High cyclooxygenase-2 expression following neoadjuvant radiochemotherapy is associated with minor histopathologic response and poor prognosis in esophageal cancer.
OBJECTIVE
High expression of cyclooxygenase-2 (COX-2) was shown to inhibit chemotherapy- and radiotherapy-induced apoptosis. We analyzed the association of COX-2 mRNA and protein expression with histomorphologic response to neoadjuvant radiochemotherapy in esophageal cancer.


METHODS
Fifty-two patients with resectable esophageal cancers (cT2-4, Nx, and M0) received neoadjuvant radiochemotherapy (cisplatin, 5-5-fluorouracil, 36 Gy) followed by transthoracic en bloc esophagectomy. Histomorphologic regression was defined as major response when resected specimens contained less than 10% of residual vital tumor cells. RNA was isolated from endoscopic biopsies (paired tumor and normal tissue) before neoadjuvant treatment and quantitative real-time reverse transcriptase-PCR (Taqman) assays were done to determine COX-2 mRNA expression levels standardized for beta-actin. COX-2 protein expression in pretreatment biopsies and post-therapeutic resection specimens was analyzed by immunostaining of tumor cells.


RESULTS
Median COX-2 mRNA expression levels were significantly (P < 0.0001) different between paired tumor (median, 2.2) and normal tissues (median, 0.159). Comparison of pre-therapeutic and posttherapeutic specimens showed a significant difference (P < 0.006) in COX-2 protein expression. Twelve of 52 tumors showed down-regulation and 3 of 52 showed up-regulation of COX-2 protein expression during neoadjuvant radiochemotherapy. High COX-2 protein expression in post-therapeutic resection specimens was significantly associated with minor histopathologic response (P < 0.04) and poor prognosis (5-year survival probabilities: 26.3 +/- 8.2% for minor and 58.6% +/- 12.9% for major histopathologic response; P < 0.01).


CONCLUSIONS
High COX-2 protein expression following neoadjuvant radiochemotherapy in resection specimens is significantly associated with minor histopathologic response to neoadjuvant therapy and very poor prognosis.
Xi
Huan
H
Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany.
Baldus
Stephan E
SE
Warnecke-Eberz
Ute
U
Brabender
Jan
J
Neiss
Susanne
S
Metzger
Ralf
R
Ling
Frederike C
FC
Dienes
Hans P
HP
Bollschweiler
Elfriede
E
Moenig
Stefan
S
Mueller
Rolf P
RP
Hoelscher
Arnulf H
AH
Schneider
Paul M
PM
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004724:Endoscopy; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D018714:Radiotherapy, Adjuvant; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate
D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D002945:Cisplatin; D005472:Fluorouracil