EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients

Siwen Hu-Lieskovan, Daniel Vallbohmer, Wu Zhang, Dongyun Yang, Alexander Pohl, Melissa J Labonte, Peter P Grimminger, Arnulf H Hölscher, Robert Semrau, Dirk Arnold, Kathrin Dellas, Annelies Debucquoy, Karin Haustermans, Jean-Pascal H Machiels, Christine Sempoux, Claus Rödel, Matej Bracko, Vaneja Velenik, Heinz-Josef Lenz, Melissa LaBonte Wilson

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Abstract

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.

Original languageEnglish
Pages (from-to)5161-9
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number15
DOIs
Publication statusPublished - 01 Aug 2011

Bibliographical note

©2011 AACR.

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols
  • Combined Modality Therapy
  • Epidermal Growth Factor
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Neoadjuvant Therapy
  • Polymorphism, Genetic
  • Proto-Oncogene Proteins
  • Rectal Neoplasms
  • ras Proteins

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    Hu-Lieskovan, S., Vallbohmer, D., Zhang, W., Yang, D., Pohl, A., Labonte, M. J., Grimminger, P. P., Hölscher, A. H., Semrau, R., Arnold, D., Dellas, K., Debucquoy, A., Haustermans, K., Machiels, J-P. H., Sempoux, C., Rödel, C., Bracko, M., Velenik, V., Lenz, H-J., & LaBonte Wilson, M. (2011). EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients. Clinical Cancer Research, 17(15), 5161-9. https://doi.org/10.1158/1078-0432.CCR-10-2666