title: EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90089, USA.
authors.forename: Siwen
authors.initials: S
authors.lastname: Hu-Lieskovan
authors.forename: Daniel
authors.initials: D
authors.lastname: Vallbohmer
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Alexander
authors.initials: A
authors.lastname: Pohl
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Labonte
authors.forename: Peter P
authors.initials: PP
authors.lastname: Grimminger
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hölscher
authors.forename: Robert
authors.initials: R
authors.lastname: Semrau
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.forename: Kathrin
authors.initials: K
authors.lastname: Dellas
authors.forename: Annelies
authors.initials: A
authors.lastname: Debucquoy
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.forename: Jean-Pascal H
authors.initials: JP
authors.lastname: Machiels
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
authors.forename: Matej
authors.initials: M
authors.lastname: Bracko
authors.forename: Vaneja
authors.initials: V
authors.lastname: Velenik
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068818:Cetuximab; D003131:Combined Modality Therapy; D004815:Epidermal Growth Factor / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D011110:Polymorphism, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000532:radiotherapy; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab