Intratumoral COX-2 gene expression is a predictive factor for colorectal cancer response to fluoropyrimidine-based chemotherapy.
OBJECTIVE
Cyclooxygenase-2 (COX-2) is generally elevated in tumors compared with normal tissue and apparently has an important role in tumor development. A number of studies have found high expression of COX-2 to be an unfavorable prognostic factor for overall survival in several cancers. However, the influence of COX-2 expression levels on tumor response to chemotherapy has been relatively little studied. The purpose of this study was to ascertain if COX-2 gene expression is associated with tumor response in the clinical treatment of colorectal cancer with the fluoropyrimidine-based therapy S-1.


METHODS
Patients with advanced (stage IV) colorectal cancer were treated with S-1 twice daily based on the patient's body surface area (BSA; BSA < 1.25 m2, 80 mg/d; 1.25 m2 < or = BSA < 1.5 m2, 100 mg/d; BSA > or = 1.5 m2, 120 mg/d) for 28 days followed by a 2-week period rest. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens and expression levels of COX-2 relative to beta-actin as the internal reference gene were measured using a quantitative reverse transcription-PCR (Taqman) system.


RESULTS
The overall response rate in a group of 44 patients treated with S-1 was 40.9%. Sufficient tumor tissue was available from 40 of these patients for COX-2 mRNA quantitation. COX-2 gene expression was significantly lower in the responding tumors compared with the nonresponders (P = 0.012, Wilcoxon test). Patients with COX-2 values above the cutoff value of 3.28 x 10(-3) had a significantly shorter survival than those with COX-2 gene expressions below the cutoff value (adjusted P = 0.031).


CONCLUSIONS
Intratumoral COX-2 gene expression is associated with likelihood of response to chemotherapy with S-1 and is a prognostic factor for survival of patients after the start of S-1 chemotherapy.
Uchida
Kazumi
K
Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan.
Schneider
Sylke
S
Yochim
Ji Min
JM
Kuramochi
Hidekazu
H
Hayashi
Kazuhiko
K
Takasaki
Ken
K
Yang
Dongyun
D
Danenberg
Kathleen D
KD
Danenberg
Peter V
PV
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2; D004338:Drug Combinations; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010094:Oxonic Acid / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011379:Prognosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011725:Pyridines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D005641:Tegafur / Q000627:therapeutic use*; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D008565:Membrane Proteins; D011725:Pyridines; D012333:RNA, Messenger; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases