title: PIK3CA Mutation, Aspirin Use after Diagnosis and Survival of Colorectal Cancer. A Systematic Review and Meta-analysis of Epidemiological Studies.
abstract: OBJECTIVE
  Regular aspirin use has been associated with inhibition of the whole spectrum of colorectal carcinogenesis, including prevention of metastases and reduced total mortality in colorectal cancer. Preclinical data show that aspirin down-regulates PI3 kinase (PI3K) signalling activity through cyclo-oxygenase-2 (COX-2) inhibition, leading to the hypothesis that the effect of aspirin might be different according to PIK3CA mutational status, but epidemiological studies have led to conflicting results. The aim of this study was to assess the relationship between PIK3CA status and the efficacy of regular use of aspirin after diagnosis on overall survival in colorectal cancer patients.
  
  
  METHODS
  We identified studies that compared post-diagnosis aspirin efficacy in colorectal cancer patients identified by PIK3CA status. Hazard ratios for overall survival were meta-analysed according to PIK3CA status by inverse variance weighting. A pooled test for treatment by PIK3CA status interaction was carried out by weighted linear meta-regression. All statistical tests were two-sided.
  
  
  RESULTS
  The overall effect of aspirin was not significant (summary risk estimate = 0.82; 95% confidence interval 0.63-1.08, P = 0.16; I(2) = 57%). In PIK3CA mutant disease (n = 588), aspirin use reduced total mortality by 29% (summary risk estimate = 0.71; 95% confidence interval 0.51-0.99, P = 0.04; I(2) = 0%), whereas in PIK3CA wild-type disease (n = 4001), aspirin use did not reduce overall mortality (summary risk estimate = 0.93; 95% confidence interval 0.61-1.40; P = 0.7; I(2) = 80%) (P interaction = 0.39). There was a beneficial trend for aspirin on cancer-specific survival in PI3KCA mutated subjects (summary risk estimate = 0.37, 95% confidence interval 0.11-1.32, P = 0.1), albeit with high heterogeneity (Q chi-squared = 3.41, P = 0.07, I(2) = 70.7%).
  
  
  CONCLUSIONS
  These findings suggest that the benefit of post-diagnosis aspirin treatment on overall mortality in colorectal cancer may be more marked in PIK3CA mutated tumours, although the low number of studies prevents definitive conclusions. Trials addressing this issue are warranted to assess the efficacy of aspirin in the adjuvant setting.
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy; Public Health Agency, Liguria Region, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Paleari
authors.affiliation: Office of the Scientific Director, E.O. Ospedali Galliera, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Puntoni
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Clavarezza
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: DeCensi
authors.affiliation: Wolfson Institute of Preventive Medicine, Queen Mary University of London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Cuzick
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy; Wolfson Institute of Preventive Medicine, Queen Mary University of London, UK; Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy. Electronic address: andrea.decensi@galliera.it.
authors.forename: A
authors.initials: A
authors.lastname: DeCensi
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D016021:Epidemiologic Studies; D006801:Humans; D009154:Mutation / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D001241:Aspirin
keywords: Adjuvant trials; PIK3CA; aspirin; colorectal cancer; overall survival; post-diagnosis use