MDR1 and ERCC1 expression predict outcome of patients with locally advanced bladder cancer receiving adjuvant chemotherapy

Abstract

Purpose: The role of adjuvant chemotherapy in patients with locally advanced bladder cancer still remains to be defined. We hypothesized that assessing the gene expression of the chemotherapy response modifiers multidrug resistance gene 1 (MDR1) and excision repair cross-complementing 1 (ERCC1) may help identify the group of patients benefiting from cisplatin-based adjuvant chemotherapy.

Experimental design: Formalin-fixed paraffin-embedded tumor samples from 108 patients with locally advanced bladder cancer, who had been enrolled in AUO-AB05/95, a phase 3 trial randomizing a maximum of three courses of adjuvant cisplatin and methotrexate (CM) versus methotrexate, vinblastine, epirubicin, and cisplatin (M-VEC), were included in the study. Tumor cells were retrieved by laser-captured microdissection and analyzed for MDR1 and ERCC1 expression using a quantitative real-time reverse transcription-polymerase chain reaction assay. Gene expression levels were correlated with clinical outcomes by multivariate Cox proportional hazards regression analysis.

Results: Expressions of MDR1 and ERCC1 were independently associated with overall progression-free survival (P = .001, relative risk = 2.9 and P = .01, relative risk = 2.24, respectively). The correlation of high MDR1 expression with inferior outcome was stronger in patients receiving M-VEC, whereas ERCC1 analysis performed equally in the CM and M-VEC groups.

Conclusions: High MDR1 and ERCC1 gene expressions are associated with inferior outcome after cisplatin-based adjuvant chemotherapy for locally advanced bladder cancer. Prospective studies are warranted to define a role for MDR1 and ERCC1 analysis in individualizing multimodality treatment in locally advanced bladder cancer.

Figure 1

Kaplan-Meier plot estimating the overall survival of patients in the CM treatment arm. Differences in survival between the high- and the low-MDR1 expression group were analyzed with the log-rank test. The upper black line represents the low-expression group, whereas the lower broken line represents the high-expression group.

Figure 2

Kaplan-Meier plot estimating the overall survival of patients in the M-VEC treatment arm. Differences in survival between the high- and the low-MDR1 expression group were analyzed with the log-rank test. The upper black line represents the low-expression group, whereas the lower broken line represents the high-expression group.

Figure 3

Kaplan-Meier plot estimating the progression-free survival of patients in both treatment arms. Differences in survival between the high- and the low-ERCC1 expression group were analyzed with the log-rank test. The upper black line represents the low-expression group, whereas the lower broken line represents the high-expression group.

Figure 4

Kaplan-Meier plot estimating the progression-free survival of patients in the CM treatment arm. Differences in survival between the high- and the low-ERCC1 expression group were analyzed with the log-rank test. The upper black line represents the low-expression group, whereas the lower broken line represents the high-expression group.

Figure 5

Kaplan-Meier plot estimating the progression-free survival of patients in the M-VEC treatment arm. Differences in survival between the high- and the low-ERCC1 expression group were analyzed with the log-rank test. The upper black line represents the low-expression group, whereas the lower broken line represents the high-expression group.