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THE USE OF BIOMARKERS FOR
TREATMENT DECISIONS IN
ONCOLOGY
Angelica Fasolo, MD and Cristiana Sessa, MD
Montabone Unit for New Drugs Development
Istituto Nazionale Tumori Milano, Italy
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Definition of a biomarker
� “Characteristic objectively measured and evaluated as indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention.” (US National Institutes of Health Biomarkers Definition Working Group)
� Key component of translational research.
Biomarkers Definitions Working Group (2001) Clin Pharmacol Ther 69:89-85
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Translational research in new drug development
Transfers preclinical research into clinical practice through subsequent steps:
� study of the biology of the disease
� evaluation of the biological effects of the drugs in animals
� study of the biological effects of those drugs in humans
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Molecular target
Molecule or pathway with causal relationship with tumor
transformation and progression which can be identified
on tumor tissue.
Download Figure 1
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Biomarkers and drug development
� Used during the subsequent steps of drug development in order to:
� define the target deregulation correlate to tumor development (proof of
target)
� verify the interaction between the drug and the target or pathway (proof
of principle)
� verify that alteration of a specific target is crucial for a specific tumor in
humans (proof of concept)
� verify that the interaction between drug and target is responsible for
biological effects (proof of activity)
� screen and optimize candidate agents
� define a range of doses
� provide rationale for combination therapies
Park JW et al. Clin Cancer Res 2004;10:3885-3896
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Biomarkers classification
Three main categories (US-NCI) :
A. Prognostic biomarkers
B. Predictive biomarkers
C. Pharmacodynamic biomarkers
Kellof GJ, et al. Clin Cancer Res 2004;10:3881-3884Sawyers CL Nature 2008;452:548-552
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A. Prognostic biomarkers
� Correlate with clinical outcome and allow prediction of the natural course of cancer.
� Guide the therapeutic decision.
They include:
1. Biological progression markers
2. Risk biomarkers (or screening biomarkers)
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A. Prognostic biomarkers
1. Biological progression markers
� Measures of tumor activity (CEA, alphaFP, PSA, CA-125, hCG).
� Often used to monitor the effects of therapy because they could be modulated by the effect of the drug but are not implicated in neoplastic progression.
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A. Prognostic biomarkers
2. Risk biomarkers (or screening biomarkers)
� Describe risk of cancer occurrence or cancer progression because they are implicated in neoplastic progression and include:
1. carcinogen exposure
2. genetic predisposition (e.g., BRCA1/2)
3. over expression of genes (e.g., PTEN, BCR-ABL, HER-2/neu, RAS, AKT)
4. pharmacogenomic parameters (genetic polymorphisms, DNA methylation,
aneuploidy)
5. environmental factors and lifestyle (e.g., HPV or HBV infection, tobacco use)
6. multifactorial risk models (e.g., Gail model, Oncotype DX, MammaPrint)
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B. Predictive biomarkers
� Correlate with probability of clinical response to treatment:
� amplification of the gene HER-2 in breast cancer for treatment with anti-
HER-2
� ER/PgR expression in breast cancer for hormonotherapy
� presence of Philadelphia chromosome (BCR-ABL fusion gene) in
leukemia for anti-BCR-ABL
� mutations of EGFR in lung tumors for anti-EGFR
� mutations in KRAS in patients failing EGFR-specific therapy
� mutations of EGFR and intact PTEN after failure of anti-EGFR in
glioblastoma multiforme
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C. Pharmacodynamic biomarkers
� Correlated to biological and clinical effects of the drug on the tumor.
� Measured in serum, circulating cells, saliva, urine or tissue biopsies.
They could be:
1. lower expression or activity of a molecular target (e.g., EGFR tyrosine
kinase inhibition)
2. induction of metabolism (e.g., interference with cytochrome P-450)
3. interference with cell growth processes (e.g., Ki-67, BCL-2, cytokeratins)
4. vascularization and metabolism (imaging biomarkers)
Sarker D et al. Biomarkers Med 2007;1:399-417
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“Proximal” and “Distal” biomarkers
� Proximal: reflect the immediate effect of the drug on its target (e.g., decrease in a protein substrate of phosphorylation downstream the target kinase).
� Distal: reflect the effect of the drug downstream the molecular target (e.g., Ki-67 expression for reduction in proliferation).
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Applications of biomarkers in drug
development
1. Target discovery and validation
2. Preclinical studies
3. Phase 0 clinical studies
4. Phase I and II clinical studies
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1. Applications of biomarkers in drug
development: Target discovery and validation
� Identify targets for therapy
(e.g., HER-2, VEGF, VEGFR, BCR-ABL, ras…):
� HER-2 amplification in breast cancer for anti-HER-2 therapy
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2. Applications of biomarkers in drug development preclinical studies
� Selection of animal models and lead compounds to test
� Definition of mechanisms of action in vitro and in vivo
� Prediction of the effects of drug combinations
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3. Applications of biomarkers in drug development: Phase 0 clinical studies
� Conducted before phase I, in a maximum of 10 patients, with no therapeutic or diagnostic intent.
� To define pharmacodinamically effective dose during a limited exposure (usually 1 week) to the drug.
� Relevant in the go versus no-go decision-making process of going into clinics.
� Crucial for defining pharmacology, bioavailability, pharmacodynamics and metabolism of microdoses of the drug.
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3. Applications of biomarkers in drug
development: Phase 0 clinical studies –an example
� Phase 0 of the oral poly(ADP-ribose)polymerase (PARP) inhibitor, ABT-888.
� To determine a dose range and time course over which ABT-888 inhibits PARP activity in tumor biopsies and PBMCs; to study thepharmacokinetics of ABT-888.
� Starting dose for phase I selected on the bases of PARP inhibition in tumor biopsies and PBMCs.
Kummar S et al. J Clin Oncol 2009;16:2705-11
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PARP-1 is a key enzyme involved in the repair of single-strand DNA breaks
PAR chains
are
degraded
via PARGRepaired
DNA
PARPDNA damage
Binds directly
to SSBs
Repair enzymes
PAR
Nicotinamide
+pADPr
NAD+
Once bound to damaged DNA, PARP modifies itself producing large branched chains of PAR
Illustration courtesy of AstraZeneca
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4. Applications of biomarkers in drug development: Phase I clinical studies
� Evaluate toxicity of a new compound and select optimal dose for subsequent efficacy trials, once defined the MTD.
� For cytotoxic agents greater drug exposure corresponds to a greater tumor-cell kill in preclinical models.
� For molecular targeted drugs a greater selectivity inhibits specific tumor factors with reduction of toxicity.
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4. Applications of biomarkers in drug development: Phase II clinical studies
� Collection of tissue samples and performance of molecular analyses to identify mechanisms responsible of biological effects.
� Could be used as surrogate endpoints of efficacy and prediction of clinical outcome to identify active drugs for phase III trials.
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Application of biomarkers in Phase I clinical studies
� PARP inhibitors and cytotoxic agents
� PARP inhibitors and DNA damaging agents
� Everolimus (RAD001)
� Antivascular agents
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Application of biomarkers in Phase I clinical studies: PARP inhibitors and cytotoxic agents
� Phosphorylated histone H2AX (γH2AX) initiates DNA repair process after double-strand breaks (DSBs) caused by radiotherapy and many cytotoxics.
� γH2AX detected by immunofluorescence in vitro system; as DSBs are repaired, the number of γH2AX foci per nucleus decreases.
� Changes of γH2AX foci reflect the activation of the DSBs repair processes.
� γH2AX is a potential pharmacodynamic marker of DNA damage in studies with radiotherapy and PARP inhibitors.
Bañuelos CA et al. Clin Cancer Res 2009;1 5:3344-3353Ashworth A. J Clin Oncol 2008;26:3785–90
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Application of biomarkers in Phase I clinical studies: PARP inhibitors and DNA damaging agents
1. Phase 0 study: assesses PARP inhibition in PBMCs (pharmacodynamic endpoint) to define the 50% PARP inhibitory dose (PID) of AG014699 as starting dose for phase I.
2. Phase I study: to define the dose of Temozolomide (TMZ) and AG014699 that could be safely combined.
Plummer R, et al. Clin Cancer Res 2008;23:7917-7923
Download Figure 2
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Application of biomarkers in Phase I clinical
studies: Everolimus (RAD001)
� Ribosomal protein S6 Kinase 1 (S6K1) and repressor of mRNA translation eukaryotic translation initiation factor 4E-Binding Protein (4E-BP1) as pharmacodynamic biomarkers for mTOR inhibitors.
� Divergent results because of different biomarkers of the same pathway (eIF-4G, 4E-BP1, S6K1) at different sites (PBMCs, skin, and tumor) can result in different optimal biologic recommended doses (RD).
� Pharmacodynamic biomarkers alone cannot allow the selection of the RD.
O’Donnell A, et al. J Clin Oncol 2008; 26:1588-1595Tanaka C, et al. J Clin Oncol 2008; 26:1596-1602Tabernero J, et al. “J Clin Oncol 2008; 26:1603-1610 Fasolo A, Sessa C. Expert Opin Investig Drugs 2008;11:1717-34
Download Figure 3
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Application of biomarkers in Phase I clinical
studies: Antivascular agents
� Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) provides parameters of tissue perfusion and permeability affected by antivascular drugs.
� DCE-MRI as biomarker of 5,6-Dimethylxanthenone-4-acetic acid (DMXAA ) biological effects in phase I.
� Recommended dose for subsequent clinical development selected according to perfusion-related parameters.
Galbraith SM, et al. J Clin Oncol 2002;18:3826-3840
Download Figure 4
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Conclusions
� Biomarkers are key components of translational studies, useful in the process of drug development of molecular targeted agents.
� Still too few cases in which the sufficient knowledge of the dynamic interaction between drug and target justifies a pharmacodynamically only driven strategy.
� Biomarkers are useful in the process of dose escalation, definition of schedule and doses for subsequent phase II studies.