Article
Prognostic Biomarker in rectal cancer patients: Thymidylate Synthase for risk stratification after 5-FU-based neoadjuvant radiochemotherapy
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Published: | May 20, 2011 |
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Introduction: Fluorouracil (5-FU) remains the backbone of neoadjuvant radiochemotherapy (RCT) as well as adjuvant therapeutic strategies in multimodal treatment of rectal cancer patients. Due to its central role as the major target of 5-FU thymidylate synthase (TS) is a promising biomarker in rectal cancer. We assessed TS in 208 patients with regard to its predictive/prognostic capacity for disease free (DFS) and overall cancer specific survival (CSS).
Materials and methods: 167 patients with cUICC stages II (28%) and III (72%) received preoperative 5-FU-based RCT followed by total mesorectal excision (TME). A comparison group (n=41) received postoperative RCT after primary TME. All patients were treated after standardized protocols within phase-II/-III-trials of the German Rectal Cancer Study Group. TS levels from pre-treatment biopsies and corresponding resection specimens were assessed by immunohistochemical staining for their impact on DFS and CSS. Additionally, a TS gene polymorphism 28 bp repeat was analysed in respect to intracellular protein expression levels and prognostic significance.
Results: Patients with low TS expression in pre-treatment biopsies showed a correlation with impaired CSS (p=0.015). After neoadjuvant RCT there was evidence of lymph node metastases (ypUICC stage III) in 32.6%. Complete histopathologically confirmed tumor regression (TRG 4) was achieved in 16 patients (9.5%). During follow-up (median 57 months) patients with low intratumoral TS expression and positive nodal status were at high risk for local and/or distant metastatic recurrence (p=0.040). Analysis of the 28bp repeat revealed a correlation of *3/*3 genotype with high TS expression in pretherapeutical biopsies (p=0.059).
Conclusion: TS represents a prognostic biomarker in locally advanced rectal cancer indicating an unfavourable outcome for patients with low TS expression and might help to adapt adjuvant therapy regimens by stratifying patients according to their risk for cancer recurrence.