Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer.
OBJECTIVE
To characterize the molecular pathways activated or inhibited by cetuximab when combined with chemoradiotherapy (CRT) in rectal cancer and to identify molecular profiles and biomarkers that might improve patient selection for such treatments.


METHODS
Forty-one patients with rectal cancer (T3-4 and/or N+) received preoperative radiotherapy (1.8 Gy, 5 days/wk, 45 Gy) in combination with capecitabine and cetuximab (400 mg/m2 as initial dose 1 week before CRT followed by 250 mg/m2 /wk for 5 weeks). Biopsies and plasma samples were taken before treatment, after cetuximab but before CRT, and at the time of surgery. Proteomics and microarrays were used to monitor the molecular response to cetuximab and to identify profiles and biomarkers to predict treatment efficacy.


RESULTS
Cetuximab on its own downregulated genes involved in proliferation and invasion and upregulated inflammatory gene expression, with 16 genes being significantly influenced in microarray analysis. The decrease in proliferation was confirmed by immunohistochemistry for Ki67 (P = .01) and was accompanied by an increase in transforming growth factor-alpha in plasma samples (P < .001). Disease-free survival (DFS) was better in patients if epidermal growth factor receptor expression was upregulated in the tumor after the initial cetuximab dose (P = .02) and when fibro-inflammatory changes were present in the surgical specimen (P = .03). Microarray and proteomic profiles were predictive of DFS.


CONCLUSIONS
Our study showed that a single dose of cetuximab has a significant impact on the expression of genes involved in tumor proliferation and inflammation. We identified potential biomarkers that might predict response to cetuximab-based CRT.
Debucquoy
Annelies
A
Lab of Experimental Radiotherapy, Department of Radiation Oncology, CDG Building, Box 815, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. annelies.debucquoy@med.kuleuven.be
Haustermans
Karin
K
Daemen
Anneleen
A
Aydin
Selda
S
Libbrecht
Louis
L
Gevaert
Olivier
O
De Moor
Bart
B
Tejpar
Sabine
S
McBride
William H
WH
Penninckx
Freddy
F
Scalliet
Pierre
P
Stroh
Christopher
C
Vlassak
Soetkin
S
Sempoux
Christine
C
Machiels
Jean-Pascal
JP