Personalised Medicine in Practice. Dr Ingrid Slade MBChB, PhD, MRCPCH, MFPH Dr Chris Spencer DPhil Dr Gabriele De Luca MD, DPhil

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1 Personalised Medicine in Practice Dr Ingrid Slade MBChB, PhD, MRCPCH, MFPH Dr Chris Spencer DPhil Dr Gabriele De Luca MD, DPhil

2 Personalised Medicine in Cancer Care

3 Personalised Medicine in Cancer Care Cancer as a genetic disease BRCA1 and BRCA2 genes Ovarian cancer Personalised medicine in ovarian cancer Prognosis Treatment Prevention Challenges in personalised medicine in cancer care

4 Cancer is a Genetic Disease Accumulation of mutations in a lifetime from fertilised egg to malignant cancer cell. [EMBO Mol Med (2013) DOI: /emmm ]

5 A Cancer Patient has Two Genomes

6 The Two Hit Hypothesis Cancer Cell

7 The Two Hit Hypothesis Cancer Cell Cancer Cell

8 DNA Repair and BRCA Genes

9 DNA Repair and BRCA Genes

10 DNA Repair and BRCA Genes

11 BRCA1 and BRCA2 Carriers of germline BRCA1 or BRCA2 mutations are at high risk of developing breast cancer They have a lifetime risk of ovarian cancer of 40% (BRCA1) or 15% (BRCA2) They also predisposed to prostate and pancreatic cancers

12 Personalised Medicine in Ovarian Cancer - Background 7500 cases each year in UK 4500 deaths annually Late presentation with poor prognosis Overall 5 year survival 31% >90% of ovarian cancers are epithelial ~10-15% of these patients have a germline BRCA1/2 mutation

13 Personalised Medicine in Ovarian Cancer - Prognosis An ovarian cancer patient with an underlying BRCA1 or BRCA2 mutation demonstrates Increased sensitivity to platinum agents Longer disease-free intervals Longer overall survival Longer survival from first relapse

14 Personalised Medicine in Ovarian Cancer - Treatment Normal tissue (BRCA1 -/+) Single strand break PARP Single strand break repair Double strand break Homologous recombination BRCA1 CELL SURVIVAL L O H Tumour tissue (BRCA1 -/-) Single strand break PARP Single strand break repair Double strand break BRCA1 Homologous recombination TUMOUR CELL DEATH

15

16 Personalised Medicine in Ovarian Cancer - Prevention Identifying individuals with underlying BRCA mutations will facilitate testing of family members Opportunity to prevent ovarian cancers

17 Personalised Medicine in Cancer Care Source: Cell, Volume 144, Issue 5, , 4 March 2011 Copyright 2011 Elsevier Inc. All rights reserved /j.cell

18 Personalised Medicine in Cancer Care Garraway L A et al. JCO 2013;31: by American Society of Clinical Oncology

19 Personalised Medicine in Cancer Care Challenges The type and number of gene faults differ from one cancer to another Tumour heterogeneity Gene faults in a tumour may change over time A single cancer type might have very small number of patients so trials need to be adapted to show whether a drug works Infrastructure and clinical pathways

20 Questions to Consider Should there be a boundary between research and clinical medicine? Financing care Translational care Access to care at specialist centres How will drug trials be redesigned to show efficacy in small numbers of patients?

21 Personalised Medicine in Practice Introduction Healthy Individual Personalised medicine in common disease risk Person with Disease Pharmacogenomics Diagnosis of a rare disease Cancer care

22 Acknowledgements The Dr Stanley Ho Medical Development Foundation St. Anne s Development Office Professor Peter Donnelly Tim Gardam

23 Panel Discussion Chair Professor Peter Donnelly Panelists Dame Mary Archer Mr Richard Girling Dr Imogen Goold Dr Tim Lancaster Dr Ingrid Slade

24 Panel Discussion Themes from todays talks Workforce and public education Availability of genetic testing on internet Data storage and linking to NHS records Intersection between clinical and research care Complexity of task ahead Changes in infrastructure required to generate evidence and deliver care

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