Use of EGF a+61G and TS-5'UTR 2R/3R polymorphisms to predict complete pathologic response in locally advanced rectal cancer patients undergoing preoperative cetuximab-based chemoradiation followed by surgery.

Abstract

3641 Background: Cetuximab has demonstrated significant clinical activity in metastatic colon cancer, however, cetuximab-containing neoajuvant chemoradiation has not been shown to improve local control or survival in locally advanced rectal cancer patients based upon recent phase II trials. In order to identify the subgroup of patients who may benefit from the cetuximab protocol, we evaluated functional germline polymorphisms of genes involved in critical pathways of cancer progression i.e., tumor growth (COX-2, EGF, EGFR, Kras), cell cycle regulation (CyclinD1), angiogenesis (VEGF, IL-8), ADCC (FCGR2A/3A), DNA repair (XRCC3, Rad51), and drug metabolism (TS, MTHFR), for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation followed by surgery. 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 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 performed 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 0-III vs grade IV: complete response). Results: Germline polymorphisms of EGF and TS were predictive for histopathologic response: 63 patients with EGF +61 G allele (AG + GG) had a 25% rate of pCR whereas the 50 patients with AA genotype had only a 2% rate of pCR (p < 0.001). In addition, the pCR rate of 69 patients with any 2R repeats in the TS 5'UTR (2R/2R + 2R/3R) was 20% while it was 0% in the 23 patients with the 3R/3R genotype (p = 0.006). Conclusions: This study suggests EGF A+61G and TS 5'UTR 2R/3R polymorphisms to be predictive markers for complete pathologic response to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, ImClone Systems, Merck Bristol-Myers Squibb, ImClone Systems, Merck, Merck Serono, Roche, sanofi-aventis Merck, Roche, sanofi-aventis