Precision Medicine. What does it mean? What s not to like? What were we doing before? How successful?

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1 Precision Medicine What does it mean? What s not to like? What were we doing before? How successful? Dr Stephen Vaughan Director, Cancer Services Institute Epworth HealthCare Epworth HealthCare 1

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3 Issues addressed Terms Conventional approach- Trial and error Cancer biology Cancer treatment - The new paradigm How to measure outcomes Change management Who pays and how much Health Literacy References

4 Terminology-recent additions Precision Health/Medicine, Genomic Medicine/Health, Moonshot Molecular medicine, targeted therapy Omics-Gene, Protein, microbome, incidental, phen, transcript Personalised Medicine Evidence informed individual care Liquid biopsy v conventional biopsy Precision=repeatability. Accuracy=Truth Patient Centred Care Continuum of care The Cloud and Big data

5 Definitions This shift is inexorably moving medicine from an endeavour in which care for individual patients is driven by trial and error informed by studies designed to measure population outcomes to one in which care is selected based on a deep understanding of health and disease attributes unique to each individual. In clinical oncology, an accepted definition of precision medicine refers to therapeutic decisions guided by the molecular or genomic features of a tumour rather than on the basis of clinicopathological features.

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7 Prevention High risk individual Population Screening Symptoms Cancer Screened No Diagnostic process?yes Tissue Diagnostic Pathology Staging Radiology Complete Cancer diagnosis Anti cancer treatment PATIENT RELATED FACTORS INITIAL TREATMENT BY TUMOUR STREAM Incomplete cancer diagnosis OR Positive family history Cancer Confirmed Yes Screening Morbidity No Complete Response Relapse Cancer Cure Living with cancer End Anti cancer treatment Palliative Care Survivorship Cancer Mortality Death Yes No No Yes Yes Yes Yes Non cancer mortality Treatment Mortality Genetic testing Predisposing Condition No No Subsequent treatment No No Dr S Vaughan Total Pathway S U P P O R T I V E C A R E E D U C A T I O N A N D R E S E A R C H GICS COPYRIGHT

8 Trial and error chemotherapy - systemic disease Chemo, hormones Group cancers by anatomical site of origin Mostly same treatment to each group Large clinical trials Limited understanding of cancer biology or how drugs worked Mostly Intravenous Toxicity significant Successes- hodgkins,testicular,lymphoma,leukemias,childhood Failures- lung,pancreas,biliary Useful palliation breast, bowel,prostate

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10 Germline V Somatic Mutations Mutations are changes in DNA of various types Germline mutations are present at conception, are inherited from parents and can be passed on to children Somatic mutations occur after conception, are not inherited and cannot be passed on to children Almost all cancer is caused by the genetic change but only a minority (10%) by inherited germline mutations Epigenetics refers to changes in the expression of DNA rather than the DNA itself and is a common cause of cancer

11 Drivers and Passengers Most cancers have many mutations Most cancers require several mutations to develop Mutations increase over time and in response to treatment Driver mutations are causal in the development of cancer Passenger mutations are incidental Sometimes difficult to tell the difference Drug resistance usually develops when a driver mutations blocked

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13 CRISPAR

14 Organism Organs Tissues Cells Sub-cellular mechanisms Pathways Proteins Genes Fig 1. The reductionist casual chain

15 DOWNWARD CAUSATION Organism Higher-level triggers of cell signalling Organs Tissues Cells Sub-cellular mechanisms Higher-level controls of gene expression Pathways Protein machinery reads genes Proteins Genes Fig 2.

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22 Health System is Complex not just Complicated No centralised control Multi-jurisdiction, Federal Emergent properties Interactions and processes produce new, unconstrained behaviour Limited view Only ever see a portion of the whole Open system New people, organisations, ideas Self-organising properties Local optimisation, community-based

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24 Five Aspects of Clinical Decision Making Empirical evidence(ebm): derived from clinical research. Experiential evidence: derived from personal clinical experience or the clinical experience of others (i.e. expert opinion). Mechanistic rationale: based on underlying theories of physiology, disease and healing. Patient values and preferences: derived from personal interaction with individual patients. System features: including resource availability, societal and professional values, legal and cultural concerns. Reference: Mark R. Tonelli MD MA 2006 Blackwell Publishing Ltd, Journal of Evaluation in Clinical Practice, 12, 3,

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26 6 Important Value Perspectives Patient Payer Clinician Manager Commercial interests Scientist The resolution of value perspectives is an intrinsically political process. It is changing rapidly.

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28 Targeted Therapies Types Vaccines Activated patient cells Small Molecules Monoclonal Antibodies

29 Early examples Targeted therapy Hormone receptors in breast cancer - 35yrs Her2 (herceptin) in breast cancer - 18yrs Imatinib (18yrs) in CML (bcr-abl) - Philadelphia chromosome - 30yrs Mabthera (CD20) - 17yrs

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32 Patient-centred care Interpersonal not molecular biology First, the doctor must be aware of the personality of the individual in order to enter into a humanistic dialogue with the person. Second, for a therapeutic alliance, there must be agreement that doctor and patient are working toward common goals. Third, calm reassurance, hope, and respect need to be communicated. Fourth, the doctor and patient need to be empathic and reflective. Fifth, they must identify and implement practical means of promoting health with available resources and a realistic understanding of facts. Conclusion, awareness of who the person is in a therapeutic encounter allows cultivation of a humanistic dialogue, which in turn accounts for most of the variation in clinical practice

33 Evaluation of health interventions Complex Interventions into complex systems Moving targets. Competing commercial /other interests Which perspective

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37 Resistance to change - Elements Affective - I don t like it Cognitive - I don t believe in it Behavioural - I won t do it Rational -Cognitive -Affective -Behavioural Actual -Affective -Cognitive -Behavioural

38 Change requirements for precision medicine All difficult Strong leadership and governance A skilled and literate genomic workforce Application of genomic knowledge is evidence-based, high quality and safe Integration of genomic knowledge into patient centred healthcare supported by equity of access to services Sustainable investment in health genomics Effective and appropriate collection, management and utilisation of clinical and genomic data

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40 A sceptical/realist view Difficult to distinguish driver from passenger mutations Too much focus on the cell rather than its microenvironment Large-scale trials for difficult to treat cancers not successful but rare super responders occur. Same mutation in different cancers usually does not respond the same Most cancers have multiple mutations and therefore multiple drugs required- cancer is a complex system COST-$5-10,000 per month mostly self funded. Equity issues. Paradox if works Commercial interests Every generation of scientists looks back and shakes its collective head in condescending disbelief at how little the previous generation knew, rarely stopping to reflect that the next generation will do the same. the perennial desire for simple solutions to complex problems leads people back time and again to biological determinism: it s all in your genes Organisational and attitudinal change the biggest challenge

41 Knowing when to stop cancer treatment Getting more difficult But these tests are not going to offer only unmitigated positive opportunities. Aside from the cost of several thousand dollars per tumour profile performed, the results of these profiling tests most often reveal not a clearly actionable mutation, but one or more rare mutations that are accompanied by a synopsis of lab-based suggestions for unapproved and clinically untested options in that particular tumour type from the testing company. While a patient and their oncologist may say that they will ignore treatment options that are poorly studied and essentially just wildly speculative (there is a rather weak correlation between cancer treatments that work in the lab and those that are safe and clearly active in human cancer patients), that s easier said than done. Instead, the molecular results often lead oncologists to be tempted to practice the black art of using the profile as a medical Ouija board to cobble together a treatment plan with no good clinical evidence to support it, all too often bypassing the treatments that are well established as helping improve treatment options in thousands of cancer patients with that tumour type.

42 Choruses from the Rock - T.S Elliot, SV Where is the Life we have lost in living? Where is the wisdom we have lost in knowledge? Where is the knowledge we have lost in information? Where is the information we have lost in data? Where is the data?

43 References National health genomics policy framework 2017 to 2020 Towards precision medicine the paradox of scientific American, April 2016 Nature reviews genetics vol 17 September 2016 page 507