Downregulation of TS, DPD, ERCC1, GST-Pi, EGFR, and HER2 gene expression after neoadjuvant three-modality treatment in patients with esophageal cancer.
BACKGROUND
To find out if neoadjuvant therapy could alter tumor response determinants that might affect tumor sensitivity to the treatment, we investigated intratumoral expressions of genes associated with chemosensitivity, radiosensitivity, or both before and after radiochemotherapy.


METHODS
Twenty-four patients with locally advanced, resectable esophageal cancer (cT2-4,Nx,M0) received neoadjuvant 5-FU/cisplatin/36 Gy treatment followed by transthoracic en bloc esophagectomy. Expression levels of thymidylate synthase, dihydropyrimidine dehydrogenase, excision repair cross-complementing gene 1 , glutathione S-transferase Pi, epidermal growth factor receptor, and HER2 were measured in matched preradiochemotherapy endoscopic tumor biopsies and in postradiochemotherapy resection specimens. mRNA was isolated from formalin-fixed, paraffin-embedded, laser microdissected tumor tissues, and a quantitative fluorescent dye real-time reverse transcription polymerase chain reaction system was used for gene expression measurement.


RESULTS
There was a significant reduction in the expression levels of thymidylate synthase (p < 0.01), dihydropyrimidine dehydrogenase (p = 0.03), excision repair cross-complementing gene 1 (p < 0.01), glutathione S-transferase Pi (p = 0.03), HER2 (p < 0.01), and epidermal growth factor receptor (p = 0.04). The change in the levels of epidermal growth factor receptor mRNA in post- compared with pretreatment specimens was significantly associated with the histopathologic grade of regression (p = 0.01).


CONCLUSIONS
The expression levels of a set of genes that are possible determinants of 5-FU/cisplatin/radiation therapy antitumor activity are significantly downregulated by neoadjuvant radiochemotherapy in esophageal cancer.
Schneider
Sylke
S
Department of Molecular Biology and Biochemistry and Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA.
Uchida
Kazumi
K
Brabender
Jan
J
Baldus
Stephan E
SE
Yochim
JiMin
J
Danenberg
Kathleen D
KD
Salonga
Dennis
D
Chen
Pei
P
Tsao-Wei
Denice
D
Groshen
Susan
S
Hoelscher
Arnulf H
AH
Schneider
Paul M
PM
Danenberg
Peter V
PV
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D015536:Down-Regulation; D004720:Endonucleases / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D016629:Esophagectomy; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D018734:Genes, erbB-2 / Q000235:genetics; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009363:Neoplasm Proteins / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000235:genetics
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D066246:ErbB Receptors; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; D005472:Fluorouracil