Polymorphisms in cyclooxygenase-2 and epidermal growth factor receptor are associated with progression-free survival independent of K-ras in metastatic colorectal cancer patients treated with single-agent cetuximab

Georg Lurje, Fumio Nagashima, Wu Zhang, Dongyun Yang, Heung M Chang, Michael A Gordon, Anthony El-Khoueiry, Hatim Husain, Peter M Wilson, Robert D Ladner, David J Mauro, Christiane Langer, Eric K Rowinsky, Heinz-Josef Lenz

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)

Abstract

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 [gamma-33P] 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 +61 A>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.

Original languageEnglish
Pages (from-to)7884-95
Number of pages12
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
Publication statusPublished - 01 Dec 2008

Keywords

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Cetuximab
  • Clinical Trials, Phase II as Topic
  • Colorectal Neoplasms
  • Cyclooxygenase 2
  • Disease-Free Survival
  • Epidermal Growth Factor
  • Genes, ras
  • Humans
  • Kaplan-Meier Estimate
  • Multicenter Studies as Topic
  • Mutation
  • Polymorphism, Restriction Fragment Length
  • Receptor, Epidermal Growth Factor
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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