Abstract 4672: Tumor dihydropyrimide dehydrogenase (DPYD) expression is associated with survival in patients with metastatic colorectal cancer treated with gefitinib, 5-fluorouracil, leucovorin, and oxaliplatin (IFOX)

Abstract

Abstract New drugs that target the EGFR signaling pathways suggest that EGFR inhibition exerts a chemosensitizing effect in colorectal cancer. We have previously reported that the combination of gefitinib, leucovorin, 5-flourouracil, and oxaliplatin (IFOX) resulted in higher response rates than those reported with FOLFOX-4 alone in patients with metastatic colorectal cancer. The aim of the present study was to examine genomic factors that might be associated with response or survival in the IFOX regimen. Patients and Methods: Seventy-two patients had stage IV colorectal adenocarcinoma and were either untreated or previously treated prior to receiving the IFOX regimen. Formalin-fixed, paraffin-embedded tissues (FFPE; n=63) were obtained, and 4-um sections were cut, placed on slides, and deparaffinized in xylene, followed by laser capture microdissection (LCM; n=42) to enrich for tumor cells. Using real-time quantitative RT-PCR, thirty-five samples had good-quality actin RNA readings following LCM, and the expression levels of dihydropyrimidine dehydrogenase (DPYD), epidermal growth factor receptor (EGFR), excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), thymidylate synthase (TYMS), and thymidine phosphorylase (TYMP) were separately quantified. To detect mutations in KRAS, DNA was extracted from fifty-eight patient samples and analyzed using the KRAS Mutector II kit (TrimGen, Sparks, MD). Results: For the 33 patients available for RT-PCR analysis, expression levels of DPYD, EGFR, ERCC1, TYMP, or TYMS did not correlate significantly with response. However, in terms of survival, the overall survival rate was significantly worse in patients with a high DPYD expression level compared to patients with a low DPYD expression level (p<0.05), and in a multivariate analysis, patients with both a high DPYD expression and a low EGFR expression had the worst survival compared to all other patients with differing expression levels of these two genes (p<0.01). KRAS mutations were identified in 24 out of 58 patients (41%), but KRAS mutational status did not correlate with either response or survival. Conclusion: Dihydropyrimidine dehydrogenase mRNA expression was a significant independent prognostic factor for overall survival in colorectal cancer patients treated with FOLFOX-4 along with EGFR inhibition by gefitinib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4672.