title: Biomarkers for cetuximab-based neoadjuvant radiochemotherapy in locally advanced rectal cancer.
abstract: OBJECTIVE
  Phase II trials in locally advanced rectal cancer have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without an improvement in complete pathologic response rates. Our goal was to identify patients who would benefit from cetuximab-based neoadjuvant chemoradiation measuring gene expression levels of proteins involved in tumor growth [endothelial growth factor receptor (EGFR)], angiogenesis [VEGF, VEGF receptors 1 and 2 (VEGFR1, VEGFR2)], DNA repair [excision repair cross-complementing 1 (ERCC1)], and drug metabolism [thymidylate synthetase (TS)]. We also determined mutation status of KRAS and BRAF.
  
  
  METHODS
  This study was carried out on 130 patients with locally advanced rectal cancer who were enrolled in 4 different phase II clinical trials, using cetuximab-based chemoradiation. Tumor tissues were obtained before neoadjuvant and at surgical therapy. After microdissection, intratumoral gene expression levels and KRAS/BRAF mutation status were analyzed.
  
  
  RESULTS
  A significant decrease of TS, VEGFR1, and VEGFR2 gene expression was seen following neoadjuvant therapy (P < 0.03). High pretreatment VEGF gene expression levels were associated with nonresponse (P = 0.070). KRAS mutations were found in 42% and mutant KRAS (KRAS mt) was significantly associated with pathologic nonresponse (P = 0.037). In patients with wild-type KRAS (KRAS wt), low EGFR was significantly associated with higher nonresponse and VEGF mRNA expressions were associated with complete pathologic response (P = 0.012; P = 0.06). KRAS transversion (KRAS tv) was associated with tumor regression: nonresponse was more common in patients with KRAS tv than with KRAS wt (P = 0.007). BRAF V600E mutations were not detected in any of the patients.
  
  
  CONCLUSIONS
  This study suggests that pretreatment intratumoral EGFR and VEGF mRNA expression levels as well as KRAS mutation status are predictive markers of pathologic response to neoadjuvant cetuximab-based chemoradiation in locally advanced rectal cancer.
authors.affiliation: Department of General, Visceral and Cancer Surgery , University of Cologne, Cologne, Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Grimminger
authors.forename: Peter
authors.initials: P
authors.lastname: Danenberg
authors.forename: Kathrin
authors.initials: K
authors.lastname: Dellas
authors.forename: Dirk
authors.initials: D
authors.lastname: Arnold
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.forename: Annelies
authors.initials: A
authors.lastname: Debucquoy
authors.forename: Vaneja
authors.initials: V
authors.lastname: Velenik
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Matej
authors.initials: M
authors.lastname: Bracko
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Hölscher
authors.forename: Robert
authors.initials: R
authors.lastname: Semrau
authors.forename: Dongyun
authors.initials: D
authors.lastname: Yang
authors.forename: Kathleen
authors.initials: K
authors.lastname: Danenberg
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Daniel
authors.initials: D
authors.lastname: Vallböhmer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D000068818:Cetuximab; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D012189:Retrospective Studies
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D000068818:Cetuximab