E2F1/TS Immunophenotype and Survival of Patients with Colorectal Cancer Treated with 5FU-Based Adjuvant Therapy.

Violetta Sulzyc-Bielicka,Pawel Domagala,Wojciech Rogowski,Dariusz Bielicki,Wenancjusz Domagala,Krzysztof Safranow

doi:10.1007/s12253-016-0043-z

Abstract

The predictive value of thymidylate synthase (TS) expression alone for 5FU-based treatment of colorectal cancer (CRC) has not been clinically confirmed. Little is known on the association of expression of E2F1, which controls the transcription of genes encoding proteins engaged in DNA synthesis including TS, and survival of patients with CRC. The purpose of this study is to assess the correlation between expression of both E2F1 and TS in CRCs and survival of patients administered adjuvant 5FU-based chemotherapy, in order to find a better predictor of treatment outcome than expression of TS or E2F1 alone. Nuclear TS and E2F1 were detected by immunohistochemistry in tissue microarrays from 190 CRCs (Astler-Coller stage B2 or C). Multivariate analysis identified significant association of the combined E2F1+TS+ immunophenotype with worse OS (HR = 3,78, P = 0,009) and DFS (HR = 2,30, P = 0,03) of patients with colon cancer. There were significant differences between E2F1+TS+ and E2F1-TS- Kaplan-Meier survival curves in relation to DFS (P = 0.008) and OS (P = 0.01). About 37 and 31 % difference in 3-year DFS and OS respectively were seen between patients with E2F1+TS+ vs. E2F1-TS- colon cancer immunophenotype. The E2F1+TS+ immunophenotype may be a marker of poor prognosis (the worst DFS and OS) of patients with colon cancer treated with 5FU-based adjuvant therapy. A subgroup of patients with this immunophenotype may require different and perhaps more aggressive treatment than 5FU-based chemotherapy. Thus, the combined E2F1/TS immunophenotype could be a potential indicator of colon cancer sensitivity to 5FU.

Highlights

Adjuvant 5-fluorouracil (5FU)-based chemotherapy in stage III colorectal cancer (CRC) decreases the frequency of cancer relapse and reduces the risk of cancer associated deaths by 30 % [1, 2]
Rectum In patients with rectal cancer, (n = 90) there was no association between the E2F1/thymidylate synthase (TS) immunophenotype and disease free survival (DFS) or overall survival (OS) (P = 0.94 and P = 0.76 respectively for multivariate analysis)
There was significant interaction between the site of the tumor and the E2F1+TS+ immunophenotype with regard to an association with OS (P = 0.047) but significance of interaction was not achieved with regard to DFS (P = 0.15) in multivariate analysis

Summary

Introduction

Adjuvant 5-fluorouracil (5FU)-based chemotherapy in stage III colorectal cancer (CRC) decreases the frequency of cancer relapse and reduces the risk of cancer associated deaths by 30 % [1, 2]. In stage II colorectal cancer, the benefit of adjuvant chemotherapy is smaller, improving the 5-year survival rate by 3–6 % [3]. In advanced CRC approximately 23 % of patients will respond to 5FU treatment combined with leucovorin [4]. It follows that a sizable percentage of CRC patients will not benefit from adjuvant 5FU-based therapy but will experience toxic side effects of the therapy and unnecessary costs [5]. The main target of 5FU is thymidylate synthase (TS) because 5fluorodeoxyuridine-5′-monophosphate (FdUMP), a 5FU metabolite, binds TS and forms a stable ternary complex

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