Etienne-Grimaldi MC et al. K-Ras mutations and treatment outcome in colorectal cancer patients receiving exclusive fluoropyrimidine therapy. Clin Cancer Res 14: 4830–4835

The treatment of choice for advanced colorectal cancer is 5-fluorouracil, but combinations of anti-EGFR therapies with fluoropyrimidine chemotherapy have shown promise. Since KRAS mutations strongly predict resistance to antibodies that target the EGFR, Etienne-Grimaldi et al. carried out a study to investigate whether KRAS mutations influence treatment outcome in patients with stage IV colorectal cancer who received 5-fluorouracil treatment.

These authors previously reported that mutations in KRAS and p53 were not associated with outcome in 56 patients treated with 5-fluorouracil. Their current study included 93 patients with stage IV colorectal cancer and unresectable liver metastases, who were treated with 5-fluorouracil and leucovorin. Tumor samples were assessed for mutations in codons 12 and 13 of KRAS, polymorphisms in codon 72 of p53, and additional tumor variables.

KRAS mutations in codons 12 and 13 were present in 36 of 93 metastases. Perfect concordance of KRAS mutations between primary tumor and liver metastases was observed in 16 of 48 samples with such mutations. The presence of KRAS mutations was not significantly associated with levels of p53, thymidylate synthase, folypolyglutamate synthetase, or dihydropyrimidine activity. The response rate in patients with mutated KRAS metastases was 44.4%, compared with 32.1% in those with wild-type metastases. KRAS status had no influence on survival.

The authors conclude that KRAS mutational status only predicts response to the anti-EGFR element of combination therapies; tumors with KRAS mutations can still respond to 5-fluorouracil-based therapy.