title: Immunohistochemical analysis of thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase in rectal cancer (cUICC II/III): correlation with histopathologic tumor regression after 5-fluorouracil-based long-term neoadjuvant chemoradiotherapy.
abstract: In locally advanced rectal cancer, neoadjuvant 5-fluorouracil (5-FU)-based long-term chemoradiotherapy leads to marked tumor reduction and decrease of local recurrence rate. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are known to be important biomarkers to predict tumor response to 5-FU-based therapy. The aim of this study was to examine the correlation between TS, TP, and DPD protein expression and histopathologic tumor regression after neoadjuvant chemoradiotherapy. The results were compared with the recently published mRNA data. Preoperative biopsies (n = 25) and resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neoadjuvant 5-FU-based chemoradiotherapy were studied for TS, TP, and DPD protein expression by immunohistochemistry using three different scoring systems (intensity, pattern, intensity + pattern). Results were compared with histopathologic tumor regression. A significant correlation between protein expression and tumor response was only seen when both staining intensity and staining pattern were considered. With this method, a significant association was seen between high TS expression in tumor biopsies as well as resection specimens and nonresponse of the tumor to therapy (P = 0.04). Furthermore, low TP expression in the resection specimens was significantly associated with lack of response (P = 0.02). For DPD no significant correlations were found at all. In conclusion, these results suggest that immunohistochemistry like RT-PCR is a suitable method to determine the correlation between TS, TP, and DPD expression and histopathologic tumor regression. However, precise results can only be achieved if staining intensity as well as staining pattern within the tumors are evaluated.
authors.affiliation: Institute for Pathology, University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany. Christiane.Jakob@uniklinikum-dresden.de
authors.forename: Christiane
authors.initials: C
authors.lastname: Jakob
authors.forename: Torsten
authors.initials: T
authors.lastname: Liersch
authors.forename: Wolfdietrich
authors.initials: W
authors.lastname: Meyer
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.forename: Peter
authors.initials: P
authors.lastname: Häusler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schwabe
authors.forename: Heinz
authors.initials: H
authors.lastname: Becker
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor / Q000032:analysis; D003131:Combined Modality Therapy; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D012004:Rectal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000628:therapy*; D013939:Thymidine Phosphorylase / Q000096:biosynthesis*; D013940:Thymidylate Synthase / Q000096:biosynthesis*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil