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Genomics in Cancer Care
- 1. City of HopeComprehensive Cancer Center and Beckman Research Institute Jeffrey N. Weitzel, M.D. Professor of Oncology and Population Sciences Director, Department of Clinical Cancer Genetics Genomics in Cancer Care: New Approaches to Genetic Cancer Risk Assessment and Precision Therapy Cancer Screening & Prevention Program FLASCO 110516
- 2. AdvancingAdvancing AgeAge GeneticsGenetics AlcoholAlcohol Lack ofLackof ExerciseExercise HormoneHormone ReplacementReplacement TherapyTherapy OverweightOverweight GenderGender ?????? PassivePassive SmokeSmoke LateLate MenopauseMenopause CloseClose RelativeRelative Age atAge at First BirthFirst Birth BenignBenign Breast DiseaseBreast Disease EarlyEarly MenarcheMenarche Risks Related to Cancer IonizingIonizing RadiationRadiation ChemicalsChemicals -Work-Work -Home-Home -Garden-Garden -Recreation-Recreation DietDiet EducationEducation & Income& Income GeneticsGenetics
- 3. Kesselheim A andMello M. N Engl J Med 2010;10.1056/NEJMp1004026 Timeline of Important Events in DNA Patenting (Top) and the Discovery and Use of Genes Conferring Susceptibility to Breast and Ovarian Cancer (Bottom) June 2013 - U.S. Supreme Court rules that as nature, genes cannot be patented
- 4. BRCA1- and BRCA2-AssociatedCancers: Lifetime Risk Breast cancer 50%-85% (often early age at onset) Second primary breast cancer 40%-60% Ovarian cancer 15%-45% Absolute risk likely to be higher than 10% - Prostate cancer Absolute risk 10% or lower - Male breast cancer - Fallopian tube cancer - Pancreatic cancer
- 5. Absolute risks forBRCA1 mutation carriers based on combined SNP profile distributions Couch et al. PLOS Genetics 9(3) e1003212, March 2013
- 6. 77-SNP polygenic riskscore (PRS) can stratify groups for absolute risk assessment with age Mavaddat E et al, JNCI 2015 Lifetime risk of breast cancer by percentiles of 77-SNP PRS Lifetimeabsoluterisk Age (years) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Age (years) All Breast Cancers >99% 95-99% 90-95% 80-90% 60-80% 40-60% 20-40% 10-20% 5-10% 1-5% <1%
- 7. Clinical Management ofMutation- Positive Patient Positive high pentrance gene test result Possible testing for other adult relatives Increased surveillance Prophylactic surgery Targeted Therapy Chemo- prevention
- 8. “Angelina Jolie’s double mastectomy putsgenetic testing in the spotlight” Study of 483 BRCA carriers: >90% risk reduction Rebbeck, T.R., et al. JCO 22:1055, 2004 An effective intervention:
- 9. Cumulative incidence ofearly-stage (stages 0 to I) breast cancer in magnetic resonance imaging (MRI) –screened cohort and comparison group (competing risk model). Warner E et al. JCO 2011;29:1664-1669 Diagnosis stage 0-I
- 10. Oophorectomy Reduces Ovarian Cancer,Breast Cancer, and all cause mortality Greatest breast cancer risk reduction among BRCA1 mutation carriers without a prior dx of breast cancer who had their oophorectomy < age 50 HR: 0.15 (95% CI 0.04-0.63) 1,9151,915
- 11. Fanconi pathway andcontribution of genomic stability genes to hereditary breast and ovarian cancer
- 12. Synthetic Lethality, BRCAStatus and PARP Inhibition McLornan DP et al. N Engl J Med 2014;371:1725-1735.McLornan DP et al. N Engl J Med 2014;371:1725-1735.
- 13. MacConaill L EJCO 2013;31:1815-1824 Advances in massively parallel technologies have dramatically reduced the cost of sequencing
- 14. How Much Breastand Ovarian Cancer Is Hereditary? It is a different answer with multiplex testing Sporadic Family clusters Hereditary Ovarian CancerBreast Cancer ~5% 15-24% 15% -20%
- 15. Proportions ovarian, fallopiantube, or peritoneal cancer patients with respective germ- line loss-of-function mutations Walsh T et al. PNAS 2011;108:18032-18037
- 16. Cancer panel genes,stratified by relative riskCancer panel genes, stratified by relative risk Cancer Site High Relative Risk (≥5.0) Moderate (≥1.5 and <5.0) Low Relative Risk (≥1.01 and <1.5) Breast TP53, PTEN, STK11, CDH1, BRCA1, BRCA2 CHEK2, ATM, PALB2, BRIP1 AXIN2, BAP1, BARD1, MRE11A, NBN, RAD50, RAD51C, XRCC2, RAD51D Colon rectum APC, MLH1, MSH2, MSH6, PMS2 CHEK2 AXIN2, BMPR1A, CDH1, DCC, EPCAM, EXO1, MUTYH, PDGFRA, PMS1, PTEN, SMAD4, STK11, TP53 Ovary RAD51D, RAD51C, BRCA1, BRCA2 MLH1, MSH2, MSH6, PALB2 BRIP1 ATM, AXIN2, BARD1, BRIP1, EPCAM, MRE11A, MUTYH, NBN, PALB2, PMS2, RAD50, , STK11, TP53 Weitzel et al. Genetics, Genomics, and Cancer Risk Assessment: State of the Art and Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 2011;61:327–359
- 17. Genetic Heterogeneity andOverlapping Phenotypes = Expanded Differential Diagnoses PancreaticPancreatic BreastBreast MelanomaMelanoma ColonColon CDKN2A BRCA2 PALB2 PRSS1 ATM CHEK2 MMR OvarianOvarian UterineUterine BreastBreast BRCA1 BRCA2 PALB2 RAD50 RAD51D BRIP1 MRE11A BARD1 RAD51C PTEN TP53 STK11 ATM CHEK2 CDH1MMR
- 18. Results of a combinedanalysis of 154 families: •good estimate of BC risk (greater with + family Hx) •Inadequate data to determine magnitude of increased OC risk
- 19. Potential Implications ofMultigene PanelPotential Implications of Multigene Panel Testing for Cancer PatientsTesting for Cancer Patients Explanation for the cancer diagnosisExplanation for the cancer diagnosis Explanation for the cancer family historyExplanation for the cancer family history Assessment of risk of additional cancersAssessment of risk of additional cancers Implications for surveillance, risk reductionImplications for surveillance, risk reduction Implications for treatment?Implications for treatment? Surgical optionsSurgical options Systemic therapy optionsSystemic therapy options Novel Therapeutic OptionsNovel Therapeutic Options
- 20. Suggested Guidance, pendingreal data b Intervention may still be warranted based on family history or other clinical factors. c Insufficient evidence for any recommendations for breast MRI, RRSO, or RRM include but are not limited to: BARD1, FANCC, MRE11A, MUTYH, NF1, NBN, RAD50, SMARCA, or XRCC2. NCCN Guidelines Version 2.2016 Genetic/Familial High-Risk Assessment: Breast and Ovarian
- 21. Negative predictive valueof “informative” testing Lee et al. Genet Med April 14, 2016; doi:10.1038/gim.2016.31
- 22. Genetic Cancer Risk Assessment PreventionTreatment Oncologic Consultation Decisions,decisions… Somatic/Tumor Genomics – Precision Rx and Germline implications
- 23. CA: A CancerJournal for Clinicians Volume 66, Issue 1, pages 75-88, 3 NOV 2015 DOI: 10.3322/caac.21329 http://onlinelibrary.wiley.com/doi/10.3322/caac.21329/full#caac21329-fig-0003 Translating cancer genomes and transcriptomes for precision oncology
- 25. Homologous recombination (HR)gene mutations in ovarian cancers and association with platinum sensitivity Pennington K P et al. Clin Cancer Res 2014;20:764-775
- 26. • Overall responserate of 33% (16/49) • Next-generation sequencing identified loss of function mutations in DNA-repair genes (n=16); BRCA2 (n=4) • The response rate was 88% (14/16) among patients with tumors with defects in DNA repair genes (P < .001) J. Mateo, et al.NEJM 2015
- 27. Frequent somatic and germlinegene mutations in: (A) colorectal (B) gastric (C) pancreatic cancers Elena M. Stoffel JCO doi:10.1200/JCO.2014.60.6764
- 28. PPM1D Mutations inPBMCs From Women With Primary and Recurrent Ovarian Carcinoma JAMA Oncol. 2016;2(3):370-372. doi:10.1001/jamaoncol.2015.6053 In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%)
- 30. Factors influencing clinicianuse of multigene panels for GCRAFactors influencing clinician use of multigene panels for GCRA
- 31. Community clinician utilizationof multigene panels or exomes for GCRA From: Blazer, et al. Genetic Testing and Biomarkers 2015 Rapidly changing landscape: 6-month interval change in use
- 32. CCGCoP Case Conferences MultigenePanel Results (N=204) *112 total VUSs (16 cases w 2; 6 w 3;1 w 4)
- 33. • ASCO affirmsthat it is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient’s personal and/or family history. • Because of the current uncertainties and knowledge gaps, providers with particular expertise in cancer risk assessment should be involved in the ordering and interpretation of multigene panels
- 34. • Ever broaderarrays of genetic tools and precision Rx may benefit carefully selected and counseled families • Surveillance and prevention can improve survival in at-risk individuals • Protocols will need to be adapted to lower risk • Clinician genomic training initiatives are needed at many levels Summary
Editor's Notes
- #3 There are many factors associated with breast cancer; some are well established. This puzzle helps illustrate what we know about risk factors and some questions that need further study. Risk factors consistently associated with an increase in breast cancer risk include, getting older, being a woman, early menarche, late menopause, early exposure of the breast to ionizing radiation, having your first child late in life or not having children at all, having a close relative with breast cancer and certain benign breast diseases. These traditional or “established” risk factors only explain about 25 to 50% of the breast cancer risk. Hence, the interest in the role of diet, exercise, use of hormone therapy, and environmental chemicals in breast cancer risk.
- #4 Timeline of Important Events in DNA Patenting (Top) and the Discovery and Use of Genes Conferring Susceptibility to Breast and Ovarian Cancer (Bottom). NIH denotes National Institutes of Health, and USPTO U.S. Patent and Trademark Office.
- #5 Case 4, Q2 Case 3, Q2, Q6 Case 1, Q3
- #7 During the next 30 minutes or so, I will talk about three important concepts in breast cancer prevention: To prevent breast cancer, we need to know its causes We cannot eliminate “risk”, but we can QUANTIFY IT Knowing about our personal risk is critical to make informed decisions about WAYS TO REDUCE OR MANAGE OUR RISK THROUGH prevention and WAYS TO DETECT CANCERS EARLY THROUGH ßscreening
- #10 Cumulative incidence of early-stage (stages 0 to I) breast cancer in magnetic resonance imaging (MRI) –screened cohort and comparison group (competing risk model).
- #12 Figure 1. Interactions of Proteins Associated with Inherited Breast Cancer and with Fanconi Anemia A complex of eight Fanconi proteins (A, B, C, E, F, G, L, and M) activates FANCD2 via monoubiquitination, allowing FANCD2 to translocate to damage-induced nuclear foci that contain BRCA1, BRCA2, and RAD51. DNA damage activates ATM and CHEK2, which in turn activate BRCA1 by phosphorylation. PTEN binds to the Rad51 promoter and may regulate its transcription (Shen et al., 2007). Proteins indicated in red carry germline mutations that predispose to breast cancer. The numbers indicate different breast-cancer-associated mutations identified thus far in each gene. A germline variant in the promoter of Rad51 (blue) may modify breast cancer risk in BRCA2 mutation carriers (Levy-Lahad et al., 2001).
- #13 Figure 3. Synthetic Lethality According to BRCA Status and PARP Inhibition. In normal cells, mechanisms exist for single-strand break repair and functional base excision repair. The DNA-repair protein XRCC1 (x-ray repair cross-complementing protein 1) functions in the repair of single-strand breaks and forms part of a multimolecular complex with PARP. Two general pathways are involved in base excision repair: short-patch repair leads to a repair tract of a single nucleotide, whereas long-patch repair involves a repair tract of at least two nucleotides. When exposed to PARP inhibitors, unrepaired single-strand breaks can accumulate, with progression to double-strand breaks and subsequent collapse of the replication fork. In cells with functional BRCA, homologous-recombination pathways repair these double-strand breaks, leading to DNA repair and cell viability. In cancers with dysfunctional BRCA, the homologous-recombination pathway is deficient, and after exposure to PARP inhibitors, double-strand breaks accumulate and DNA damage is irreparable, leading to cell death. PARP inhibitors also have other pleiotropic effects on the cancer cell.
- #14 The decrease in cost of genome sequencing facilitated by massively parallel sequencing technologies. The cost of sequencing has decreased at a rate faster than Moore&apos;s law in the past 10 years. The data from 2001 through 2007 represent the costs of generating DNA sequences by using Sanger-based chemistries and capillary-based instruments (first-generation sequencing platforms). Starting in 2008, the data represent the costs of generating DNA sequences by using second-generation sequencing technologies. The change in instruments represents the rapid evolution of DNA sequencing technologies that has occurred in recent years. Landmark events are also indicated on the timeline. The release of various second- and third-generation technologies is indicated in blue boxes. IHGSC, International Human Genome Sequencing Consortium. Data adapted from the National Human Genome Research Institute Web site.35
- #15 Case #4, question 1
- #16 Proportions of patients with primary ovarian, fallopian tube, or peritoneal cancers with germ-line loss-of-function mutations in BRCA1 (red); BRCA2 (blue); BARD1, BRIP1, CHEK2, MRE11, NBN, PALB2, RAD50, or RAD51C (green); MSH6 (purple); or p53 (yellow).
- #24 Research and Clinical Opportunities for Precision Cancer Medicine Through Genomic and Transcriptome Sequencing. A systematic framework for implementing precision cancer medicine through genome and transcriptome sequencing can support multiple clinical and research efforts. Genomics can support the development of molecular diagnostics, drug target discovery, innovative genomics‐based trials, evaluation of exceptional responders, and study of the mechanisms of acquired resistance. IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY&apos;S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE &apos;REQUEST PERMISSIONS&apos; LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER.
- #26 Mutation rates in homologous recombination (HR) genes. A, overall, 115 of 367 subjects (31.3%) had deleterious mutations in 13 homologous recombination genes: 83 (22.6%) with germline homologous recombination mutations, 28 (7.6%) with somatic homologous recombination mutations, and 4 (1.1%) with both germline and somatic homologous recombination mutations. Mutations were detected in every homologous recombination gene tested. B, 87 subjects (24%) had 88 germline mutations in 11 homologous recombination genes. Germline homologous recombination mutations included 49 (13.4%) in BRCA1, 17 (4.6%) in BRCA2, and 22 (6%) in other homologous recombination genes, including BARD1, BRIP1, CHEK1, CHEK2, FAM175A, NBN, PALB2, RAD51C, and RAD51D. C, 32 carcinomas (8.7%) had a total of 35 somatic mutations in 7 homologous recombination genes. Somatic homologous recombination mutations included 19 (5.2%) in BRCA1, 6 (1.6%) in BRCA2, and 10 (2.7%) in other homologous recombination genes, including ATM, BRIP1, CHEK2, MRE11A, and RAD51C.
- #28 Frequent somatic and germline gene mutations in (A) colorectal, (B) gastric, and (C) pancreatic cancers.