Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada clinical trials group study BR.21

Chang Qi Zhu, Gilda Da Cunha Santos, Keyue Ding, Akira Sakurada, Jean Claude Cutz, Ni Liu, Tong Zhang, Paula Marrano, Mario Whitehead, Jeremy A. Squire, Suzanne Kamel-Reid, Lesley Seymour, Frances A. Shepherd, Ming Sound Tsao

Research output: Contribution to journalArticlepeer-review

625 Citations (Scopus)

Abstract

Purpose: To evaluate the effect of KRAS and epidermal growth factor receptor (EGFR) genotype on the response to erlotinib treatment In the BR.21, placebo-controlled trial. Patients and Methods:We analyzed 206 tumors for KRAS mutation, 204 tumors for EGFR mutation, and 159 tumors for EGFR gene copy by fluorescent in situ hybridization (FISH). We reanalyzed EGFR deletion/ mutation using two highly sensitive techniques that detect abnormalities in samples with 5% to 10% tumor cellularity. KRAS mutation was analyzed by direct sequencing. Results:Thirty patients (15%) had KRAS mutations, 34 (17%) had EGFR exon 19 deletion or exon 21 L858R mutations, and 61 (38%) had high EGFR gene copy (FISH positive). Response rates were 10% for wild-type and 5% for mutant KRAS (P = .69), 7% for wild-type and 27% for mutant EGFR (P = .03), and 5% for EGFR FISH-negative and 21% for FISH-positive patients (P = .02). Significant survival benefit from erlotinib therapy was observed for patients with wild-type KRAS (hazard ratio [HR] = 0.69, P = .03) and EGFR FISH positivity (HR = 0.43, P = .004) but not for patients with mutant KRAS (HR = 1.67, P = .31), wild-type EGFR (HR = 0.74, P = .09), mutant EGFR (HR = 0.55, P = .12), and EGFR FISH negativity (HR = 0.80, P = .35). In multivariate analysis, only EGFR FISH-positive status was prognostic for poorer survival (P = .025) and predictive of differential survival benefit from erlotinib (P = .005). Conclusion:EGFR mutations and high copy number are predictive of response to erlotinib. EGFR FISH is the strongest prognostic marker and a significant predictive marker of differential survival benefit from erlotinib.

Original languageEnglish
Pages (from-to)4268-4275
Number of pages8
JournalJournal of Clinical Oncology
Volume26
Issue number26
DOIs
Publication statusPublished - 2008 Sep 10
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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