Polymorphisms potentially mediating NSAID chemoprevention for colorectal neoplasia

1
Polymorphisms potentially mediating NSAID
chemoprevention for colorectal neoplasia

• Alex Demarsh
• MSc Epidemiology
• Supervisor Dr. Julian Little

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Overview

• Systematic review of association studies to
  identify potential modifiers of NSAID effect.
• Select candidate variants for profile
• (ongoing)
• Modeling potential clinical validity and
  predictive power of profile
• Impact of shifting preventive efforts to likely
  responders
• Empirical evaluation of profile using ARCTIC data

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Nonsteroidal anti-inflammatory drugs

• Inhibitors of cyclooxygenase (COX) enzymes.
• Many families
• Salicylates
• Aspirin (acetyl salicylic acid)
• Preferentially inhibits COX1 at low dose
• Non-selective, COX1/COX2 inhibitor at higher dose
• Irreversible
• Propionic acids
• Ibuprofen
• Non-selective COX1/COX2 inhibitor
• Pyrazole
• Celecoxib
• Selective COX2 inhibitor (COXib)

Aspirin
Ibuprofen
Celecoxib
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Chemopreventive potential

• Tumor tissue
• Bane Dell Tacca (1975)
• Animal Models
• Kudo et al. (1980), Pollard Luckert (1980),
  Narisawa (1981)
• Observational Studies of aspirin
• Kune et al (1988), Gann et al (1993), Greenberg
  et al (1993), Suh et al (1993), Thun et al (1993)
  
• RCTs of COXibs for FAP
• Bertaignolli (2006), Arber (2006), Baron (2006)
• RCT of Sulindac DFMO
• 375 participants
• Adenoma recurrence RR 0.30 (0.18,0.49)
• Meyskens et al (2008)

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Current evidence

• Considerable evidence for aspirin adenoma -
  Dube et al (2007)
• Cohort RR 0.72 (0.61,0.85)
• Case-Control RR 0.87 (0.77, 0.98)
• RCTs RR 0.82 (0.70, 0.95)
• Risk Benefit ratio
• Gastric upset, ulcer, asthma, renal toxicity,
  bleeding, heart failure
• Not recommended to prevent CRC for average risk
  populations.

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Genetic mediation?

• Ex) COX1 P17L (Ulrich et al., 2004)
• 40 reduction with NSAID in wt
• 715 cases

http//www.nature.com/nrc/journal/v6/n2/fig_tab/nr
c1801_F5.htmlfigure-title
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Metabolism and excretion
Glucuronide conjugation by UGTs
Oxidation by cytochrome P450 enzymes
http//www.nature.com/nrc/journal/v6/n2/fig_tab/nr
c1801_F4.htmlfigure-title
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COX mechanisms

• Eicosanoid inhibition
• Prostaglandin E2
• Angiogenesis
• Apoptosis
• Cell proliferation
• Migration
• Genes highly conserved (ie few, rare
  polymorphisms)

http//www.nature.com/nrc/journal/v6/n2/fig_tab/nr
c1801_F2.htmlfigure-title
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Inflammation
http//www.nature.com/nrc/journal/v6/n2/fig_tab/nr
c1801_F1.htmlfigure-title
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Methods

• OVID Medline, EMBASE, BIOSIS, and ISI Science
  Citations Index
• 231 citations (after removing duplicates and
  irrelevant studies)
• 53 articles full-text screened
• 23 relevant articles (included genetic measure,
  CRA/CRC outcome, and NSAID measure)
• Risk of bias assessment
• Data extraction

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General comments - Limitations

• Many small, uncoordinated studies.
• Variety of NSAID measures, doses, durations.
• Numerous replications in same population
• Michigan, Utah
• Sample sizes not adequate to detect interaction
• Need 1000 cases to detect a priori hypothesized
  moderate GXE interaction
• Few studies designed to test for interaction
• Multiple hypothesis testing
• Publication bias/selective reporting?

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General comments - Strengths

• Candidate gene/pathway approach
• Incorporates biological knowledge
• Generally full description of assessment of NSAID
  status
• Most recent studies approached power necessary to
  look at interactions.

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The Fab Five
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One hit wonders

• PPARd C789T (Siezen et al, 2006)
• 244 cases
• Carriers (CT or TT) had greatest protective
  effect.
• COX1 P17L (Poole et al., 2007)
• 522 cases
• Protective effect confined to homozygous
  wildtype.

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Next steps

• Main effects of variants
• 2nd round of searching
• Supplement with existing reviews
• Model building
• Potential use of 5-7 variant profile
• Small increase in NSAID effectiveness
• Test in ARCTIC data
• Few candidate variants tagged in ARCTIC

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Thanks!

• To the CIHR TIRCRC for continued support.