Changing Clinical Care

Transforming the NHS through genomic

& personalised medicine

Professor Sue Hill OBE

NHS Chief Scientific Officer for England

Care in the era of non-communicable disease • Traditional ‘One size fits all’ model of care failing to account for much of

the chronic inflammatory and degenerative disease facing society,

These non-communicable diseases are increasing as survival improves

• Life style influences are creating a time bomb in non communicable

diseases for example in cancer, obesity, diabetes, hypertension

• Drug treatment based on a drug discovery approach of ‘one size fits all’

business model is ineffective in between 30 and 60% of patients

• Five Year Forward View recognises that NHS sustainability requires

revolutionary change in service provision – informed by research

and innovation, with a new focus on prevention and earlier detection of

disease and delivery by new ways of working.

Condition Efficacy Rate (%)

Alzheimer’s 30 Asthma 60 Diabetes 57 Hep C 47 Cancer 25 Osteoporosis 48 Rheumatoid arthritis 50 Schizophrenia 60

Limits of pharmaceutical effectiveness

Profound scientific and technological innovation influencing NHS transformation

and effectiveness ; a major step change in the pathway to personalised care

The 100,000 Genomes project -a major catalyst for change in an integrated health system

• Project will sequence 100,000 whole genomes (WGS) from patients with cancer and rare disease representing a 300 fold increase in the genetic information available for diagnostic purposes

• Other samples from across the functional genomic pathway will be collected to enable complex cellular processes and the expression of genetic variants in these diseases to be understood

• Detailed clinical and diagnostic data will be collected both at the start and longitudinally and stored together with the WGS in the Genomics England secure Data centre to enable analysis of the individual genotype and phenotype and comparison within others

Major legacies for patients,

the NHS and the UK

economy by 2017

Increased discovery of pathogenic variants leading to new treatments, devices and diagnostics

Stimulate and advance UK life sciences industry and commercial activity in genomics

Accelerate uptake with advanced genomic medicine practice integrated into the NHS

Increase public understanding and support for genomic medicine

Involvement of multiple clinical

specialities in new MDTs

Step change in analysis of

information , validation &

reporting

Partnerships & networks

working across

geographies

Capture of data from multiple systems against defined datasets and

standards

Key roles of NHS GMCs

Upskilling the NHS

Workforce

Sample collection, processing & logistics to defined protocols &

quality standards

Return of results to participants & clinical

care according to guidelines

Transforming the NHS – improving

outcomes & reducing variation

Patient & Public

Involvement

Transforming the NHS for the future – Genomic Medicine Centres

Network of 11 Wave One GMCs overseeing genomic services for population of 3-5 million

Informing the personalised medicine approach • Technological advances and the breadth of information captured about patients - exemplified in

the 100,000 Genomes Project - are moving the NHS to a new model of diagnosis and treatment based on identifying and understanding the underlying causes of disease rather than deduction from symptoms and individual tests

• Effective capture and analysis of all diagnostic (including genomic)and other clinical data will identify novel disease pathways – and the patient subgroupings that will inform effective management.

• 4 Ps of Change: Medicine will move from a reactive to a proactive discipline over the next decade; one that is predictive, personalised, preventive and participatory

• Integral to delivering this step-change in provision will be further developments in informatics and other underpinning diagnostic services driven by scientific and technological advances

Personalised medicine - definition

• Personalised medicine: ..the tailoring of medical treatment to the individual characteristics of each patient... using diagnostic tests to select the most appropriate treatment for individual patients – the right drug at the right time, earlier screening and treatment, smarter monitoring and adjustment of treatments.

• Interventions can then be concentrated on those who will benefit and preventing side effects in those who will not

• First generation of personalised pharmaceuticals

already here (100+ licensed by 2014) – eg Herceptin®, Zelboraf ®

BRAF inhibitor treatment for malignant melanoma

9

Why this is important in improving outcomes

Targeted disease prevention Identification of predisposition markers or

underlying processes can predict future disease

Early disease detection 2-8 yrs before onset & symptoms become

obvious with low cost stratification

Accelerated diagnosis based on underlying cause and incidental findings – rather than

just grouped symptoms

Targeted therapy Identification of effective personalised treatments

Improves outcomes

• Greater efficiency from streamlined care pathways • Earlier and more precise diagnosis and treatment • Fewer and less complicated surgical interventions • Fewer patients getting cancer and other diseases

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Combining the elements for delivery Informing and transforming common treatments such as Anticoagulant therapy

The need for cultural change • Personalised medicine demands a new approach – to treat the patient’s

disease and not the disease in general, to understand variation from patient to patient and within a patient across the life course

• Treatment decisions will increasingly be driven by individual patient data – requiring a much greater focus on new management and analysis of the data that professionals capture

• Effective integration of multiple different types of data and its intelligent interrogation will identify novel disease pathways

• Need to maintain the momentum and the NHS transformation that participation initiated through the 100,000 Genomes Project has initiated

Where is the wisdom

we have lost in knowledge ?

Where is the knowledge

we have lost in information?

TS Elliot

Manchester Centre for Genomic Medicine

William G Newman MD PhD

Professor of Translational Genomic Medicine, University of Manchester

Manchester Genomic Medicine Centre

Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust – rare diseases

Christie Hospital NHS Foundation Trust – Cancer care

Mission : to deliver the benefits of Genomic Medicine to all

Manchester Genomic Medicine Centre

Rare Diseases - MCGM

• Largest Centre in Europe • Translation from research to

service serving a diverse local population of 6m.

• 12,000 patients /year • >50,000 genetic tests

• unified laboratory - biochemical genetics, cytogenetics, molecular genetics including cancer pharmacogenomics

Cancer- Christie

• Largest Centre in Europe

• Close links between research (especially clinical trials) and treatment

• >44,000 patients /year

• Expertise in personalised medicine – lung cancer, melanoma

Innovation Pathway

INVENTION EVALUATION

Understanding the molecular basis of Genetic Disease

Studies: Understanding

Molecular Basis of Genetic

Disorders

Neurological & Immune

function

Renal Tract Abnormalities

Developmental disorders

Learning disability

RASMAP-K pathway

Schwannomatosis

Neurofibromatosis 2

Breast Cancer

Cardiac disorders

Retinal dystrophies

Congenital cataracts

Evaluation of Novel Therapies

Novel therapies for

•Marfans syndrome

•Neurofibromatosis 1 & 2

•Huntington’s disease

•Fragile X

•Niemann-Pick B

•Mucopolysaccharidoses

•Lysosomal Acid Lipase deficiency

(infant and adult)

Gene therapy

•Choroideraemia

Screening

•women at risk of breast cancer

•Mammography-Predicting the Risk

at Screening

Studies: Improving Services

• Accessibility for patients with

sensory impairment

•Improving services for those with

inherited retinal disease

•Improving Communication in the

Genetic Eye Clinic

•Patient Empowerment in clinical

genetics services

•Delivering therapies for rare

diseases – ERT for MPS I, II, VI

•Management: Nationally

commissioned specialist services

(Complex NF1, NF2, LSDs)

ADOPTION

Use of WGS in Discovery

cleft lip/palate,

hearing loss,

choanal atresia (blocked nose)

= Burn-McKeown Syndrome

Advantages of Whole Genome Sequencing in Discovery

Wieczorek et al Am J Hum Genet 2014 December

Basal Cell Carcinoma

Affects ~1 million people/ year in the USA

Familial Basal cell carcinoma – Gorlin syndrome

•Multiple basal cell carcinomas (>5 in lifetime)

•Jaw cysts

•Brain calcification

•First degree relative with Gorlin's syndrome

Some cases

•Skeletal problems - Vertebral/rib anomalies

•5% medulloblastoma (childhood brain tumour)

•Most have mutations in a gene – PTCH1

Discovery • Genome Sequencing of 4 PTCH1 -ve familial cases

• Causative mutations in SUFU

Family 1

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Fragment

10E

c.550C>T (p.Gln184*)

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Fragment

10D

c.544G>T (p.Asp182Tyr)

• Negative regulator of hedgehog signalling pathway

Implications for treatment:

• SUFU cases not responsive to

hedgehog inhibitors

(vismodegib) - £6k /month

Hedgehog inhibitor

Medulloblastoma risk

• Present in 3 of 10 SUFU mutation +ve cases

• Contrasts with 2 of 115 PTCH1 mutation +ve cases (p=0.003)

• Implications for screening:

? MRI brain surveillance in SUFU mutation +ve, -6 monthly till 2 years, then

annually, but not justified in PTCH1 +ve cases

Smith et al Journal of Clinical Oncology December 2014

Providing the evidence to alter clinical practice Diagnostic yield in retinal disease – inherited blindness

NGS panel WGS

Increased pick up of 27%

Pathogenic variants identified

No pathogenic variants identified Heterozygous pathogenic variant identified in a gene expected to cause recessively inherited disease

Unpublished – Prof Graeme Black

Cancer diagnostics

• Transition from single gene tests e.g. EGFR in lung cancer to panels of all relevant genes

• Increase identification of patients eligible for trials of new therapeutics

• Identify genetic changes (translocations) challenging to detect by other

types of genetic test

• Discovery of markers for resistance – swap treatment

100,000 Genome Project

EVALUATION ADOPTION INVENTION

100,000 Genome Project

Participant Experience

Seana Donaghy

Diagnosis • 8 months pregnant

• Usual pregnancy symptoms

• Echocardiogram

• Left ventricular dilated cardiomyopathy

Reasons for participating • Family

• Early detection

• Peace of mind

• Improvements in treatments

• Acceptance

Taking part • No pressure invitation

• Sit down meeting

• Blood test

THANK YOU