Annals of Oncology Advance Access originally published online on January 17, 2007
Annals of Oncology 2007 18(3):522-528; doi:10.1093/annonc/mdl435
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© 2007 European Society for Medical Oncology
urogenital tumors |
Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy
1 Vall d'Hebron University Hospital, Barcelona
2 Hospital 12 de Octubre, Madrid
3 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona
4 Clínica Quirón, Barcelona
5 Instituto Valenciano de Oncología, Valencia
6 Consorci Parc Taulí, Sabadell
7 Hospital del Mar, Barcelona
8 Statistics Dpt, Universidad Autonoma de Madrid, Spain
* Correspondence to: Dr J. Bellmunt, Hospital Valle Hebron, Paseo Valle Hebron 119-126, Barcelona 08035, Spain. Tel: +34-93-2746085; Fax: +34-93-2034256; E-mail: jbellmunt{at}imas.imim.es
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Abstract |
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Background: Customizing chemotherapy on the basis of chemosentitivity prediction may improve outcome in advanced bladder cancer patients. Since DNA damaging agents are the cornerstones of therapy, we hypothesized that levels of DNA repair genes could predict survival.
Patients and methods: Messenger RNA expression levels of excision repair cross complementing 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit M1 (RRM1) and caveolin-1 were determined by RT-PCR in tumor DNA from 57 advanced and metastatic bladder cancer patients treated with either gemcitabine/cisplatin or gemcitabine/cisplatin/paclitaxel (Taxol). Levels were correlated with survival, time to disease progression and chemotherapy response.
Results: Median survival was significantly higher in patients with low ERCC1 levels (25.4 versus 15.4 months; P = 0.03) (median follow-up 19 months). A trend towards longer time to progression was observed in patients with tumors expressing low levels of all markers. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival and a clear link with chemotherapy response could not be established. On multivariate analysis with pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for survival.
Conclusion: The results of the study indicate that ERCC1 may predict survival in bladder cancer treated by platinum-based therapy.
Key words: advanced bladder cancer, BRCA1, caveolin, ERCC1, NER system, RRM1
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Chemotherapy in advanced bladder cancer has reached a plateau with no evidence of survival improvement using new combinations [1]. Therefore, there is an increased interest in the development of new treatment strategies in these patients. Better understanding of the genetic basis of chemotherapy response may offer promise in optimizing treatment [2, 3]. Clinicopathological factors as Karnofsky performance status and the presence of visceral metastases are well-established prognostic markers for poor survival. This has been shown in patients receiving M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) [4, 5] and in the Spanish Oncology Genitourinary Group (SOGUG) phase I/II trial combining gemcitabine (Gemzar; Eli-Lilly and Co., Indianapolis, IN), cisplatin (Neoplatin; Bristol-Myers Squibb, SA. Almansa, Madrid), and paclitaxel (GCT) (Taxol; Bristol-Myers Squibb, Princeton, NJ). Even though these clinicopathological markers are useful as survival indicators or ‘prognostic’ (related to the natural history of the tumor), however, they are inadequate to predict the optimal therapeutic regimen for each individual patient (‘predictive factors’).
Attention has recently been drawn to the role of genes in chemotherapy response. The cytotoxic effect of platinum-based chemotherapy has been attributed to the formation of bulky platinum DNA adducts. Cisplatin resistance appears to be associated with the removal of these adducts by the nucleotide excision repair (NER) system, which plays a major part in cisplatin resistance [6]. Excision repair cross complementing 1 (ERCC1) plays a pivotal role in NER, and an increase in ERCC1 expression is likely to cause the cisplatin resistance phenotype. High tumor tissue levels of ERCC1 messenger RNA (mRNA) have been associated with clinical resistance to cisplatin-based chemotherapy in human ovarian, gastric, cervical, colon and non-small-cell lung cancer (NSCLC) patients [7–11]. Furthermore, a recent report has confirmed that ERCC1 expression is the most useful marker of resistance to cisplatin and its analogues [12]. Breast cancer 1 (BRCA1) also plays a crucial role in DNA repair [13] and decreased BRCA1 mRNA expression in breast cancer cell lines led to greater cisplatin sensitivity but greater resistance to the microtubule-interfering agents paclitaxel and vincristine [14]. In the clinical setting, NSCLC patients in the bottom quartile of BRCA1 mRNA levels obtained the maximum benefit from neo-adjuvant gemcitabine plus cisplatin [15]. Similarly, Ribonucleotide reductase subunit M1 (RRM1) has been shown to be involved in gemcitabine metabolism and DNA repair after chemotherapy damage. Increased mRNA expression of RRM1 has been related to gemcitabine/cisplatin resistance in NSCLC patients [16] and to gemcitabine resistance in NSCLC cell lines [17]. Finally, caveolae are vesicular invaginations of the plasma membrane that play a crucial role in communication between cell surface membrane receptors and intracellular signaling protein cascades responsible for processes such as apoptosis [18]. Caveolin-1 modulates Akt signaling and survival in colorectal cancer, and up-regulation of caveolin-1 has been observed in paclitaxel-resistant cancer cells [19]. Multidrug-resistant cancer cells, including NSCLC cells, express very high caveolin-1 levels [20].
The ability to identify tumors with increased sensitivity to certain chemotherapy agents could potentially allow the selection of therapy according to individual genetic profile. Patients with tumors displaying a platinum resistance profile or signature, for example, would be the ideal candidates for new agent testing. On the contrary, patients with a platinum sensitivity profile could benefit the most from standard platinum-based regimens. In order to elucidate the predictive role of ERCC1, BRCA1, RRM1 and caveolin-1 in survival of advanced bladder cancer patients, we assessed mRNA transcripts of these genes in tumor tissue from patients treated with gemcitabine plus cisplatin (GC) or GCT.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients and samples
Clinical data were retrieved from the databases of two consecutive prospective clinical trials carried out by the SOGUG from March 1997 to June 2004 in patients with advanced bladder cancer: GC (14 patients) and GCT (43 patients). Inclusion criteria for these trials were histologically documented metastatic or locally advanced, surgically incurable (T4b, N0-1) transitional cell carcinoma (TCC) of the urothelium (renal pelvis, ureter, bladder or urethra). Patients who had received previous chemotherapy for metastatic disease were excluded. All patients had bidimensionally measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) two or less. Archival primary tumor specimens from each patient were retrieved from the participating SOGUG centers; for all cases tumor sample origin was the primary bladder tumor. All patients gave their signed informed consent, and the study was approved by the institutional ethics review boards.
clinical evaluation and response criteria
Baseline assessment consisted of a complete history, physical examination, appropriate imaging studies (chest X-rays, abdomen and pelvis computed tomography scan) and a complete blood count and biochemistry. Patients' weight and ECOG PS were also recorded. Blood cell counts and biochemistry were repeated at the start of each treatment cycle. Patients received treatment with GCT (gemcitabine 1000 mg/m2 on days 1 and 8 plus cisplatin 70 mg/m2 on day 1 plus paclitaxel (Taxol) 80 mg/m2 on days 1 and 8) every 21 days [3] or GC (gemcitabine 1000 mg/m2 on days 1, 8 and 15 plus cisplatin 70 mg/m2 on day 1) every 28 days for a maximum of six cycles. Response was assessed using Response Criteria in Solid Tumors by reevaluation of known sites of disease by physical examination, cystoscopy and imaging after every two cycles of treatment or as clinically indicated. Patients who received two complete cycles of treatment were considered assessable for response. Follow-up evaluations were recorded for PS, weight, toxicity, complete blood counts and serum creatinine and blood urea nitrogen levels. After achieving a maximum response to chemotherapy, some patients were referred for surgical resection of residual carcinoma and assessment of pathologic response.
gene expression analysis by real-time quantitative PCR (RT-QPCR)
ERCC1, BRCA1, RRM1 and caveolin-1 gene expression was assessed in formalin-fixed, paraffin-embedded surgical specimens from 57 patients. Using laser capture microdissection technique (Palm Microlaser, Oberlensheim, Germany) ensured a minimum of 80% of tumor tissue. After standard tissue sample deparaffinization using xylene and alcohols, samples were lysed in a tris–chloride, EDTA, sodium dodecyl sulphate and proteinase K containing buffer. RNA was then extracted with phenol–chloroform–isoamyl alcohol followed by precipitation with isopropanol in the presence of glycogen and sodium acetate. RNA was resuspended in diethyl pyrocarbonate water (Ambion Inc., Austin, TX) and treated with DNAse I (Ambion Inc., Austin, TX) to avoid DNA contamination. Complementary DNA was synthesized using Maloney Murine Leukemia Virus retrotranscriptase enzyme. Template cDNA was added to Taqman Universal Master Mix (AB, Applied Biosystems, Foster City, CA) in a 12.5-µl reaction with specific primers and probe for each gene. The primer and probe sets were designed using Primer Express 2.0 Software (AB) and the RefSeq sequences (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene). Primers and probes for all the genes are listed in Table 1. Quantification of gene expression was carried out using the ABI Prism 7900HT Sequence Detection System (AB).
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Relative gene expression quantification was calculated according to the comparative cycle threshold (Ct) method using ß-actin as an endogenous control and commercial RNA controls (Stratagene, La Jolla, CA) as calibrators. Final results were determined as follows: 2–(
Ct sample–Ct calibrator), where CT values of the calibrator and sample are determined by subtracting the CT value of the target gene from the value of the ß-actin gene. In all experiments, only triplicates with a standard deviation of the Ct value <0.20 were accepted. In addition, for each sample analyzed, a retrotranscriptase minus control was run in the same plate to assure lack of genomic DNA contamination.
statistical analyses
QPCR analyses yield values expressed as ratios between two absolute measurements (gene of interest: internal reference gene). The maximal 
2 method of Halpern was adapted to determine the cut-off value that best dichotomized patients into low expression and high expression of ERCC1, BRCA1, RRM1 and caveolin-1. Proportions were compared with Fisher's exact test. The Kaplan–Meier method was used to calculate survival and time to progression; with overall survival (OS) being the primary end point. The Cox proportional hazards model was used to examine the prognostic value of gene expression levels together with other pretreatment factors, including PS, presence of visceral metastases, number of disease sites, age, lactate dehydrogenase (LDH), hemoglobin and histology. Factors that showed individual prognostic value in the univariate model were used to examine their joint prognostic value in a multivariate model. Spearman correlation coefficients were calculated to assess associations between the mRNA expression levels of the four genes. All analyses were carried out with the SPSS software package, version 12.0 (SPSS Inc., Chicago, IL).
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patient characteristics
Baseline characteristics for all 57 patients are shown in Table 2. The median age was 61 years (range 37–76 years), and 77% of patients were male. Twenty-three patients (40.4%) had a PS of zero and 34 (59.6%) had a PS of one. Visceral metastases (lung, liver, or bone disease) were present in 16 patients (28.1%). Postchemotherapy surgery was preformed in four (8.5%) patients. With a median follow-up of 19 months, the overall median survival was 23.4 months [95% confidence interval (CI), 19.1–27.8 months]. At the time of analysis, 27 patients (47.4%) were alive.
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gene expression levels
ERCC1 mRNA expression was assessed in all 57 samples. The median ERCC1 mRNA expression relative to the housekeeping ß-actin was 6.6 (range 2.2–19.9). After ERCC1 assessment, limited availability of tissue restricted the evaluation of other genes expression in certain samples. BRCA1 expression was assessed in 56 samples. The median BRCA1 mRNA expression was 10.3 (range 1.2–9.18). RRM1 mRNA expression was assessed in 54 samples. The median RRM1 mRNA expression was 2.9 (range 0.6–0.1). Caveolin-1 mRNA expression was assessed in 56 samples. The median caveolin-1 mRNA expression was 2.7 (range 0.02–12.1). There was a significant association between ERCC1 and BRCA1 levels (Spearman r 0.300, P = 0.025) and between BRCA1 and RRM1 levels (Spearman rs = 0.751, P < 0.001) and marginally significant for ERCC1 and RRM1 (Spearman rs = 0.256, P = 0.061).
gene expression levels and survival
With a cut-off of seven, 37 patients were classified as having low ERCC1 expression and 20 as having high ERCC1 expression. OS was significantly longer for patients with low ERCC1 levels (25.47 months, 95% CI 22.65–28.29 months) than for those with high ERCC1 levels (15.40 months, 95% CI 11.01–19.79 months, P = 0.030) (Figure 1). No differences were observed according to BRCA1, RRM1 or caveolin-1 mRNA levels (data not shown).
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Univariate analysis was carried out on prognostic groups based on nine predefined factors (Table 3). Of these variables, the following were associated with an adverse prognosis: PS one, more than one disease site, presence of visceral metastasis, and high ERCC1 mRNA levels. Histology, sex, age, LDH and hemoglobin did not show a significant effect on survival. When the four variables that emerged as significant in the univariate analyses were included in a multivariate regression model, ERCC1 levels and PS were identified as independent prognostic markers. A worse outcome was observed in patients with PS one (hazard ratio 4.80, 95% CI 1.88–12.21, P = 0.001) and in patients with high levels of ERCC1 (hazard ratio 3.72, 95% CI 1.33–10.40, P = 0.012).
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Based on these results, patients were divided according to whether they had zero, one or two adverse prognostic factors identified in the multivariate analysis: PS one and high ERCC1 levels. Sixteen patients (28.6%) had neither factor; 28 patients (50.0%) had one and 12 (21.4%) had two. Median survival was 26.4 months (95% CI 25.4–27.4 months) for patients classified with neither factor, 23.4 months (95% CI 17.6–29.4 months) for patients with one factor and 13.2 months (95% CI 10.5–15.7 months) for patients with two factors.
gene expression levels and time to disease progression
Median time to progression was longer for all tumors expressing low levels of the four markers. The Cox regression analysis showed a correlation between time to disease progression and both ERCC1 (P = 0.087) and RRM1 levels (P = 0.045).
gene expression levels and response to chemotherapy
The overall response rate to chemotherapy in our pooled patient population was 74.1% (complete response 31.5% and partial response 42.6%). There were no significant differences in response according to ERCC1, BRCA1, RRM1 or caveolin-1 when comparing levels of expression by quartiles (Table 4). Only patients in the low quartile of expression of RRM1 and caveolin-1 showed a trend towards significance for chemotherapy response (P = 0.062 for RRM1 and P = 0.087 for caveolin-1).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The report indicates that low ERCC1 expression correlates with increased OS in metastatic TCC patients treated with cisplatin-based chemotherapy. A significantly longer median survival was observed in patients with low ERCC1 mRNA expression levels (25.4 months) than in those with higher levels (15.4 months). Besides analyzing the role of ERCC1, we also tested whether mRNA levels of RRM1, BRCA1 and caveolin-1, genes that have also been implicated in DNA repair, could have a predictive value on outcome. A trend towards longer time to progression was observed for patients with low expressing tumors for all markers evaluated. Levels of RRM1, BRCA1 and caveolin-1, however, failed to predict the survival outcome. In addition, a clear link between chemotherapy response and expression levels of all four markers could not be established.
These molecular parameters have been correlated with well-established pretreatment clinical prognostic factors [2]. The univariate analysis confirmed our previous findings regarding the prognostic role of both performance status and visceral disease [2]. When including ERCC1 levels on both univariate and multivariate analysis, this marker also emerged as independently associated with survival.
This report addresses the possible role of ERCC1 expression levels in OS of advanced bladder cancer patients treated with platinum-based chemotherapy. Our report has limitations, namely, that the genetic study was conducted retrospectively and that the chemotherapy regimens, while similar, were not identical (GCT versus GC). Clinical data, however, were collected prospectively and genetic studies were carried out in a blinded fashion. In addition, our series might present a selection bias on the basis of better long-term outcome of initially surgically treated patients and a higher percentage of locally advanced and nonvisceral metastasis cases. Finally, we failed to demonstrate a relationship between molecular marker levels and chemotherapy response; however, a trend to improved progression free survival was observed with all four markers. A plausible explanation for this is that quantifying clinical response in solid tumors and especially in bladder cancer is highly inaccurate. Consequently, both survival and time to disease progression are probably better surrogate end points.
The strong association of ERCC1 expression with survival still supports the hypothesis that enhanced DNA repair decreases the benefit of platinum-based treatment. Recent studies indicate that patients with lower DNA repair capacity are more chemosensitive than those who carry a proficient DNA repair system [21]. DNA repair, especially NER, plays an important role in the defense of platinum-based drug-induced DNA damage, including the removal of DNA adducts [22]. ERCC1 is the lead enzyme in the NER process. High ERCC1 levels are associated with increased removal of platinum-induced DNA adducts and relative platinum resistance [23], and both ERCC1-defective cells and knockout mice are highly sensitive to DNA cross-linking agents [24]. Associations between ERCC1 expression and survival outcome, with or without chemoresponse, have been previously documented in other platinum-sensitive tumor types [8, 10, 11, 25]. Finally, it has been recently shown that patients with ERCC1-negative non-small-cell lung tumors appear to benefit from adjuvant cisplatin-based chemotherapy, whereas patients with ERCC1-positive tumors do not [12].
Preclinical and clinical studies have also identified BRCA1 as an important factor in modulating response to therapeutic DNA damage [14, 15], with low BRCA1 levels indicating sensitivity to cisplatin and resistance to paclitaxel, while the opposite effect is observed in patients with high levels [14]. In accordance, in our study, the use of paclitaxel as a third drug in 75% of patients might have eluded to support the hypothesis of a survival benefit of this marker by masking its effect. Along the same lines, RRM1 has been identified as a significant indicator of survival in patients receiving GC [16], with low expression levels correlating with greater survival benefit. These observations compare similarly with our finding of a trend towards longer time to progression in tumors with low RRM1 expression. We failed to demonstrate a significant association with chemotherapy outcome. Interestingly, it has been previously reported that the predictive role of RRM1 disappeared in patients who received a triplet of gemcitabine/cisplatin/vinorelbine [16]. Finally, multidrug-resistant cancer cells have also been shown that express very high caveolin-1 levels [19]. In our study, patients in the low quartile of caveolin-1 expression showed a better response to platinum-based chemotherapy, but an association between caveolin-1 mRNA levels and survival could not be demonstrated.
There are limited data regarding molecular prognostic or molecular pharmacology predictive markers in patients with established metastatic urothelial disease. Studies on P-glycoprotein [26], glutathione [27] and metalloproteinase [28] expression in tumor specimens of metastatic bladder cancer have indicated that these parameters could predict resistance and toxicity to chemotherapy. The identification of prognostic and predictive markers has guided the way for a series of ‘first-generation,’ biologically driven trials. One of the lead trials involves the study of M-VAC in patients with organ-confined bladder cancer based on p53 status, and results of this currently ongoing study are eagerly awaited. Alterations in p53 and pRb have been reported to occur in 
50% and 35%, respectively, of bladder cancers and to correlate with high grade and stage [29, 30]. There are conflicting reports regarding the relationship between chemosensitivity and p53, and while several authors suggest that altered expression of p53 may be associated with resistance to M-VAC others support the contrary [31]. Paclitaxel seems to act independently to the presence of p53 mutations [32]. The metastatic potential of bladder cancer has also been suggested to correlate with the expression of several genes that regulate proliferation (epidermal growth factor receptor) and angiogenesis (basic fibroblast growth factor, vascular endothelial growth factor, matrix metallo proteinase and interleukin-8), some of them being also predictors of response [33]. At the moment, however, none of these molecular markers has yet proved useful in routine clinical practice.
Collectively, these findings support that the metabolism of cytotoxic agents might be affected by genetic factors and that there are significant differences in drug metabolism systems among individuals and also among population groups [34]. Optimizing chemotherapy with the use of chemosensitivity predictor markers such as intratumoral molecular pharmacology markers (pharmacogenomics) might aid in improving outcome. Based on detailed molecular biologic information of each tumor, the clinician will be able to more accurately select the appropriate therapy for each patient according to individual predicted response.
In the current report, we show that ERCC1 might act as a novel marker of survival in bladder cancer. Our preliminary results go on to indicate that DNA repair genes may play an important role in the prognosis of advanced stage bladder cancer patients. Genetic testing of ERCC1 mRNA expression levels could potentially be used to personalize chemotherapy by defining a subset of patients who would benefit the least from platinum-based chemotherapy. These, with high ERCC1 levels, would be the ideal target for new agent testing. Conversely, those with low levels may attain a better outcome with standard cisplatin-based regimens. We believe that our data warrant further research. Further validation of these findings with larger sample size and prospectively randomized studies are needed to confirm our results and better define the clear biological basis of these findings.
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This paper was presented in part at the Educational Session of the 41st Annual Meeting of the American Society of Clinical Oncology, 13 May 2005, Orlando, FL.
Received for publication September 6, 2006. Revision received October 22, 2006. Accepted for publication October 24, 2006.
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