Genetic Panel Testing and Implications for Cancer Care

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1 Genetic Panel Testing and Implications for Cancer Care Dana Zakalik, M.D. Nancy and James Grosfeld Cancer Genetics Center Professor, OUWB Medical School MCC Board of Directors Meeting September 28, 2016

2 Precision Medicine Initiative

3 Outline Gene Panel Testing: Overview Clinical Applications of Gene Panel Testing Hereditary (Germline) Testing Cancer prevention Early detection Therapeutics Tumor (Somatic) Testing Prognostic/predictive implications Therapeutic implications Future directions

Implications of Genetics on Cancer Molecular Diagnostics Tumor Classification Prognostic/Predictive Information Targeted Therapies Pharmacogenomics

4 Implications of Genetics on Cancer Molecular Diagnostics Tumor Classification Prognostic/Predictive Information Targeted Therapies Pharmacogenomics Molecular Monitoring Hereditary Cancer Syndromes Risk Assessment High Risk Surveillance Early Detection Better Outcomes & Improved Survival Cancer Prevention

5 A New Era in Cancer Genetics 1990 s: discovery of rare, highly penetrant cancer predisposition genes BRCA1 and 2, p53, APC 100+ known cancer susceptibility syndromes Significant recent changes Next-generation sequencing (NGS) technology Multiplex gene-panel testing

6 Definition of Terms Next-generation sequencing (NGS) Massively parallel sequencing High throughput parallel sequencing of thousands to millions of fragments of DNA Multiplex gene-panel testing Targeted analysis of multiple genes of interest simultaneously using NGS Variant of unknown significance (VUS) Genetic sequence change whose association with disease is currently unknown

8 Gene Panel Testing Allows for efficient analysis of multiple genes Next generation sequencing (NGS) technology Rapid, simultaneous gene analysis Efficiency, decreasing cost Caveat: Variants of uncertain significance (VUS) Potential for misinterpretation May lead to confusion re: management of risk? Clinical utility? which genes are actionable? Potential for uncertainty re: optimal management Lack of evidence-based guidelines for many genes Genetic evaluation/counseling important

9 Gene Panel Testing Multiple labs offering a variety of different combinations of genes including: RAD 51D, RAD 51C, BRIP1, NBN, BARD1, CHEK2, PTEN, CDH1.. Paucity of management guidelines Increasingly utilized in clinical setting Germ line (hereditary) testing Somatic (tumor) testing 4-16% prevalence of non-brca1/2 mutations reported 11% in Beaumont series Potential for clinical benefit (?) Uncertainty regarding gene panel selection, interpretation of results High VUS rate Discordant interpretation of variants Need further research, sharing of data ( e.g. PROMPT )

Prospective Registry of Multiplex Panel Testing Data collection research project open to any patient undergoing panel testing Goal to collect large numbers of mutation carriers, learn

10 Prospective Registry of Multiplex Panel Testing Data collection research project open to any patient undergoing panel testing Goal to collect large numbers of mutation carriers, learn about cancer risks, outcomes, and facilitate classification of uncertain variants Registry of results from large numbers of patients Biologic sample collection for translational research

11 Gene Panel Testing Analytic validity Accuracy and reproducibility of test Clinical validity Ability of test to predict disease Clinical utility Improved health outcomes Early detection, prevention, higher responses Usefulness/added value to patient management

12 Genetic Testing Red Flags (hereditary) Early onset breast cancer (or multiple cases) Ovarian cancer All cases Breast and ovarian cancer in the same woman Bilateral breast cancer Ashkenazi Jewish ancestry Male breast cancer Pancreatic cancer Triple negative breast cancer

13 Case Example BRCA1 +

14 Hereditary Breast Cancer Genes (pre-panel era or good old days ) Breast Cancer Gene 1 BRCA1 (1994) Chromosome 17 Breast Cancer Gene 2 BRCA2 (1995) Chromosome 13 Tumor Suppressor Genes DNA repair Important in repair of double-strand DNA breaks maintains normal DNA in all individuals Alteration (mutation) high risk of breast cancer Cause inherited breast and ovarian cancer Seen more often in Ashkenazi Jews (1 in 40)

15 BRCA1/2 Mutations: Lifetime Cancer Risks BRCA 1 BRCA2 Breast cancer to age % 35-60% Ovarian cancer to age % Up to 25% Male breast cancer 1-2% 7-8% Prostate cancer 9% 33% Pancreatic cancer 2-4% 3-6% Melanoma No incr. Slight incr.

16 Management Of BRCA Carriers High Risk Surveillance Breast MRI and mammography Other: Ovary, prostate, pancreas Chemoprevention Tamoxifen 50% reduction of breast cancer risk Novel agents (research) Prophylactic Surgery Bilateral Mastectomy 90-95% reduction of risk Risk-reducing salpingo-oophorectomy 90% reduction

17 Surveillance for Breast Cancer Procedure Breast self-exam Age to begin 18 yrs Frequency Monthly Clinical breast exam Mammography 25 yrs 30 yrs 6-12 months Yearly Breast MRI 25 yrs Yearly

18 Screening for Other Cancers Prostate (starting at age 40): BRCA1 Consider prostate screening BRCA2 Recommend prostate screening Male breast: Breast Self Exam training and education at age 35 Clinical Breast Exam every 12 mos starting at age 35 Pancreas no proven benefit Consider EUS/MRI in high risk families Screening registry enrollment Research trials e.g. CAPS-5

22 The Other Ovarian Cancer Genes

24 Beyond BRCA: Other Hereditary Breast Cancer Syndromes Gene PTEN Syndrome Cowden Syndrome P53 Li Fraumeni Syndrome (LFS) PALB2 CDH1 STK11 PALB2 Hereditary Diffuse Gastric Cancer (HDGC) Peutz Jeghers Syndrome (PJS)

25 Beyond BRCA: Other Hereditary Breast Cancer Syndromes Syndrome Cowden Syndrome (PTEN) Li Fraumeni Syndrome (LFS p53) PALB2 Hereditary Diffuse Gastric Cancer (HDGC CDH1) Peutz Jeghers Syndrome (PJS) (STK11) Key Features Breast, Uterine, Thyroid Cancers; Large head size; Skin findings Breast, Brain, and Lung Cancers, Sarcomas, Adrenocortical Carcinoma; very early age at diagnosis Breast and Pancreatic Cancers (? Ovary) Breast and Stomach Cancers Breast, Colon, Pancreatic and Stomach Cancers; Freckling of lips in childhood

27 PALB2 and Cancer Risk Breast Cancer Risk (association with triple negative breast cancer) 14% by age 50 35% by age 70 Impact of family history 33%-58% Pancreas Cancer Risk Identified in 3-4% of familial pancreatic cancer cases Ovarian Cancer Risk conflicting results Other cancers (? Male breast, prostate, ovarian?)

30 Cowden s Syndrome PTEN hamartoma syndrome Breast (30-60% lifetime risk), thyroid cancer (3-10%), endometrial cancer (19-28%) Skin manifestations: papillomatous papules Trichilemmomas Acral keratoses Macrocephaly Thyroid nodules, goiter Uterine fibroids Developmental delay

31 Dutch German/English d.70s Prostate ca dx 50s Heart attack d. 77 Breast ca 50-60s Heart attack d. 60s Lung ca? Bladder ca Smoker 86 Thyroidectomy Goiter Breast mass removed Moles, benign tumors on back, foot, arm and breast Breast Melanoma Benign brain tumor Colon Benign breast masses Thyroid ca Goiter s Breast dx 35 Papillary thyroid ca dx 31 HC 58cm 55 Skin BCC Benign tumor-brain Breast fibroadenoma x 2 Kidney-nephrectomy (2000)-benign Multiple moles TAH 40s 60s 60s 3 ADD Learning disabilities Pap thyroid ca dx 55 Multiple lipomas facial fibromas Possible renal ca Melanoma dx 38 Pap thyroid ca dx 40 Melanoma dx Two moles removed from the back and head grew back

34 Multigene Panel Testing (Kapoor et al AnnSurgOncol 2015) 966 patients 629 limited testing (BRCA1/2) 337 panel testing (5-43 genes, 15 avg) Deleterious BRCA 1/2 mutations found in 4.0% (limited) and 3.6% (panel) Multigene panel testing identified additional 3.9% (up to 11%) non-brca mutations Most common non-brca: PALB2, CHEK2, ATM

43 Management of New or Moderate Risk Genes Paucity of evidence-based guidelines Risk not fully defined - evolving Actionability? and lack of consensus High rate of variants of unknown significance Improving with added experience Implication for family members who test negative? May still be high risk

45 Actionability of Panel Testing (JAMA Oncol 2015) 1046 pts seen for genetic testing (BRCA neg) Stanford, MGH, BIDMC Multigene panel testing (25-29 genes) 40 pts (3.8%) harbored deleterious mutations Most commonly: CHEK2, ATM, PALB2 Additional screening/prevention offered Management change considered in 33 of 40 pts Guidelines for management??

51 Distribution of Presumed Pathogenic Germline Mutations. Pritchard CC et al. N Engl J Med 2016;375:

53 1120 pediatric cancer patients (< 20y) Multigene panel testing 8.5% yield of pathogenic or likely pathogenic mutations germline mutations Family history not predictive Only 40% had a family history of cancer May aid in surveillance and prevention of second cancer

57 Case Example BRCA1+

58 Case Example: Impact of Genetics Role of genetic testing in personalized care: Surgical management Novel targeted systemic therapy Cancer screening Cancer prevention Family members decisions

59 Targeted Treatment - Defined Molecular therapies that specifically target pathways Require knowledge of underlying cancer-associated abnormality Directed specifically against cancer cells Spare healthy cells Fewer adverse side-effects smart drugs, personalized medicine

60 Targeted Treatment - examples Her2 directed therapy (Herceptin) Vascular Endothelial Growth Factor Receptor Inhibitors Epidermal Growth Factor Receptor Inhibitor PARP Inhibitors

61 Genetics and Personalized Care PARP inhibitors: target the defect in DNA repair in BRCA mutation carriers Poly ADP ribose polymerase (PARP) Important role in DNA repair Olaparib, Veliparib etc inhibit PARP enzyme Block alternate DNA repair pathway Promising results in BRCA + Expand to other genes (PALB2, CHEK2, ATM) Molecularly targeted treatments for cancer Clinical trials open in breast, ovarian, pancreas, other Personalized Medicine

62 Homologous recombination defects

63 Targeting DNA Repair

64 Figure 3: Massive Genome Instability Induced by PARPi in BRCA2 Mutant Cells

65 NSABP B-55 Clinical Trial First molecularly targeted trial for BRCA mutation carriers with early stage breast cancer Inclusion Criteria: Triple Negative Breast Cancer (> 2cm or lymph node + ) ER +, high risk BRCA1 /2 mutation carriers Chemotherapy given to each patient per std of care Anthracycline, taxane or both Olaparib 300mg p.o. twice a day for 12 mos Personalized medicine prototype

66 Lynparza (Olaparib)- FDA approval Oral PARP inhibitor FDA approved 12/2014 for advanced ov ca in BRCA + 4 th line treatment Single open label trial of 137 patients Overall response rate 34% - 60% Median duration of response 7.9 months Side effects fatigue, nausea, vomiting, headache Further studies in progress Companion diagnostic test approved Personalized medicine

68 BRCA

71 Multigene Panel Testing Germline Hereditary Somatic (Tumor) Acquired

72 Tumor (Somatic) Gene Panel Testing Progress in understanding genetic basis of cancer Boveri linked somatic genetic changes to origin of cancer 1960 Discovery of Ph chromosome in CML Advent of high-throughput gene sequencing methods Discovery of hundreds of recurrent somatic alterations in various malignancies Dramatic impact on diagnostic and therapeutic approaches to cancer Personalized (targeted) molecular therapies

73 Tumor (Somatic) Testing Classification of variants Actionability Variants of uncertain significance Conflicting interpretations Decision support (molecular tumor board) Incidental findings Germline implications/genetic counseling Research Clinical trial identification

76 JNCCN Journal of the National Comprehensive Cancer Network Volume 14 Number 9 September 2016

80 JNCCN Journal of the National Comprehensive Cancer Network Volume 14 Number 6 June 2016

81 Karki et al. BMC Medical Genomics (2015) 8:37

86 = p.lys1881glnfster27 a.k.a. K1881fs*27

99 NCI MATCH NCI MATCH TRIAL PRECISION MEDICINE TRIAL Molecular Analysis for Therapy Choice Opened Aug 2015 Reached 500 pts 10/15 Pause for analysis 11/15 Reopened 5/ Sites

100 NCI MATCH Trial Molecular analysis of tumors to identify a genetic alteration which may serve as a target Tumor biopsy specimens sent for sequencing Targeted drugs selected to match the genetic defect (initial match: 9% ; goal: over 20%) Plan to analyze over 24 agents Molecular targets include ALK, BRAF, EGFR, ckit, ROS1

101 NCI MATCH Trial Targeted Agents

102 First-ever ASCO clinical trial Patients with advanced cancer Genomic profile/tumor sequencing Molecular Tumor Board support Actionable genomic variant(s) Molecularly targeted anticancer agents Provided free of charge Safety and efficacy end points

103 Non randomized trial 37 sites 49 participants 18 on treatment, 31 in screening Evaluating use of targeted agents in different tumor types Off label use of FDA approved agents

104 Human genome sequenced 2001 Knowledge of genetics increasingly important Need to educate physicians Shortage of genetic counselors How can increasingly complex genetic knowledge be made readily accessible to all? Need to anticipate and plan for consequences of profound change in medicine

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109 Multigene Panel Testing ASCO 2015 Multigene (panel) testing is rapidly expanding Clinical utility of testing for moderate risk genes is not fully established Genetic counseling is important ASCO encourages research to delineate optimal use of panel testing and development of evidence-based practice guidelines, and education of providers

110 ASCO Recommendations 2015 Germ-line implications of somatic profiling Multigene panel testing for hereditary cancer Collaboration and sharing of databases Quality assurance in genetic testing Education of Oncology professionals Access to cancer genetic services

111 ASCO Leadership Statement Robust discussions among a diverse set of stakeholders will be needed to ensure that all perspectives are listened to and that genetic cancer susceptibility services are comprehensive and patient-centric. Julie M. Vose, MD, MBA Peter Yu, MD Daniel F. Hayes, MD

112 Precision Medicine Initiative

113 Summary NGS technology allows for efficient and thorough analysis of molecular basis of cancer Understanding of the genetic basis and molecular biology of cancer has dramatically improved Gene panel testing is an integral part of both hereditary risk assessment and novel cancer treatment approaches

114 Conclusions An individualized approach to cancer is at the core of current innovation in Oncology Understanding of oncogenic mechanisms will guide risk assessment, screening, prevention, and therapy of cancer Further research is needed to identify the best targets for novel personalized therapies Partnership among clinicians, researchers, laboratories is needed to assure success

115 Thank you

Multigene Panel Testing for Hereditary Cancer Risk

Multigene Panel Testing for Hereditary Cancer Risk Dana Zakalik, M.D. Director, Nancy and James Grosfeld Cancer Genetics Center Professor, OUWB Medical School MCC Annual Meeting November 4, 2015 Outline