Title: Polymorphisms potentially mediating NSAID chemoprevention for colorectal neoplasia
1Polymorphisms potentially mediating NSAID
chemoprevention for colorectal neoplasia
- Alex Demarsh
- MSc Epidemiology
- Supervisor Dr. Julian Little
2Overview
- 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
3Nonsteroidal 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
4Chemopreventive 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)
5Current 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.
6Genetic 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
7Metabolism 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
8COX 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
9Inflammation
http//www.nature.com/nrc/journal/v6/n2/fig_tab/nr
c1801_F1.htmlfigure-title
10Methods
- 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
11General 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?
12General 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.
13The Fab Five
14One 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.
15Next 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
16Thanks!
- To the CIHR TIRCRC for continued support.