Low ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinum-based neoadjuvant chemotherapy

Ozcan, Muhammet Fuat; Dizdar, Ömer; Dinçer, Nazmiye; Balcı, Serdar; Güler, Gülnur; Gök, Bahri; Pektaş, Gökhan; Şeker, Mehmet; Aksoy, Sercan; Arslan, Çağatay; Yalçın, Şuayib; Balbay, Mevlana Derya

doi:10.1016/j.urolonc.2012.06.014

Cited by 36 publications

(24 citation statements)

References 27 publications

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“…There are several available clinical and preclinical studies on the association of ERCC1 expression with resistance to platinum agents (11,12,17,(27)(28)(29) and radiosensitivity (15,18,30). The ERCC1 gene has 10 exons and generates 4 isoforms by alternative splicing; however, only 1 of these 4 isoforms is actively involved in the repair of platinum-DNA adducts.…”

Section: Discussionmentioning

confidence: 99%

“…Excision repair cross-complementation group 1 (ERCC1) is a key part of the nucleotide-excision repair pathway that removes platinum-DNA adducts and counteracts the cytotoxic effects of platinum agents (12). ERCC1 expression was reported to confer resistance to platinum derivatives and has been evaluated as a predictive and prognostic marker in various tumors, where platinum is the cornerstone of chemotherapy (12)(13)(14)(15)(16)(17). ERCC1 was also implicated in repairing DNA double-strand breaks and conferring resistance to ionizing radiation, which may help identify the patients that are most suitable to undergo radical cystectomy compared to trimodality therapy (15,18).…”

Section: Introductionmentioning

confidence: 99%

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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

Shilkrut

Thomas

et al. 2014

Molecular and Clinical Oncology

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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 ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Shilkrut

Thomas

et al. 2014

Molecular and Clinical Oncology

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“…Overexpression of the DNA repair machinery has been associated with poor clinical outcomes for individuals with bladder cancer [34,35]. Moreover, in bladder cancer, a link has been identified between both DNA damage resistance and tumor aggressiveness in response to treatment [36].…”

Section: Discussionmentioning

confidence: 99%

Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors

Doi

Yoshino²,

Shitara³

et al. 2015

Anti-Cancer Drugs

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This phase I trial evaluated LY2603618, a selective inhibitor of the DNA damage checkpoint kinase 1, in combination with gemcitabine. Japanese patients with advanced solid tumors were enrolled. All patients received gemcitabine (1000 mg/m on days 1, 8, and 15 every 28 days) and either 170 mg (cohort 1) or 230 mg (cohort 2) of LY2603618. The primary objective was assessment of safety/tolerability. Pharmacokinetic/pharmacodynamic marker profiles were secondary objectives. Of the 17 patients enrolled, dose-limiting toxicities were observed in one patient in cohort 1 (n=7) and in two patients in cohort 2 (n=10). The most common grade 3 or more drug-related treatment-emergent adverse events were hematological. Three patients discontinued because of adverse events. Dose-dependent decreases in LY2603618 exposure were observed, but the LY2603618 pharmacokinetics at each dose were consistent within and between cycles and did not influence gemcitabine pharmacokinetics. Circulating plasma DNA decreased from baseline in all four patients who achieved a partial response. Administration of 170 or 230 mg of LY2603618 following a standard dose of gemcitabine showed acceptable safety and tolerability in Japanese patients with solid tumors.

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“…Deletion or mutation of p14 ARF would result in increased MDM2 levels and increased p53 degradation (153)(154)(155)(156)(157) Excision repair cross complementing 1 (ERCC1) is a component of the nucleotide excision repair (NER) pathway, which is a major repair mechanism of DNA damage. ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinumbased neoadjuvant chemotherapy (158,159).…”

Section: P14mentioning

confidence: 99%

Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer

Aljabery¹

2017

Linköping University Medical Dissertations

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Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinico-pathologic data. Patients and Methods:We studied prospectively 122 patients with UBC, pathological stage pT1-pT4 treated with RC and pelvic lymph node dissection (PLND) during [2005][2006][2007][2008][2009][2010][2011] at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. We also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression pro-

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Low ERCC1 expression is associated with prolonged survival in patients with bladder cancer receiving platinum-based neoadjuvant chemotherapy

Cited by 36 publications

References 27 publications

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

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

Phase I study of LY2603618, a CHK1 inhibitor, in combination with gemcitabine in Japanese patients with solid tumors

Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer

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