Institute How can we achieve an integrated cancer medicine approach - - PowerPoint PPT Presentation

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Institute How can we achieve an integrated cancer medicine approach - - PowerPoint PPT Presentation

Oct 28, 2022 128 likes •310 views

Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Lisbon Dr James D. Brenton Cancer Research UK Cambridge Institute How can we achieve an integrated cancer medicine approach for women

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Gynecologic Cancer InterGroup Translational Research Brainstorming October 2016 Lisbon

Dr James D. Brenton Cancer Research UK Cambridge Institute

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   

Model-based clinical data capture

How can we achieve an integrated cancer medicine approach for women with HGSOC?

Tissue biopsy Liquid biopsy Imaging Highly annotated record

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TP53

Tissue biomarker Clonal marker Plasma biomarker

p53 IHC as a diagnostic biomarker TP53 circulating DNA as a response assay Absolute copy number estimation

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Analytical reliability in HGSOC

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Christine Parkinson Davina Gale Anna Piskorz Nitzan Rosenfeld

Exploratory comparison of ctDNA quantification to CA125

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3D volume analysis from CT imaging

ROI calculated by outlining volumes in Syngo.via (Siemens)

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What volume of disease is detectable?

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Correlation of volume with ctDNA and CA-125

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Nadir value is reached earlier for ctDNA than CA-125

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Ascites is a “third space” for cfDNA

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ctDNA rise in brain metastasis

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ctDNA fall after 1 cycle of chemotherapy predicts 6 month PFS

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Ongoing analyses in current trials

  • PHL093 Phase II trial evaluating gemcitabine/AZD 1775 in platinum resistant
  • varian cancer
  • Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2

Part 1): an international, multicentre, open-label, phase 2 trial

  • PiSARRO: a EUTROC Phase Ib Study of APR-246 with Carboplatin (C) and

Pegylated Doxorubicin (PLD) in Relapsed Platinum-Sensitive High Grade Serous Ovarian Cancer (HGSOC)

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Why is absolute copy-number critical?

  • Accurate CN comparison between samples
  • Accurate identification of loss/gain of actionable

drivers

  • Ability to use genome-wide CN based prognostic

measures such as the complex aberration index* Can we do it cheaply in a clinical workflow and use DNA from FFPE?

* Vollan et al Mol. Oncology 2015, Lartigue et al EJC 2015, or Schwartz et al, PLoS Med 2015

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Why is this important?

  • May provide a “formal grammar” to interpret

genomic profiles of HGSOC and development of more powerful molecular classification

  • Immediately applicable to large FFPE collections

(e.g. OTTA, and trials including ICON7, ICON8).

  • Genometypes may be important candidate

covariates for

  • Nanostring gene expression signatures
  • Molecular pathology, in particular patterns of immune

infiltration

  • ctDNA analyses
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Acknowledgements

Maria Vias Anna Piskorz Teodora Goranova Geoff Macintyre Debbie Sanders Samantha Boyle Dilrini De Silva Elizabeth Moore Douglas Hall Sarwah Al-Khalidi Stephanie Owen Filipe Martins Florian Markowetz Nitzan Rosenfeld Davina Gale Iain McNeish Darren Ennis CI Core facilities Biorepository Genomics Bioinformatics Paul Pharoah Jennifer Alsop Marie Mack Kristy Driver Marc Tischkowitz Martin Koebel Evis Sala John Stingl Bauke Ylstra BRITROC collaborators OTTA collaborators Addenbrooke’s Hospital Merche Jimenez-Linan Christine Parkinson Helena Earl Charlotte Hodgkin Heather Biggs Ilene Cannon Karen Hosking Sue Freeman Helen Addley