Polymorphisms in IL-8 and the GSTP1 are associated with survival of metastatic colorectal cancer patients treated with CPT-11

Abstract

3606 Background Irinotecan (CPT-11), an analogue of Camptothecins, demonstrates a broad spectrum of antitumor activity. Currently, there are no prognostic molecular markers for CPT-11 efficacy. Therefore, we investigated associations between polymorphisms in genes involved in CPT-11 metabolism (UGT1A1), chemoresistance (GSTP1), DNA repair (XPD, ERCC1, XRCC1, Werner 1074, and Werner 1367), and angiogenesis (IL-8 and COX-2) and survival of patients with metastatic colorectal cancer receiving CPT-11 based chemotherapy. In vivo studies show GSTP1 to detoxify chemotherapeutic agents by glutathione conjugation. In vivo and in vitro studies show IL-8 to possess angiogenic properties and its overexpression is associated with metastasis potential in colorectal cancer. Positional cloning studies identified Werner as the gene responsible for Werner Syndrome (WS), and cells from these patients have been shown to be particularly sensitive to Camptothecin. Methods The gene polymorphisms were tested using PCR-RFLP method on genomic DNA extracted from peripheral blood from metastatic colorectal cancer patients treated with CPT-11. Results 55 patients were collected; 31 males and 24 females; median age 55 (range 34–77) years. The response to CPT-11 was 40% (18/45, 1 pt was inevaluable, and 9 pts are still receiving treatment and were too early to be evaluated), with median survival of 22.9 (95% CI: 18.4, 29.3) months. The median time of follow-up and range was 15.4 (4.7–26.1) months. Individually, IL-8 and GSTP1 showed trends for overall survival (log rank p=0.07 and p=0.077, respectively). A combined analysis of these two genes showed patients carrying two favorable genotypes (homozygous Ile for GSTP1 and T allele for IL-8) had longer survival when compared with those patients carrying no favorable genotypes or only 1 favorable genotype (p=0.005). The Werner Loci polymorphisms also showed a trend for overall survival. Conclusion These data suggest that IL-8, GSTP1, and the Werner Loci polymorphisms may be potential prognostic molecular markers for clinical outcome of metastatic colorectal cancer patients treated with a CPT-11 regimen. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron NCI; NIH; Roche; Lilly; Pharmacia; Bayer; Bristol-Myers Squibb; Chiron; Aventis; Genentech; ImClone; Cellpathway; Newbiotics; Sanofi