Our preliminary data suggest that these two polymorphisms may be useful molecular markers to predict clinical outcome in metastatic CRC patients treated with cetuximab and that they may indicate a role of ADCC of cetuximab.

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40 mg m À2 b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80 mg m À2 depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70 mg m À2 , because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60 mg m À2. In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1 -8). The incidences of severe (grades 3 -4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9À90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.

Chromoendoscopy with magnification is the most reliable method for determining whether a colorectal lesion is non-neoplastic or neoplastic.

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High expression variants of VEGF C+936T and IL-8 T-251A were associated with shorter time to tumor recurrence, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.

Purpose: Recently, an objective response rate of 12% was reported in a phase II study of cetuximab in patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer (mCRC) refractory to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy (IMC-0144). In this large molecular correlates study, we tested whether K-ras mutation status and polymorphisms in genes involved in the EGFR-signaling pathway were associated with clinical outcome in IMC-0144. Experimental Design: We analyzed all available tissue samples from 130 of 346 mCRC patients enrolled in the IMC-0144 phase II clinical trial of cetuximab. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissues, and K-ras mutation status and the genotypes were analyzed using PCR-RFLP, direct DNA-sequencing, and 5 ¶-end [g-33 P] ATP^labeled PCR-protocols. Results:The PFS of patients with cyclooxygenase-2 (COX-2) -765 G>C [C/C; risk ratio (RR), 0.31; 95% confidence interval (95% CI), 0.12-0.84; P = 0.032], COX-2 +8473 T>C (C/C; RR, 0.67; 95% CI, 0.40-1.13; P = 0.003), EGF +61A>G (G/G; RR, 0.57; 95% CI, 0.34-0.95; P = 0.042), and EGFR +497 G>A (A/G; RR, 0.82; 95% CI, 0.56-1.20; P = 0.017) genotypes was significantly longer compared with those with other genotypes. In addition, patients whose tumors did not have K-ras mutations showed better RR, PFS, and overall survival than patients with K-ras mutations. In multivariable analysis, COX-2 +8473 T>C (adjusted P = 0.013) and EGFR +497 G>A (adjusted P = 0.010) remained significantly associated with progression-free survival, independent of skin rash toxicity, K-ras mutation status, and Eastern Cooperative Group performance status. Conclusions: Polymorphisms in COX-2 and EGFR may be useful independent molecular markers to predict clinical outcome in patients with mCRC treated with single-agent cetuximab, independent of skin rash toxicity, K-ras mutation, and Eastern Cooperative Oncology Group performance status.

Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.