Expression of ribonucleoside reductase subunit M1, but not excision repair cross-complementation group 1, is predictive in muscle-invasive bladder cancer treated with chemotherapy and radiation

Abstract

Abstract. The aim of this study was to determine the prognostic and predictive values of ribonucleoside reductase subunit M1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) expression in patients with muscle-invasive bladder cancer treated with chemoradiotherapy. The expression of RRM1 and ERCC1 in pretreatment tumor samples of retrospectively identified patients was determined by immunohistochemical analysis. A total of 39 patients were included in this study; 49% were treated with neoadjuvant chemotherapy and 67% with concomitant chemoradiotherapy; 56% were treated with gemcitabine-based and 51% with platinum-based chemoradiotherapy. The median follow-up was 19 months (interquartile range, 11-50 months). Based on the immunohistochemical analysis, 44 and 32% of the tumors exhibited increased expression of RRM1 and ERCC1, respectively. The complete response (CR) and local recurrence rates following chemoradiotherapy were 79 and 21%, respectively. A low expression of RRM1 was associated with a higher rate of CR to chemoradiotherapy (95 vs. 57%, P=0.012); however, there was no such association with low ERCC1 expression (67 vs. 84%, P=0.39). RRM1 expression predicted an improved CR in patients treated with gemcitabine-based chemoradiotherapy (57 vs. 100%, P=0.036), but not in those treated with other agents (56 vs. 88%, P=0.29). ERCC1 expression was not found to be correlated with CR (67 vs. 84%, P=0.39), even when restricted to patients treated with platinum agents (71 vs. 75%, P=1.0). In the univariate analysis, RRM1 expression, but not ERCC1 expression, was identified as a prognostic marker for worse cancer-specific survival in all the patients and in those treated with gemcitabine-based regimens. No independent prognostic factor was identified in the multivariate model, which included tumor stage, vascular invasion, hydronephrosis and RRM1 status. Although these findings require further validation, they suggest that RRM1 may be a beneficial stratification variable for the selection of chemotherapy regimens for chemoradiotherapy, with patients with low RRM1 expression being considered suitable for gemcitabine treatment. IntroductionMuscle-invasive bladder cancer (MIBC), which constitutes 30% of all bladder cancers (BCs), is responsible for an annual death toll of ~15,000 individuals in the United States (1). A viable treatment option for MIBC includes trimodality therapy with a combination of transurethral bladder resection (TURBT), chemotherapy and radiation (with cystectomy for failures), although this method has never been compared to radical cystectomy in randomized clinical trials. This type of treatment has achieved cure rates comparable to extirpative surgery, while preserving a functional bladder (2-4). This combined-modality approach is also a treatment of choice for several patients who may be unsuitable for surgery.Chemotherapy administered either sequentially or concomitantly with radiation is crucial for organ preservation in BC by improving local effectiveness (5-7) and increasing ...

Predictive and Prognostic Value of Ribonucleotide Reductase Regulatory Subunit M1 and Excision Repair Cross-Complementation Group 1 in Advanced Urothelial Carcinoma (UC) Treated with First-Line Gemcitabine Plus Platinum Combination Chemotherapy

“…These conflicting data may result from differences in study population and methods for evaluating biomarkers. Similar with our results, Shilkrut et al [ 17 ] recently reported that the expression of RRM1, but not ERCC1, may predict response to gemcitabine-based chemoradiotherapy and worse cancer-specific survival in patients with muscle-invasive UC. They suggested that low RRM1 expression may help identify patients suitable for gemcitabine-based chemoradiotherapy.…”

RRM1 predicts clinical outcome of high-and intermediate-risk non-muscle-invasive bladder cancer patients treated with intravesical gemcitabine monotherapy

“…There are preclinical and clinical data indicating that high RRM1 protein levels in various cancers are associated with gemcitabine resistance [13, 14]. Moreover, several clinical studies have demonstrated the association between elevated RRM1 levels and unfavourable clinical outcomes in advanced bladder tumour patients treated with gemcitabine­based therapy [9, 15]. However, the relationship between RRM1 mRNA level and gemcitabine activity in NMIBC has not been addressed.…”

Predictive Value of Ercc1 and Xpd Polymorphisms for Clinical Outcomes of Patients Receiving Neoadjuvant Therapy

“…To the best of our knowledge, low expression of the ERCC1 protein will result in a longer OS after neoadjuvant therapy. 10 , 40 However, with detecting other ERCC1 and XPD polymorphisms, we were unable to discriminate between shorter OS and longer OS. Similarly, no differences were detected in the subgroup analyzes.…”