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

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

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

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.

Prevention

High risk

individual

Population

ScreeningSymptoms

Cancer ScreenedNoDiagnostic

process?Yes

Tissue

DiagnosticPathology

Staging Radiology

Complete

Cancer

diagnosis

Anti cancer

treatment

PATIENT

RELATED

FACTORS

INITIAL

TREATMENT

BY TUMOUR

STREAM

Incomplete

cancer

diagnosisOR

Positive

family history

Cancer

Confirmed

Yes

Screening

MorbidityNo

Complete

ResponseRelapse

Cancer

Cure

Living with

cancer

End Anti

cancer

treatment

Palliative

Care

Survivorship

Cancer

MortalityDeath

Yes No

No Yes

Yes

Yes

Yes

Non

cancer

mortality

Treatment

Mortality

Genetic

testing

Predisposing

Condition

No

No

Subsequent

treatment NoNo

Dr S Vaughan

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GICS

COPYRIGHT

Trial and error – chemotherapy - systemic diseaseChemo, 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

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

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

CRISPAR

Organism

Organs

Tissues

Cells

Sub-cellular

mechanisms

Pathways

Proteins

Genes

Fig 1. The reductionist casual chain

Organism

Organs

Tissues

Cells

Sub-cellularmechanisms

Pathways

Proteins

Genes

Fig 2.

Higher-level triggers of cell signalling

Higher-level controls of gene expression

Protein machinery reads genes

DOWNWARD CAUSATION

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

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, 248 - 256

• Patient

• Payer

• Clinician

• Manager

• Commercial interests

• Scientist

The resolution of value perspectives is an intrinsically political process.

It is changing rapidly.

6 Important Value Perspectives

Targeted Therapies Types

• Vaccines

• Activated patient cells

• Small Molecules

• Monoclonal Antibodies

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

Patient-centred careInterpersonal 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

Evaluation of health interventions

• Complex Interventions into complex systems

• Moving targets.

• Competing commercial /other interests

• Which perspective

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

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

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

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 ofcancer patients with that tumour type.

Knowing when to stop cancer treatmentGetting more difficult

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?”

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