title: The use of molecular markers as a method to predict the response to neoadjuvant therapy for advanced stage rectal adenocarcinoma.
abstract: OBJECTIVE
  The response to combined neoadjuvant therapy for advanced stage rectal adenocarcinoma is predictive of outcome. In addition to both clinical and pathological features, the expression of a variety of molecules may provide another method of identifying tumour responsiveness to pre-operative therapy. The aim of this study was to evaluate several markers in the apoptotic pathway as well as expression of Cox-2 and vascular endothelial growth factor (VEGF) to determine their ability to predict response to neoadjuvant therapy.
  
  
  METHODS
  In total, 152 patients with advanced rectal adenocarcinoma were treated with neoadjuvant therapy followed by resection. Paraffin-embedded sections obtained before and after therapy were assessed by immunohistochemical staining for Cox-2, VEGF, p53, p21, p27, Bax, BCL-2 and apoptosis protease-activating factor 1 (APAF-1). These stains were correlated with tumour regression grade, complete pathological response and T-downstaging of the surgical specimen. Clinical and pathological data were also collected. Data were analysed using the χ2 and Spearman's correlation tests.
  
  
  RESULTS
  Pathological complete response was seen in 24.5% of patients. Amongst the apoptosis-associated markers, only APAF-1 expression was found to be significantly associated with tumour regression grade (P<0.001), complete pathological response (P<0.031) and T-downstaging (P<0.004). On multivariate analysis, APAF-1 expression was found to be independently associated with good tumour regression grade. In contrast, overexpression of Cox-2 and VEGF in pretreatment biopsies was related to less tumour regression (P<0.003) and less likelihood of T-downstaging (P<0.03).
  
  
  CONCLUSIONS
  Immunohistochemical evaluation of initial biopsy specimens of rectal cancer with APAF-1, Cox-2 and VEGF may predict tumour response to neoadjuvant therapy in patients with advanced rectal adenocarcinoma. Those with an expected limited response may be considered for other investigational neoadjuvant protocols.
authors.affiliation: Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, Florida 33331, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Edden
authors.forename: S D
authors.initials: SD
authors.lastname: Wexner
authors.forename: M
authors.initials: M
authors.lastname: Berho
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D059248:Chemoradiotherapy; D016009:Chi-Square Distribution; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012004:Rectal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D018709:Statistics, Nonparametric; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D000964:Antimetabolites, Antineoplastic; D053477:Apoptotic Protease-Activating Factor 1; C494826:BAX protein, human; D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D051028:bcl-2-Associated X Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D005472:Fluorouracil