Increases Risk of a Second Cancer Up to 50% Risk of Cancer (%) Up to 30% 3.5% 5% Cancer 1977;40:1849 Dis Colon Rectum 1986;29:160 Cancer 1993;36: Lynch Syndrome Management Colorectal Cancer Surveillance Procedure Age to Begin Interval Colonoscopy years 40 Annually Colonoscopy NOT Sigmoidoscopy: Adenomas/cancers are typically right-sided Reduces CRC risk by over 50% and overall mortality by 65% Results in prevention or early diagnosis Gastroenterology 1993;104: Gastroenterology 2000;118: Dis Colon Rectum 2002;45:

20 Lynch Syndrome Management Patients With Colorectal Cancer Frequency of colonoscopy after surgery Indication Yr 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr 6 Yr 7 Yr 8 Yr 9 Subsequent Sporadic CRC Every 5 years Lynch (over 40) Annual Surgical Considerations Colorectal cancer (or more than one advanced adenoma) Colectomy with ileorectal anastomosis OR Hemicolectomy with annual colonoscopy Diseases of the Colon & Rectum 2003;46: CA Cancer J Clin May-Jun;56(3):160-7 Lynch Syndrome Management Gynecologic Cancer Surgical Considerations Hysterectomy/salpingo-oophorectomy Option after childbearing is complete Option for Lynch syndrome patients at time of any intra-abdominal surgery Surveillance Procedure Age to Begin Interval Endometrial aspiration Transvaginal ultrasound CA years JAMA Sep 27;296(12): J Clin Oncol Oct 1;24(28): N Engl J Med Jan 19;354(3):

21 Inheritance of Hereditary Cancer Syndromes Father with a mutation on one chromosome Each child has a ½ or 50% chance of inheriting the same mutation Who Should be Screened for Lynch Syndrome? Best Approach Under Current Debate 1. Amsterdam II Criteria rule: 3 individuals affected, 2 of which are first degree relatives of each other, and 1 of which is <50 FAILS TO DETECT 50% OF LYNCH PATIENTS 2. Revised Bethesda Criteria Colorectal cancer diagnosed in an individual <50 years Presence of synchronous or metachronous colorectal or other HNPCC-associated tumors regardless of age Colorectal cancer with the MSI-H histology diagnosed in an individual <60 Colorectal cancer in 1 or more 1 st degree relatives with an HNPCC-related tumor, with 1 dx <50 Colorectal cancer diagnosed in 2 or more 1 st or 2 nd degree relatives of any age FAILS TO DETECT 30% OF LYNCH PATIENTS DIFFICULT TO REMEMBER/IMPLEMENT 3. Screen all individuals with colon cancer <50 FAILS TO DETECT 50% OF LYNCH PATIENTS 4. Screen all newly diagnosed colorectal cases Detects % of Lynch patients Has been supported by EGAPP and proven to be cost effective 21

22 Other Cancers? Inherited predisposition NOT only breast, ovary, polyposis and Lynch syndrome ACMG meeting 3/2014 (Nashville) B cell neoplasia (ALL) Families with inherited (AD) predisposition for ALL All with germline mutations in PAX5 PAX5 is a B cell lineage activator All with same mutation! Multigene Testing in Cancers Gene Expression Profiling of tumors Many multiarray technologies are in early stages of clinical evaluation Few have made way into market Finding meaningful predictive and therapeutic differences in a sea of data remain elusive Firehose effect Are increasingly used in oncologic testing and therapies GEP science is poorly understood by clinicians If all cancers are clonal and unique, how useful? PATTERNS OF EXPRESSION!! 22

23 Multigene Testing in Cancers Gene Expression Profiling Why does it matter? ~ 1 in 7 (15%) of stage 1 breast CA recurs In those that recur, chemo will benefit a minority Chemo regimens expensive ($15-30k); morbidity Gene signature tests Used in identifying those for whom chemo would likely benefit (otherwise poorer prognosis) Underwriters OK since cost less than chemo Multigene Testing in Cancer 23

24 Cancer of Unknown Primary 47 RG , Rev1, 2/ Rosetta Genomics Proprietary Case Report: 67 yo Female Presented with Brain Metastases Unknown Primary Clinician: Non-Hodgkin Lymphoma Pathologist: Carcinoid? Histology and IHC: excluded lymphoma & melanoma Cytokeratins and Synaptophysin weakly + Cancer Origin Test: Sarcoma IHC markers for mesenchymal antigens were positive Findings now consistent with Sarcoma Meiri, E, Mueller, WC, Rosenwald, S, et al. A Second-Generation MicroRNA-Based Assay for Diagnosing Tumor Tissue Origin. Oncologist, 2012; 17(6): RG , Rev1, 2/ Rosetta Genomics Proprietary 24

control of gene expression at level of translation DNA Transcription

development Transcribed from Junk DNA Translation mrna Fully processed

25 Introduction to micrornas 49 RG , Rev1, 2/ Rosetta Genomics Proprietary MicroRNAs: Master control of gene expression at level of translation DNA Transcription micrornas Master Regulators at level of translation of differentiation and development Transcribed from Junk DNA Translation mrna Fully processed micrornas are ~22nt long single stranded RNAs Protein 50 RG , Rev1, 2/ Rosetta Genomics Proprietary 50 25

tumor suppressors o Target steps in oncogenesis: Proliferation signals Metastasis and tissue invasion Sustained angiogenesis Apoptosis

26 mirnas Play a Central Role in Cancer o Thousands of peer-reviewed papers discussing the central role of mirnas in cancer o mirnas have been shown to be aberrantly expressed in all cancers o Map to regions of known genomic instability in cancers o Some are oncogenes and tumor suppressors o Target steps in oncogenesis: Proliferation signals Metastasis and tissue invasion Sustained angiogenesis Apoptosis inhibition Iorio and Croce, EMBO Molecular Medicine RG , Rev1, 2/ Rosetta Genomics Proprietary Cancer therapy is changing 26

27 Targeted therapy is here (to stay?) 19% PI3K/MAPK inhibitors 14% RTK inhibitors 26% monoclonal or ADCs Only 2% cytotoxic alone Many genomic targets are low-prevalence (<5%) in disease(s) of interest Created by David Hyman, MD, MSKCC 27

28 Is this where we re going? YES!!! Genomic landscape (from TCGA or other sources) will form backbone for drug development and clinical trial design Expected alterations do not result in response to targeted agents with defined mechanisms of action Selection vs. stratification Properly designed clinical trials and laboratory testing will allow us to learn about mechanisms of response and resistance Molecular testing is an important standard of care today and will become increasing important for cancer care of tomorrow Cancer Genomics Determining Genetically Compatible Therapies to Guide Patient Treatment September in Boston, MA 250+ attendees: oncologists, surgeons, geneticists, hospital and health plan administrators, underwriters, basic researchers, information tech specialists, academic, corporate and private practice 4 invited poster presentations (including ours) Technologies: couple genomics with risk assessment, diagnosis, treatment/therapies and surveillance 28

Cancer Genomics Cancer Genomics Christine Micheel, Vanderbilt-Ingram Center Establish reflex testing of common clinically relevant genetic alterations in melanomas and lung carciomas Develop

29 Cancer Genomics Cancer Genomics Christine Micheel, Vanderbilt-Ingram Center Establish reflex testing of common clinically relevant genetic alterations in melanomas and lung carciomas Develop bioinformatic algorithms to report result in EMR in a way useful to oncologists Collaboration between medicine, pathology, genetics, and informatics Goal: approach cancer diagnostics, therapies and surveillance examining common genetic features MyCancerGenome.org: 19 cancers; 35 genes; 321 disease-gene relationships WITH TARGETED THERAPEUTICS!!! 29

30 Cancer Genomics Early results (Vanderbilt) Melanoma Panel 925 patients 65% with actionable mutations NRAS (18%), KIT (2.3%), GNAQ (2.9%), GNA (1.4%), CTNNB1 (1.1%), BRAF (39.1%) No mutation detected: 35.2% Lung Panel 997 patients 44% with actionable mutations AKT1 (0.3%), BRAF (2.1%), EGFR (14.7%), ERBB2 (0.9%), KRAS (22.3%), MEK1 (0.8%), NRAS (0.6%), PIK3CA (2.1%) PTEN (0.2%) No mutation detected: 55.9% mycancergenome.org 30

Cancer Genetic Counseling Take Home Messages Hereditary Cancer isn t as rare as you may think For every 10 patients you see with cancer (especially breast, ovarian, colon, uterine, thyroid, etc): 1

31 Cancer Genetic Counseling Take Home Messages Hereditary Cancer isn t as rare as you may think For every 10 patients you see with cancer (especially breast, ovarian, colon, uterine, thyroid, etc): 1 will have a hereditary cancer syndrome This individual is at a dramatically increased risk to develop ANOTHER primary cancer in their lifetime» HBOC: 40-60% for a 2 nd Breast, 20% for ovarian» HNPCC/Lynch: 50% for a 2 nd Colon or other HNPCC cancer Most are autosomal dominant in inheritance» NOT just about whether they have children or not» Their parents, siblings, aunt/uncles, nieces/nephews, cousins, grandparents, great aunts/uncles ARE ALL AT RISK 3 others will have some amount of increased risk due to their family history (familial cancer) And ALL cancers have unique changes in DNA which will (soon) allow specific, focused therapeutics 31

GEN ETICS AN D GEN OM ICS IN CANCER PREVENTION AN D TREATM EN T. Robert Nathan Slotnick MD PhD Director, Medical Genetics and Genomics

GEN ETICS AN D GEN OM ICS IN CANCER PREVENTION AN D TREATM EN T Robert Nathan Slotnick MD PhD Director, Medical Genetics and Genomics The Medical/Surgical/Radiation Oncologist s View of Genetics Cancer