Predictive Biomarkers and Drug Resistance
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Transcript of Predictive Biomarkers and Drug Resistance
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• Acquisition of tumour multidrug resistance inevitable in most advanced solid tumours– Failing to cure the majority of advanced solid tumours– Declining therapeutic benefits at higher drug cost
• Drug resistance highly complex: – Approx 10% of kinases alter resistance to one or more drugs (Swanton et al 2007 Cancer Cell ; Swanton et al 2007 Cell Cycle)
• Failure of Biomarker Validation– 150,000 biomarkers only 100 for clinical use
Predictive Biomarkers and Drug Resistance
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Intratumour Heterogeneity
• Evidence of intratumour heterogeneity
• Possible Implications for biomarker studies
• Practical approaches to address heterogeneity
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Breast Cancer Intra-tumour Heterogeneity
Sector Ploidy Profiling and DNA Copy Number Analysis
• Multiple intermixed cell subpopulations within one tumour differ by large genomic events/focal amplifications/ deletions
Navin N, et al. Genome Res 2010Navin N, et al Nature 2011
Geyer and Reis-Filho J Path 2010Shah and Aparicio Nature 2012
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Does a Single Tumour Biopsy:
Represent the tumour somatic/transcriptomic landscape ?
Provide robust biomarkers of outcome ?
Demonstrate that all mutations are ubiquitously present in every region of a tumour Predicted by a linear/clonal sweep model of tumour evolution
Provide reliable data following Deep Sequencing Analysis to stratify patients for trials ?
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Ubiquitous
SharedPrimary
SharedMets
Private
65% mutations are heterogeneous and not present in every biopsy
Primary Mets
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Re-construct Phylogenetic Evolution of Tumour
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Normal
Evidence for Convergent EvolutionSETD2 Loss of Function: H3K36 tri-methylation
3 distinct SETD2 mutations associated with loss of function: Mutational capacity?
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Evidence intratumour heterogeneity may impact upon drug response?
6 weeks of Everolimus therapy Assess status of mTOR pathway across different regions of the tumour Evidence of Differential Pathway Activity post-Everolimus exposure?
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mTOR active in all primary regions except R4 and metastases
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Heterogeneous Kinase Domain mTOR mutation L2431P
mTOR mutation L2431P
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Kinase Domain mTOR mutation L2431P Associated with Constitutive Activation of the mTOR Kinase
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Kinase Domain mTOR mutation L2431P Lies in A Repressor Domain Close to Activation Loop of Kinase
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Tracking Tumour Growth
Seeding of metastatic sites can be tracked to one tumour region
M2a,b M1
Chest Wall Metastasis Perinephric Metastasis
NormalR9
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Primary Tumour Regions Metastatic SitesPrimary Tumour Regions Metastatic Sites
Allelic Imbalance: ITH within Chest wall metastasis
Only somatic mutations with >20x coverage were included
Only somatic mutations with >20x coverage were included
M2a,b M1
Chest Wall Metastasis Perinephric Metastasis
R9
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Primary Tumour Regions Metastatic Sites
Only somatic mutations with >20x coverage were included
Only somatic mutations with >20x coverage were included
Primary Tumour Regions Metastatic Sites
Heterogeneity of RCC Prognostic Signature Expression
MedianccA 103 monthsccB 24 months
Gen
es u
preg
ulat
ed in
ccA
Gen
es in
ccB
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Darwin and cancer branched evolution
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Relevance of ITH and Cancer Branched Evolution
Patient 1
Tumour Diversity Supports Evolutionary Fitness (Maley et al 2006)
Tumour Adaptation and Selection for• Drug resistance (Su et al 2012; Lee et al 2011)
• Metastatic growth (Yachida and Campbell 2010, Shah 2009)
Tumour Sampling Bias • Different tumour biopsies different results• Sites of disease evolve independently
Clonal Dominance and Actionable Mutations?• Mutations present at one site but not another