Jakob Christiane, Aust Daniela E, Meyer Wolfdietrich, Baretton Gustavo B, Schwabe Wolfgang, Häusler Peter, Becker Heinz, Liersch Torsten
Institute for Pathology, University of Technology, Fetscherstrasse 74, D-01307 Dresden, Germany.
J Pathol. 2004 Dec;204(5):562-8. doi: 10.1002/path.1663.
Pre-operative 5-fluorouracil (5-FU)-based chemoradiotherapy in locally advanced rectal cancer (UICC-II/III) may significantly reduce local tumour mass. Response to pre-operative treatment, however, varies significantly. Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are thought to be important predictors for the efficiency of 5-FU-based treatment. The aim of this study was to determine the correlation between TS-, TP-, and DPD-gene expression and the response to 5-FU-based long-term pre-operative chemoradiotherapy assessed by histopathological tumour regression. Additionally, the predictive value of intra-tumoural TS-, TP-, and DPD-gene expression in pre-operative rectal tumour biopsies was assessed by correlation with the histopathological regression grade. Formalin-fixed, paraffin wax-embedded pre-operative biopsies (n = 14) and surgical resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neo-adjuvant 5-FU-based chemoradiotherapy were studied for TS-, TP-, and DPD-gene expression by quantitative TaqMan real-time PCR after laser microdissection. Results were compared with standardized histopathological tumour regression analysis. There was a significant association between low TS-gene expression in pre-operative tumour biopsies and tumour response (p = 0.02). TS- and TP-gene expression was significantly lower in resection specimens of responders than of non-responders (p = 0.02) when microdissection was used. Statistical significance was even higher when TS and TP were combined (p = 0.0001). For the DPD gene, no significance was found at all. In conclusion, this study shows that TS gene expression in a pretreatment biopsy predicts the response of local rectal cancer to neo-adjuvant 5-FU-based chemoradiotherapy in a high percentage. Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied.
局部晚期直肠癌（UICC-II/III期）术前基于5-氟尿嘧啶（5-FU）的放化疗可能会显著缩小局部肿瘤体积。然而，术前治疗的反应差异很大。胸苷酸合成酶（TS）、胸苷磷酸化酶（TP）和二氢嘧啶脱氢酶（DPD）被认为是基于5-FU治疗疗效的重要预测指标。本研究的目的是确定TS、TP和DPD基因表达与通过组织病理学肿瘤消退评估的基于5-FU的长期术前放化疗反应之间的相关性。此外，通过与组织病理学消退分级的相关性，评估术前直肠肿瘤活检中肿瘤内TS、TP和DPD基因表达的预测价值。对接受新辅助基于5-FU的放化疗的直肠癌患者（临床UICC II/III期）的福尔马林固定、石蜡包埋术前活检标本（n = 14）和手术切除标本（n = 40），在激光显微切割后通过定量TaqMan实时PCR研究TS、TP和DPD基因表达。将结果与标准化组织病理学肿瘤消退分析进行比较。术前肿瘤活检中TS基因低表达与肿瘤反应之间存在显著关联（p = 0.02）。当使用显微切割时，反应者切除标本中的TS和TP基因表达显著低于无反应者（p = 0.02）。当TS和TP联合时，统计学意义更高（p = 0.0001）。对于DPD基因，未发现任何显著性。总之，本研究表明，预处理活检中的TS基因表达在很大程度上可预测局部直肠癌对新辅助基于5-FU的放化疗的反应。此外，应用显微切割时，新辅助放化疗后手术直肠标本中的肿瘤内TS和TP基因表达与组织病理学肿瘤消退显著相关。
