ORCID Profile
0000-0001-7811-6722
Current Organisations
Oxford University Hospitals NHS Trust
,
University Of Strathclyde
,
University of Oxford
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Publications
Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2013
Abstract: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin. We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status. We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2 95% CI, 0.53 to 2.72 P = .66 P INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87 95% CI, 0.64 to 1.16 P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11 95% CI, 0.001 to 0.832 P = .027 P INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92 95% CI, 0.60 to 1.42 P = .71). Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.
Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
Publisher: Springer Science and Business Media LLC
Date: 13-02-2023
Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis
Publisher: Elsevier BV
Date: 10-2017
Genome‐wide association study and meta‐analysis in Northern European populations replicate multiple colorectal cancer risk loci
Publisher: Wiley
Date: 12-10-2017
DOI: 10.1002/IJC.31076
Variation at 2q35 (PNKDandTMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease
Publisher: Oxford University Press (OUP)
Date: 22-03-2016
DOI: 10.1093/HMG/DDW087
Use of multivariate analysis to suggest a new molecular classification of colorectal cancer
Publisher: Wiley
Date: 25-01-2013
DOI: 10.1002/PATH.4139
Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer
Publisher: Springer Science and Business Media LLC
Date: 23-06-2016
DOI: 10.1038/BJC.2016.188
The TERT variant rs2736100 is associated with colorectal cancer risk
Publisher: Springer Science and Business Media LLC
Date: 09-08-2012
DOI: 10.1038/BJC.2012.329
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
Publisher: Springer Science and Business Media LLC
Date: 20-12-2022
Survival in stage II/III colorectal cancer is independently predicted by chromosomal and microsatellite instability, but not by specific driver mutations
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2013
DOI: 10.1038/AJG.2013.292
Abstract: Microsatellite instability (MSI) is an established marker of good prognosis in colorectal cancer (CRC). Chromosomal instability (CIN) is strongly negatively associated with MSI and has been shown to be a marker of poor prognosis in a small number of studies. However, a substantial group of "double-negative" (MSI-/CIN-) CRCs exists. The prognosis of these patients is unclear. Furthermore, MSI and CIN are each associated with specific molecular changes, such as mutations in KRAS and BRAF, that have been associated with prognosis. It is not known which of MSI, CIN, and the specific gene mutations are primary predictors of survival. We evaluated the prognostic value (disease-free survival, DFS) of CIN, MSI, mutations in KRAS, NRAS, BRAF, PIK3CA, FBXW7, and TP53, and chromosome 18q loss-of-heterozygosity (LOH) in 822 patients from the VICTOR trial of stage II/III CRC. We followed up promising associations in an Australian community-based cohort (N=375). In the VICTOR patients, no specific mutation was associated with DFS, but in idually MSI and CIN showed significant associations after adjusting for stage, age, gender, tumor location, and therapy. A combined analysis of the VICTOR and community-based cohorts showed that MSI and CIN were independent predictors of DFS (for MSI, hazard ratio (HR)=0.58, 95% confidence interval (CI) 0.36-0.93, and P=0.021 for CIN, HR=1.54, 95% CI 1.14-2.08, and P=0.005), and joint CIN/MSI testing significantly improved the prognostic prediction of MSI alone (P=0.028). Higher levels of CIN were monotonically associated with progressively poorer DFS, and a semi-quantitative measure of CIN was a better predictor of outcome than a simple CIN+/- variable. All measures of CIN predicted DFS better than the recently described Watanabe LOH ratio. MSI and CIN are independent predictors of DFS for stage II/III CRC. Prognostic molecular tests for CRC relapse should currently use MSI and a quantitative measure of CIN rather than specific gene mutations.
Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial
Publisher: Elsevier BV
Date: 11-2016
Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer
Publisher: Wiley
Date: 06-04-2017
DOI: 10.1002/IJC.30709
Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2503
Related Organisations
Oxford University Hospitals NHS Trust
Location: United Kingdom of Great Britain and Northern Ireland
Queen Elizabeth Hospital Birmingham
Location: United Kingdom of Great Britain and Northern Ireland
University Of Glasgow
Location: United Kingdom of Great Britain and Northern Ireland
University Of Birmingham
Location: United Kingdom of Great Britain and Northern Ireland
University Of Strathclyde
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for David Kerr.