THE IDENTIFICATION OF BIOMARKERS RELATED TO CLINICAL RESPONSE OF GC (GEMCITABINE + CISPLATIN) THERAPY FOR METASTATIC BLADDER CANCER PATIENTS

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Abstract

Introduction and objective

Human Equilibrative Nucleoside Transporter 1 (hENT1) and Ribonucleotide reductase M1 (RRM1) play important roles in pharmacokinetics of gemcitabine, and excision repair cross-complementing 1 (ERCC1) is related to drug resistance to CDDP. We evaluated the expression level of these molecules in patients with metastatic bladder cancer treated with gemcitabine—cisplatin (GC)-based chemotherapy.

Methods

Clinical data were retrieved from the databases from May 2002 to October 2011 in 40 patients (age 35–88; male 36; female 4) with advanced bladder cancer treated by GC (Gemcitabine + Cisplatin) regimen (17 patients) and GCT (GC + Paclitaxel) regimen (23 patients). Inclusion criteria for this study were clinically and/or histologically documented advanced and/or metastatic (stage 4) bladder cancer. We carried out immunohistochemical staining chemo-naive primary bladder tumor specimens with specific hENT1, RRM1 and ERCC1 antibodies. Pathologist blinded to clinical outcomes evaluated the expression level of these molecules. The clinical and histopathological data were analyzed to evaluate predictive factors.

Results

With regards to anti tumor response, high hENT1 expression group showed better clinical response comparing with low hENT1 expression group (90% versus 35%, P = 0.001). High hENT1 expression group and low RRM1 expression group showed significantly better survival (log-tank test P < 0.001, P = 0.01 respectively, Kaplan–Meier curve: Fig). Moreover, we classified the cohort patients into 3 subgroups based on the expression level of hENT1 and RRM1 as follows; group A: high hENT1 + low RRM1, group B: both expression of hENT1 and RRM1, group C: low hENT1 + high ERCC1. The median survival time in group A was 19.3 months, which was significantly longer than that in group C (9.9 months). Group B showed the intermediate survival curve between group A and C (P < 0.001, Kaplan–Meier curve, Fig).

Conclusions

The expression of hENT1 and RRM1 was associated with prolonged survival in patients with metastatic bladder cancer treated with GC-based chemotherapy. The combined analysis of hENT1 and RRM1 expression can be a promising biomarker which can predict the clinical response and the prognosis of patients with advanced bladder cancer treated by gemcitabine-based chemotherapy.

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