BACKGROUND: Cetuximab has shown significant clinical activity in metastatic 
colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not 
been shown to improve tumor response in locally advanced rectal cancer patients 
in recent phase I/II trials. We evaluated functional germline polymorphisms of 
genes involved in epidermal growth factor receptor pathway, angiogenesis, 
antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, 
for their potential role as molecular predictors for clinical outcome in locally 
advanced rectal cancer patients treated with preoperative cetuximab-based 
chemoradiation.
METHODS: 130 patients (74 men and 56 women) with locally advanced rectal cancer 
(4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were 
enrolled in phase I/II clinical trials treated with cetuximab-based 
chemoradiation in European cancer centers were included. Genomic DNA was 
extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was 
done by using PCR-RFLP assays. Fisher's exact test was used to examine 
associations between polymorphisms and complete pathologic response (pCR) that 
was determined by a modified Dworak classification system (grade III vs. grade 
IV: complete response).
RESULTS: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR 
of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) 
in patients homozygous for the A/A allele (P < 0.001). In addition, this 
association between EGF 61 G allele and pCR remained significant (P = 0.019) in 
the 59 patients with wild-type KRAS.
CONCLUSION: This study suggested EGF A+61G polymorphism to be a predictive 
marker for pCR, independent of KRAS mutation status, to cetuximab-based 
neoadjuvant chemoradiation of patients with locally advanced rectal cancer.