Abstract 1004: Impact of genetic polymorphisms on colorectal adenoma recurrence and toxicity in a COX-2 inhibitor trial (Celecoxib): Results from a pilot study

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Chemoprevention trials have shown that Celecoxib, a selective COX-2 inhibitor can reduce adenoma recurrence but can also increase risk of cardiac toxicity. Therefore, in this pilot study, we evaluated the associations between genetic variation in several candidate pathways (e.g. prostaglandin, arachidonic acid and leukotriene synthesis), the incidence of adenoma recurrence as well as toxicity (any, gastrointestinal, cardiac, and non-gastrointestinal/non-cardiac toxicities). Methods: This analysis includes 119 Israeli patients with colorectal adenoma who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trial. Reassessment followed after ∼3 years on Celecoxib, followed by 2 years off drug. Incidence of colorectal adenomas was measured by colonoscopy at years 1, 3, and 5. The presence of any, gastrointestinal, cardiac and non-gastrointestinal/non-cardiac toxicities was assessed by investigators for the on-treatment period and collected by patient self-report after treatment. A linkage-disequilibrium-based tagSNP selection algorithm (r2≥0.90, MAF≥4%) identified tagSNPs in candidate pathways. Genotyping was performed using IlluminaTM GoldenGate bead-based genotyping technology. Results: Multiple variants were associated with adenoma recurrence and toxicities. Variability, particularly in COX-1 (rs10306164, rs1236913, rs1330344, rs3119773), COX- 2 (rs4648268), and ALOX12 (rs2073438, rs2292350) played a major role in adenoma recurrence risk among patients on placebo compared to patients on Celecoxib. The highest risk was observed for the COX-1 rs3119773 variant (1890 G>A intron 2) (HR=4.65, 95%CI 1.71-12.64, p=0.0026). Variants in COX2 (rs2206593, rs2745557), EGFR (rs1558544, rs17336919), ALOX15 (rs2619112, rs2619118, rs4796535), SRC (rs6018027, rs7269342), SEPP1 (rs230819, rs230820), and WNT6 (rs6747776, rs6754599) genes were associated with any toxicity. In contrast to gastrointestinal toxicity, a larger number of gene variants (especially variants in PGES, CRP, SRC and GPX3) were associated with increased risk of cardiac toxicity. The increased risk of cardiac toxicity associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 7- to 11-fold. Conclusion: Genetic polymorphisms in multiple inflammation-related genes appear to mediate the effect of Celecoxib on adenoma recurrence and the resultant toxicity, particularly cardiac toxicity. Identification of these genetic variants can potentially help in the provision of tailored and optimum care for colorectal adenoma patients. Larger studies validating these pharmacogenetic relationships are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1004. doi:1538-7445.AM2012-1004