Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab.
OBJECTIVE
The antiepidermal growth factor receptor (EGFR) antibody cetuximab shows activity in multiple epithelial tumor types; however, responses are seen in only a subset of patients. This study was conducted to identify markers that are associated with disease control in patients treated with cetuximab.


METHODS
One hundred ten patients with metastatic colorectal cancer were enrolled onto a cetuximab monotherapy trial. Transcriptional profiling was conducted on RNA from mandatory pretreatment metastatic biopsies to identify genes whose expression correlates with best clinical responses. EGFR and K-ras mutation analyses and EGFR gene copy number analyses were performed on DNA from pretreatment biopsies.


RESULTS
Gene expression profiles showed that patients with tumors that express high levels of the EGFR ligands epiregulin and amphiregulin are more likely to have disease control with cetuximab (EREG, P = .000015; AREG, P = .000025). Additionally, patients whose tumors do not have K-ras mutations have a significantly higher disease control rate than patients with K-ras mutations (P = .0003). Furthermore, patients with tumors that have high expression of EREG or AREG also have significantly longer progression-free survival (PFS) than patients with low expression (EREG: P = .0002, hazard ratio [HR] = 0.47, and median PFS, 103.5 v 57 days, respectively; AREG: P < .0001, HR = 0.44, and median PFS, 115.5 v 57 days, respectively).


CONCLUSIONS
Patients with tumors that have high gene expression levels of epiregulin and amphiregulin and patients with wild-type K-ras are more likely to have disease control on cetuximab treatment. The identified markers could be developed further to select patients for cetuximab therapy.
Khambata-Ford
Shirin
S
Bristol-Myers Squibb Co, Princeton, NJ 08543, USA. shirin.ford@bms.com
Garrett
Christopher R
CR
Meropol
Neal J
NJ
Basik
Mark
M
Harbison
Christopher T
CT
Wu
Shujian
S
Wong
Tai W
TW
Huang
Xin
X
Takimoto
Chris H
CH
Godwin
Andrew K
AK
Tan
Benjamin R
BR
Krishnamurthi
Smitha S
SS
Burris
Howard A
HA
Poplin
Elizabeth A
EA
Hidalgo
Manuel
M
Baselga
Jose
J
Clark
Edwin A
EA
Mauro
David J
DJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D066255:EGF Family of Proteins; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D015996:Survival Rate; D016896:Treatment Outcome
C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000068818:Cetuximab