EGF61 Polymorphism Predicts Complete Pathologic Response to Cetuximab-Based Chemoradiation Independent of KRAS Status in Locally Advanced Rectal Cancer Patients

Abstract

Background Cetuximab has demonstrated 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 EGFR pathway, angiogenesis, ADCC, 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 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 Patients with the 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. Conclusions This study suggests 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.

DNA Repair Gene Polymorphisms Do Not Predict Response to Radiotherapy-Based Multimodality Treatment of Patients with Rectal Cancer: a Meta-analysis

“…Peter etal found that no significant associations were detected between rs861539 and the response in rectal cancer patients treated with neoadjuvant chemoradiation (Grimminger et al, 2010). Other studies have found no data are available up to date on the effect of rs861539 on tumor response to radiation (Hu-Lieskovan et al, 2011). Meta-analysis found that rs861539 is not association with rectal cancer with radiation therapy.…”

Association of EGF and p53 gene polymorphisms and colorectal cancer risk in the Slovak population

“…The possible explanation of these results is the different effect of increased EGF activity in different stages of cancer development and possibility of EGFinducing apoptosis or increase of cancer susceptibility to treatment. In this respect, recent studies showing the complete pathological response of advanced rectal cancer patients treated with cetuximab-based neoadjuvant chemoradiation were strongly associated with EGF G allele suggesting possible enhanced inhibition of EGFR pathway or increased sensitivity to radiation therapy [62]. The protective role of EGF 61G allele may suggest also possible influence of the 61A allele that might be masked by the presence of other as-yet unidentified causal genes involved in CRC development.…”

Intergenic polymorphisms in the amphiregulin gene region as biomarkers in metastatic colorectal cancer patients treated with anti-EGFR plus irinotecan

“…13 This SNP has been associated with the outcome in mCRC patients treated with cetuximab-based therapy. 14,15 Although EGF is the natural ligand of EGFR, other members of the EGF family, such as amphiregulin (AREG) and epiregulin (EREG), can bind to this receptor. 16 The study of these ligands as biological markers has evolved around expression studies measured by immunohistochemical staining and mRNA levels.…”