Association of Cyclin D1 (CCND1) gene A870G polymorphism and clinical outcome of EGFR-positive metastatic colorectal cancer patients treated with epidermal growth factor receptor (EGFR) inhibitor cetuximab (C225)

Abstract

3518 Background Cetuximab (C225) is a chimeric anti-EGFR monoclonal antibody with efficacy against EGFR-positive metastatic colorectal cancer. Recently, the link between EGFR signaling and the cell cycle has been identified. In vitro studies show blockade of EGFR by C225 can induce cell cycle arrest in the G1 phase which mediated by inhibition of interactions between cyclins and CDKs and increases expression of the cell cycle inhibitor p27KIP1. A frequent A870G polymorphism in the final codon of exon 4 of the Cyclin D1, leads gene alternatively spliced to produce two different mRNA transcripts [a] and [b] was also identified. In vivo studies have indicated this polymorphism can affect the prognosis of patients with different types of solid tumors. We hypothesized that CCND1 A870G polymorphism will predict clinical outcome in EGFR-positive metastatic colorectal cancer patients treated with EGFR inhibitor Cetuximab(C225). Methods Cyclin D1 A870G gene polymorphism was tested using PCR-RFLP method in genomic DNA extracted from peripheral blood from 39 metastatic colorectal cancer patients enrolled in a phase II EGFR inhibitor Cetuximab(C225) clinical trial. ResultsWe found a significant association between A870G polymorphism and overall survival of patients treated with Cetuximab(C225). With median follow-up 8.7 months (range 2.5, 11.7) and median survival time 4.8 months (95%C.I 2.7, 8.5), Patients with AA homozygous genotype survived a median time of 2.3 months (95%C.I 2.1, 5.7) compared with those have homozygous GG genotype 4.4 months (95%C.I 1.8, 9.8+) or heterozygous AG genotype 8.5 months(95%C.I 5.5, 11.7+), respectively (p<0.05, logrank test). ConclusionsThese data suggest that Cyclin D1 A870G polymorphism may be a potential prognostic molecular marker for clinical outcome of the EGFR-positive metastatic colorectal caner patients treated with third line EGFR inhibitor Cetuximab (C225). Prospective studies are needed to confirm these preliminary findings. 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