Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial

Abstract

Objective Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities. Methods Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2 ≥ 0.90, MAF ≥ 4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology. Results Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66–26.36, P < 0.01) to 10.71 (95% confidence interval 1.96–58.60, P < 0.01). Conclusion Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.

Hierarchical investigating the predictive value of p53, COX2, EGFR, nm23 in the post-operative patients with colorectal carcinoma

“…Colorectal carcinoma (CRC) is one of the most common malignant tumors worldwide [ 1 – 3 ], and it is also the third most common malignant disease in Asia [ 4 ]. Previous studies have shown that various biomarkers, such as p53, COX2, EGFR and nm23, were involved in multiple stages of tumor development [ 4 – 15 ]. These biomarkers, most of which are oncogenes and tumor suppressors, play a crucial role in carcinoma formation [ 3 , 15 , 16 ].…”

Celecoxib for the Right Person at the Right Dose and Right Time: An Updated Overview

“…In fact, two PTGS1 SNPs (rs10303135 and rs12353214) were significantly associated with acute coronary syndrome in patients taking celecoxib as found by St Germaine et al [29]. Kraus et al [20] found two variants of the prostaglandin E2 synthase gene (rs2241271 and rs2302821), one in the C-reactive protein gene (rs1800947) and three in the epidermal growth factor receptor signaling gene (rs6017996, rs6018256, and rs6018257), to be associated with celecoxib cardiovascular side effect. Moreover, CYP2C9*2 and CYP2C9*3 genotypes carriers have higher risk of cardiovascular adverse events with 400 mg celecoxib twice daily as compared to the wild carriers (RR 2.76; 95 % CI 1.08-7.06) as stated by Chan et al [8].…”

Genetic variation in UGT genes modify the associations of NSAIDs with risk of colorectal cancer: Colon cancer family registry

“…Colorectal cancer is a heterogeneous disease and targeted prevention strategies are required to reduce the public health burden of the disease (Colussi et al, ). In light of extensive data on the preventive effects of aspirin and other NSAIDs on risk of cancer, there is growing interest in determining whether genetic variation in NSAID‐metabolizing enzymes can be used to predict the protective effect of NSAIDs on cancer development and on complications such as gastrointestinal bleedings (Derry and Loke, ; Ulrich et al, ; Cross et al, ; Cuzick et al, ; Chia et al, ; Kraus et al, ; Rothwell et al, , b, 2013). Since metabolizing enzymes can modify, conjugate, and/or excrete endobiotic or xenobiotic compounds, including the detoxification of carcinogens and metabolism of chemopreventive or chemotherapeutic compounds, genetic variability in these enzymes may thus alter the toxicity or efficacy of xenobiotics and consequently alter cancer susceptibility.…”