Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Zhu
Chang-Qi
CQ
FRCPC, Princess Margaret Hospital, 610 University Ave, Toronto, Ontario, Canada M5G 2M9; Ming.Tsao@uhn.on.ca.
da Cunha Santos
Gilda
G
Ding
Keyue
K
Sakurada
Akira
A
Cutz
Jean-Claude
JC
Liu
Ni
N
Zhang
Tong
T
Marrano
Paula
P
Whitehead
Marlo
M
Squire
Jeremy A
JA
Kamel-Reid
Suzanne
S
Seymour
Lesley
L
Shepherd
Frances A
FA
Tsao
Ming-Sound
MS
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002170:Canada; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D000069347:Erlotinib Hydrochloride; D005260:Female; D018773:Genes, erbB-1 / Q000235:genetics*; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins