Biomarkers and Clinical Practice: Aspirations and Challenges

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Biomarkers and Clinical Practice Aspirations and
Challenges

• George V. Thomas, MD

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Targeted Drugs and Solid Tumors No insight into
why some patients respond and others do not
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Where do PATHOLOGISTS fit in?
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Personalizing Cancer TherapeuticsAspiration
Biomarker based Screening Protocolthat
stratifies patients to Early Phase Clinical
Trialsbased on their molecular profile
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Molecular Classification of Cancer
Stratify tumors according to aberrantsignaling
pathways Why?Therapies against a
specifictarget(e.g.B-RAF) work best in tumors
having a defect in this pathway

Facilitates Target Specific Diagnosis Tissue
SpecificMelanoma Target Specific Melanoma
with V600E B-RAF mutation

Biomarker Driven Early Clinical Trials in
Oncology e.g. PLX4032 targets V600E BRAF
enrolled patients with B-RAF mutations and
regression was seen in 83 of these patients
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Defining Biomarkers
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mTOR signalingpathway

• mTOR mammalian Target of Rapamycin
• Signaling through mTOR plays a critical role in
  many human cancers.
• Pathway activation is mainly due to
• Loss of function mutations in the tumor
  suppressor gene PTEN
• Activating mutations in PI3KCA, which encodes
  for p110a.
• Amplification of AKT

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Which drug to use?
e.g. mTOR inhibitors in cancers with PI3K pathway
aberrations
AKT amplification
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Challenges to Personalized Medicine

• Heterogeneity
• Heterogeneity
• Heterogeneity
• Tissue
• Regulatory
• Assays

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Heterogeneity 101

• Variable Expression
• expression
• Variable Intensity
• weak/moderate/strong
• Subcellular Localization nuclear/cytoplasmic/
• membranous/combination
• Assay Related
• reproducibility/robustness
• Biological Significance
• functional protein

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Objective Assessment through Digital Image
Analysis
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Biological Significance
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Biomarker Audit Trail
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So, where do Pathologists fit in?

• Frontline role in patient Rx decisions
• Tissue Gatekeeper
• Tissue annotator
• Quality Control
• Biomarker Development Validation

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Thank You

• Pathology Visions
• UCLA
• ICR
• Manuela Graf
• Elsa Vanhecke
• Natsuko Suwaki
• Kate Swabey
• Juliet Dukes
• Joana Moreira