Excision Repair Cross-complementation Group 1 Expression Research Articles

Analysis of ERCC1, BRCA1, RRM1 and TUBB3 as predictors of prognosis in patients with non-small cell lung cancer who received cisplatin-based adjuvant chemotherapy: A prospective study.

Although adjuvant platinum-based chemotherapy has been demonstrated to improve survival in patients with completely resected non-small cell lung cancer (NSCLC), individualized approaches to therapy are urgently required to improve the treatment efficacy and reduce unnecessary toxicity. It was hypothesized in the present study that the protein levels of excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase M1 (RRM1) and class III β-tubulin (TUBB3) may influence the therapeutic effect of adjuvant cisplatin-based chemotherapy. The expression of ERCC1, BRCA1, RRM1 and TUBB3 in tissues obtained from 84 patients with NSCLC was analyzed in the present non-interventional study by immunohistochemistry prior to adjuvant chemotherapy. All patients received adjuvant cisplatin-based chemotherapy. The primary endpoint in the present study was disease free survival (DFS). Out of the 84 tumors, the expression of ERCC1, BRCA1, RRM1 and TUBB3 was identified in 46 (55%), 11 (13%), 73 (87%) and 76 (90%) tissues, respectively. A beneficial response to adjuvant cisplatin-based chemotherapy in DFS was associated with the absence of the expression of ERCC1 [hazard ratio (HR), 2.166; 95% confidence interval (CI), 1.049-4.474; P=0.037] and BRCA1 (HR, 2.419; 95% CI, 1.127-5.193; P=0.023), but not with the expression status of RRM1 (HR, 0.568; 95% CI, 0.234-1.379; P=0.212) or TUBB3 (HR, 1.874; 95% CI, 0.448-7.842; P=0.39). In addition, patients lacking the expression of ERCC1 and BRCA1 benefited more from adjuvant cisplatin-based chemotherapy compared with patients that expressed either ERCC1 or BRCA1 (HR, 3.102; 95% CI, 1.343-7.163; P=0.008). The expression of ERCC1 and BRCA1 was significantly associated with the DFS time in patients with NSCLC treated with adjuvant cisplatin-based chemotherapy, respectively. The combination of the ERCC1 and BRCA1 expression levels may be a promising prognostic prediction for adjuvant cisplatin-based chemotherapy.

Factors affecting platinum sensitivity in cervical cancer.

The present study aimed to investigate the association between nedaplatin (NDP) sensitivity and the expression of biological factors in cervical cancer. A total of 45 cervical cancer specimens, including 18 pretreatment biopsies and 27 surgical specimens, were used in histoculture drug response assays to determine the chemosensitivity of cervical cancer specimens to NDP. Each specimen was assessed for immunohistochemical expression of Ki-67, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), cleaved caspase-3, cyclooxygenase-2 (COX-2), and excision repair cross-complementation group 1 (ERCC1). The results revealed that low or negative expression of p53, Bcl-2 and COX-2, and high or positive expression of cleaved caspase-3 were significantly correlated with high sensitivity to NDP. However, there were no significant differences in Ki-67, Bax or ERCC1 expression between the low and high sensitivity groups. These findings indicate that sensitivity to platinum may be easily predicted by immunostaining for the detection of these specific factors in pretreatment biopsies or surgical specimens. The expression profiles of these targets may therefore provide additional information for planning individualized chemotherapy in the treatment of cervical cancer.

The prognostic and predictive value of excision repair cross-complementation group 1 (ERCC1) protein in 1288 patients with head and neck squamous cell carcinoma treated with platinum-based therapy: a meta-analysis.

Excision repair cross-complementation group 1 (ERCC1) protein has been extensively investigated as a prognostic and predictive factor for platinum-based treatment in head and neck squamous cell carcinoma (HNSCC) but with inconsistent results. We performed the present meta-analysis to better elucidate this issue in advanced HNSCC. A literature search was conducted using the PubMed and Web of Science databases. The inclusion criteria were head and neck cancer patients with platinum-based treatment and evaluation of the correlation between ERCC1 expression and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), both unadjusted and adjusted estimates]. In high vs. low pooled analyses, high ERCC1 expression was associated with unfavorable OS [hazard ratio (HR)=1.95, 95% confidence interval (CI) 1.18-3.21, p=0.009], PFS (HR=2.39, 95% CI 1.74-3.28, p=0.000) and ORR (odds ratio=0.48, 95% CI 0.23-0.98, p=0.044). In the subgroup analysis of adjusted OS estimates, ERCC1 was a predictor of shorter survival in Asians (HR=3.13, 95% CI 2.09-4.70, p=0.000) and Caucasians (HR=2.02, 95% CI 1.32-3.07, p=0.001) but of longer survival in South Americans (HR=0.17, 95% CI 0.07-0.40, p=0.000). Immunohistochemistry proved to be of predictive value irrespective of used antibody (p=0.009). In the stratified analysis according to the tumor site, ERCC1 expression was associated with OS in nasopharyngeal cancer (HR=2.72, 95% CI 1.79-4.13, p=0.000). ERCC1 has a potential to become predictive and prognostic factor enabling treatment tailoring in HNSCC patients.

Expression of tumor heterogeneity-related genes in esophageal squamous cell carcinoma and its predictive value for chemotherapy sensitivity

Objective To investigate the expression of excision repair cross-complementation group 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) in patients with esophageal squamous cell carcinoma, and the relationship between the expression of ERCC1 and RRM1 genes and chemotherapy sensitivity. Methods A total of 77 patients with esophageal squamous cell carcinoma admitted in hospital from Jan. 2008 to Dec. 2012 were recruited. ERCC1 and RRM1 mRNA levels in the cancerous tissue were detected by real-time fluorescent quantitative RT-PCR. The relationship between short-term effects of chemotherapy and ERCC1 and RRM1 mRNA levels was analyzed. Results Levels of mRNA in stages Ⅰa, Ⅰb, Ⅱa, and Ⅱb were (0.578±0.081), (0.560±0.084), (0.521±0.080), (0.464±0.091) for ERCC1 and( 0.511±0.089), (0.539±0.086), (0.584±0.092), (0.637±0.101 )for RRM1, respectively. As the clinical stage advanced, the ERCC1 mRNA level declined and the RRM1 mRNA level increased (t=2.679 and 2.952, P=0.034 and 0.025, respectively). Levels of mRNA in patients with complete remission, partial remission, stable disease and progressive disease were (0.487±0.097, 0.511±0.095, 0.552±0.086, 0.568±0.088)for ERCC1 and(0.504±0.091, 0.544±0.095, 0.595±0.093, 0.616±0.097)for RRM1, respectively. The clinical effect of chemotherapy was negatively correlated with mRNA expression of ERCC1 and RRM1 (r=0.567, P=0.032). Conclusions Levels of ERCC1 and RRM1 mRNA expression are correlated with the staging of esophageal squamous cell carcinoma and chemotherapy sensitivity, and can be used as a predictive parameter for chemotherapy sensitivity in patients with esophageal squamous cell carcinoma. Key words: DNA-Repair; Esophageal neoplasms; Antineo plastic combined chemotherapy Protocols; Genes, tumor suppressor

Predictive Role of ERCC1 Expression in Head and Neck Squamous Cell Carcinoma Patients Treated with Surgery and Adjuvant Cisplatin-Based Chemoradiation

Objective: ERCC1 (excision repair cross-complementation group 1) expression predicts survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation. In order to evaluate the predictive role in the adjuvant setting, we investigated ERCC1 expression in radically resected HNSCC patients who underwent surgery and cisplatin chemoradiation. Methods: ERCC1 expression levels were determined by immunohistochemistry in primary tumor tissues from 48 patients with stage III-IV cancers. The median follow-up was 38.5 months (range: 5-121). Results: High ERCC1 expression was observed in 36 (75%) patients. Univariate analysis showed that patients with high levels of ERCC1 had significantly worse disease-free survival and overall survival (OS) than patients with low levels (HR = 7.15; 95% CI, 1.68-30.35; p = 0.008 and HR = 9.90; 95% CI, 1.33-73.96; p = 0.025, respectively). In the multivariate analysis, high ERCC1 expression (HR = 7.36; 95% CI, 1.72-31.4; p = 0.007) together with high-risk category (HR = 2.69; 95% CI, 1.01-7.18; p = 0.048) were the best predictors for relapse. High ERCC1 expression was the only unfavorable independent determinant for OS (HR = 9.53; 95% CI, 1.27-71.35; p = 0.028). Conclusions: This investigation suggests that ERCC1 expression might be useful to predict prognosis in radically resected HNSCC patients treated with surgery and chemoradiation.

Excision repair cross-complementation group 1 protein expression predicts survival in patients with high-grade, non-metastatic osteosarcoma treated with neoadjuvant chemotherapy.

To evaluate the clinical impact of excision repair cross-complementation group 1 (ERCC1) expression in high-grade osteosarcoma (OS). Immunohistochemistry was performed on biopsies from 99 OS patients enrolled in the ISG/OS-Oss training set or ISG/SSG1 validation set neoadjuvant chemotherapy protocols, based on the use of cisplatin, adriamycin, methotrexate, and ifosfamide. In the training set, ERCC1 positivity was found in eight of 31 (26%) patients, and was significantly associated with worse event-free survival (EFS) (P=0.042) and overall survival (OVS) (P=0.001). In the validation set, ERCC1 positivity was found in 22 of 68 (32%) patients, and its significant associations with poorer EFS (P=0.028) and OVS (P=0.022) were confirmed. Multivariate analyses performed on the whole patient series indicated that ERCC1 positivity was the only marker that was significantly associated with a higher risk of worse prognosis, in terms of both EFS and OVS (P=0.013). Co-evaluation of ERCC1 and ABCB1 expression showed that patients who were positive for both markers had a significantly worse prognosis. The ERCC1 level at diagnosis is predictive for the outcome of patients with non-metastatic, high-grade OS treated with neoadjuvant chemotherapy, and co-evaluation with ABCB1 can identify high-risk groups of OS patients who are refractory to standard regimens.

ERCC1 as a prognostic factor for survival in patients with advanced urothelial cancer treated with platinium-based chemotherapy: A systematic review and meta-analysis.

351 Background: Platinium based chemotherapy (CT) is an essential part in the treatment of advanced urothelial cancer (AUC). However, not all patients derive benefit. A body of evidence suggests that excision repair cross-complementation group 1 (ERCC1) expression level may correlate with outcome in platinum treated patients. We thought to perform a systematic review and meta-analysis to better elucidate its role in AUC. Methods: A comprehensive literature review was performed to identify all studies comparing platinum-based regimens according to expression levels of ERCC1 for patients with AUC. The search included the PubMed, Embase, Cochrane Central Register of Controlled Trials databases, and abstracts from the American Society of Clinical Oncology meetings up to June 2014. Pooled analyses were conducted using fixed and random effects models. Results: A total of 554 patients included in eight studies were evaluated. ERCC1 expression was positive in 270 (49%) patients and negative in 284 (51%) patients. The median age of patients was 63 years. The overall survival (OS) was significantly better in patients with negative ERCC1 expression (pooled hazard ratio (HR) 1.90 (95% confidence interval [CI], 0.98–3.67; p=0.006). There was moderate amount of between-study heterogeneity present (I-square 70%). Conclusions: This study's findings support the hypothesis that low ERCC1 expression is associated with benefit from cisplatin-based treatment. The substantial amount of between-study heterogeneity may indicate the need for standardized methods to classify ERCC1 expression level. Prospective studies are necessary to determine the role of ERCC1 levels for treatment selection in patients with AUC.

Prognostic value of excision repair cross-complementation group 1 expression in gastric cancer: A meta-analysis.

The prognostic impact of excision repair cross-complementation group 1 (ERCC1) expression in gastric cancer (GC) has been investigated for decades, but has yielded controversial results. The aim of the present study was to provide a precise evaluation of whether the expression levels of ERCC1 are associated with overall survival (OS) in patients with GC. A systematic search of Medline and Embase was conducted. Original studies concerning OS and ERCC1 expression were included for critical appraisal. A total of 15 studies comprising 1,425 patients with GC were identified. The results revealed that high/positive ERCC1 expression was an indicator of poor survival in patients with GC [hazard ratio (HR) 1.48; 95% confidence interval (CI) 1.02–2.10; P=0.036; I2=83.8%; random-effects model] compared with low/negative ERCC1 expression. Subgroup analysis indicated that high/positive ERCC1 expression had a significant unfavorable impact on OS in the group of patients evaluated by reverse transcription polymerase chain reaction (RT-PCR; HR 2.57; 95% CI 1.49–4.45). Furthermore, high/positive ERCC1 expression was found to be associated with poor survival in patients receiving platinum-based chemotherapy in the RT-PCR group (HR 2.13; 95% CI 1.06–4.27). These data suggest that ERCC1 may be a useful prognostic factor for GC. In addition, low mRNA levels of ERCC1 appear to be associated with a significant favorable OS benefit from platinum-based chemotherapy.

Efficacy markers for cisplatin and S-1 in biliary tract carcinoma.

334 Background: Gemcitabine (GEM) + cisplatin (CDDP) combination chemotherapy is the first choice for advanced biliary tract carcinoma (BTC). In Japan, the GEM + S-1 therapy has shown promise for the treatment of BTC. Our aim was to investigate the cytotoxic effects of GEM, CDDP and S-1 on BTC cell lines and find an immunohistochemical marker for predicting the efficacy of chemotherapy. Methods: We evaluated the efficacy of GEM, CDDP, and S-1 by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of 17 BTC cell lines. Furthermore, we subdivided the cell lines into sensitive and insensitive groups on the basis of the sensitivity of each drug. Moreover, pairwise studies were conducted using the MTT assay, Bliss additivism model, and Combination Index for analysis. Immunohistochemical expression analysis of excision repair cross-complementation group 1 (ERCC1), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) were also performed in each cell line to compare the results of the cytotoxic effects of CDDP and S-1. Results: In the single-agent MTT assays, among the 17 tumor cell lines, 11 were sensitive to GEM, 13 to CDDP, and 11 to S-1. In 5 cell lines, <30% of the cells showed ERCC1 expression; these lines belonged to the CDDP-sensitive group. Conversely, the cell lines with >30% ERCC1-positive cells mostly belonged to the CDDP-insensitive group. CDDP IC50 correlated with the percentage of ERCC1-positive cells (P <.05). In contrast, none of the immunohistochemical markers could be used to select a cutoff level that would point to the sensitivity to S-1. In pairwise MTT assays (combination therapy), we demonstrated the synergy of GEM with CDDP in 9 tumor cell lines (53%) and the synergy of GEM with S-1 in 4 tumor cell lines(24%). Although 3 cell lines with the synergy of GEM with CDDP showed <30% ERCC1-positive cells, there was no correlation between them. Conclusions: ERCC1 expression in <30% of cells may help to identify CDDP-sensitive tumors; however, it is unknown whether expression of ERCC1 can help to predict efficacy of treatment with GEM + CDDP.

ERCC1 as a Predictive Marker for FOLFOX Chemotherapy in an Adjuvant Setting

PurposeThe purpose of this study was to identify the excision repair cross-complementation group 1 (ERCC1) as a predictive marker for FOLFOX adjuvant chemotherapy in stages II and III colon cancer patients.MethodsA total of 166 high risk stages II and III colon cancer patients were retrospectively enrolled in this study, and data were collected prospectively. They underwent a curative resection followed by FOLFOX4 adjuvant chemotherapy. We analyzed ERCC1 expression in the primary colon tumor by using immunohistochemical staining. The oncological outcomes included the 5-year disease-free survival (DFS) rate. The DFS was analyzed by using the Kaplan-Meier method with the log-rank test. A Cox proportional hazard model was used for the prognostic analysis.ResultsERCC1-positive expression was statistically significant in the older patients (P = 0.032). In the multivariate analysis, the prognostic factors for DFS were female sex (P = 0.016), N stage (P = 0.009), and postoperative carcinoembryonic antigen level (P = 0.001), but ERCC1 expression was not a statistically significant prognostic factor for DFS in the univariate analysis (P = 0.397). The 5-year DFS rate was not significantly associated with the ERCC1 expression in all patients (P = 0.396) or with stage III disease (P = 0.582).ConclusionWe found that ERCC1 expression was not significantly correlated with the 5-year DFS as reflected by the oncologic outcomes in patients with high-risk stages II and III colon cancer treated with FOLFOX adjuvant chemotherapy.

ERCC1 and the Prognosis for Patients With Colon Cancer Receiving Oxaliplatin-Based Adjuvant Chemotherapy.

See Article on Page 92-97 Oxaliplatin is known to be a platinum-based chemotherapeutic agent that carries a 1, 2-diamino-cyclohexane ring. This drug has shown in vitro and in vivo antitumor activities in patients with colorectal cancer (CRC) [1]. The addition of oxaliplatin to 5FU (FOLFOX regimen) was shown to improve the adjuvant treatment of stage-III colon cancer by reducing the risk of recurrence and increasing overall survival [2,3]. Oxaliplatin exerts its action by forming DNA-platinum mono-adducts, primarily with guanines. Oxaliplatin also inhibits DNA replication and transcription and induces apoptosis [1]. Generally, oxaliplatin-induced adducts are not recognized by the mismatch repair system, but are repaired by the nucleotide excision repair and base excision repair pathways [4,5]. An enhanced DNA repair efficiency may contribute to a resistance to platinum-based cytotoxic drugs. Several studies have demonstrated that single nucleotide polymorphisms involved in DNA repair, such as excision repair cross-complementing group 1 (ERCC1) [6], may predict the clinical outcome for patients receiving oxaliplatin-based chemotherapy for the treatment of CRC. In metastatic CRC, measurements of the ERCC1 and the thymidylate synthase (TS) expressions have potential clinical utility in managing patients, and several studies have addressed the role of ERCC1 in terms of adjuvant colon-cancer treatment. The authors used immunohistochemical staining in an attempt to identify ERCC1 as a predictive marker for FOLFOX adjuvant chemotherapy in treating patients with stage-II and -III colon cancer [7]. They found that ERCC1 expression was not significantly correlated with the 5-year disease-free survival as reflected by the oncologic outcomes in patients with high-risk stage-II and -III colon cancer treated with FOLFOX adjuvant chemotherapy. Although the authors could not show any predictive impact of ERCC1, negative results regarding ERCC1 in the era of colon cancer are not unusual, which is the reason a further prospective, large-scale study is needed regarding this issue.

Correlation Analysis and Prognostic Impact of 18F-FDG PET and Excision Repair Cross-Complementation Group 1 (ERCC-1) Expression in Non-Small Cell Lung Cancer

The aim of this study was to determine the relationship between [(18)]-2-fluoro-2-deoxy-D-glucose (FDG) uptake and excision repair cross-complementation group 1 (ERCC-1) expression and to evaluate the prognostic effect of these two factors in resectable non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed 212 patients with resectable NSCLC who underwent FDG positron emission tomography/computed tomography (PET/CT) scan for cancer staging and ERCC-1 expression analysis between January 2008 to December 2011. All patients were then followed-up for survival analysis. Semiquantitative evaluation of ERCC-1 was performed with the H-scoring system and was correlated with maximum standardized uptake value (SUVmax) of NSCLC. Univariate and multivariate analyses were performed to evaluate for FDG uptake and ERCC-1 expression predicting overall survival. In 212 patients (139 male, median age 68 ± 9.11), 112 patients had ERCC-positive tumors and 100 patients had ERCC-negative tumors. There was no significant difference in SUVmax between ERCC-1-positive tumors (8.02 ± 5.40) and ERCC-1-negative tumors (7.57 ± 6.56, p = 0.584). All patients were followed-up for a median of 40.5months (95% confidence interval [CI], 38.5-42.2months). Univariate analysis and multivariate analysis for all patients showed that both ERCC-1 expression (hazard ratio [HR], 2.78; 95% CI, 1.20-6.47) and FDG uptake (HR, 4.50; 95% CI, 2.07-9.77) independently predicted overall survival. We have found no statistical correlation between FDG uptake and ERCC-1 expression in NSCLC. However, both higher FDG uptake and positive ERCC-1 expression are independent predictive markers of prognosis, suggesting that both should be obtained during patient workup.

The prognostic value of excision repair cross-complementation group 1 (ERCC1) in patients with small cell lung cancer (SCLC) receiving platinum-based chemotherapy: evidence from meta-analysis.

Recently, the correlation between the efficacy of platinum-based chemotherapy and ERCC1 expression in patients with SCLC has attracted wide-spread attention, and a lot of investigations have been conducted, whereas conflicting results were presented. Therefore, we performed the present meta-analysis of eligible studies to derive a more precise evaluation of the association between ERCC1 expression and the clinical outcome in SCLC patients receiving platinum-based chemotherapy. A literature search for relevant studies was conducted in the electronic databases of PubMed, EMBASE and Web of Science. The inclusive criteria were SCLC patients treated by platinum-based chemotherapy, and evaluated the relationship between ERCC1 expression and the clinical outcomes [including overall response rate (ORR), overall survival (OS) or progression-free survival (PFS)]. Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) was calculated to assess the risk. A total of nine studies including 1129 patients were included in final analysis. Our analysis indicated that positive/high ERCC1 expression was associated with unfavorable OS (HR = 1.18, 95%CI = 1.02–1.37) and PFS (HR = 1.46, 95%CI = 1.14–1.88). Subgroup analysis according to disease stage suggested the significant relationship was found in limited stage (LS-SCLC), but not in extensive stage (ES-SCLC). However, no significant association was found between ERCC1 expression and ORR. Our analysis suggested ERCC1 expression may be a prognostic factor in SCLC patients receiving platinum-based chemotherapy, especially for LS-SCLC.

ERCC1-positive circulating tumor cells in the blood of ovarian cancer patients as a predictive biomarker for platinum resistance.

Platinum resistance constitutes one of the most recognized clinical challenges for ovarian cancer. Notably, the detection of the primary tumor-based excision repair cross-complementation group 1 (ERCC1) protein by immunohistochemistry was recently shown to be inaccurate for the prediction of platinum resistance. On the basis of the previous finding that circulating tumor cells (CTC) in the blood of ovarian cancer patients are prognostically significant, and given our hypothesis that the negative prognostic impact of CTC may arise from a cellular phenotype associated with platinum resistance, we asked whether expression of the excision repair cross-complementation group 1 (ERCC1) gene in the form of the ERCC1 transcript in CTC may be a suitable blood-based biomarker for platinum resistance. The presence of CTC was analyzed by immunomagnetic CTC enrichment (n = 143 patients) targeting the epithelial epitopes epithelial cell adhesion molecule (EPCAM) (also known as GA733-2) and mucin 1, cell surface associated (MUC1), followed by multiplex reverse-transcription PCR to detect the transcripts EPCAM, MUC1, and mucin 16, cell surface associated (MUC16) (also known as CA125), including ERCC1 transcripts in a separate approach. ERCC1 expression in primary tumors was comparatively assessed by immunohistochemistry, using the antibody 8F1. At primary diagnosis, the presence of CTC was observed in 14% of patients and constituted an independent predictor of overall survival (OS) (P = 0.041). ERCC1-positive CTC (ERCC1(+)CTC) were observed in 8% of patients and constituted an independent predictor, not only for OS but also for progression-free survival (PFS) (P = 0.026 and P = 0.009, respectively). More interestingly, we discovered the presence of ERCC1(+)CTC at primary diagnosis to be likewise an independent predictor of platinum resistance (P = 0.010), whereas ERCC1 expression in corresponding primary tumor tissue predicted neither platinum resistance nor prognosis. The presence of ERCC1(+)CTC can serve as a blood-based diagnostic biomarker for predicting platinum resistance at primary diagnosis of ovarian cancer.

192P - Prognostic Biomarkers in Malignant Pleural Mesothelioma

ABSTRACT Aim: The standard of care for malignant pleural mesothelioma (MPM) includes combination of platinum compounds and pemetrexed. Despite this, the median survival of MPM patients is still bad (12 months). Excision Repair Cross Complementing Group 1 (ERCC1) acts removing DNA adducts formed by platinum compounds, whereas Pemetrexed inhibits Thymidylate Synthase (TS), a folic enzyme also involved in ex novo synthesis of DNA. This study aims to analyse retrospectively, in a large series of MPM specimens, the ERCC1 and TS gene and protein expression to investigate their prognostic and predictive role. Methods: Pleural biopsies were collected from140 consecutive MPM patients (98 males and 42 females, mean age 68 years, range 27-90). Histologic subtypes were: epithelioid (#103, 73%), sarcomatoid (#19, 14%) and biphasic (#18, 13%). At the end of the study 113 patients were died (average disease specific survival (DSS) 13 months; range 1-60); mRNA was extracted from formalin fixed paraffin embedded blocks and reverse transcribed in cDNA to perform gene expression assay by qRT-PCR. Immunohistochemistry was performed by anti-ERCC1 and anti-TS mAbs and the results were scored from 0 to 3 depending on the percentage of positive tumour cells and staining intensity. The results were statistically correlated with the clinical features and with the DSS of the patients respectively by Fisher's exact test and Logrank test. Results: Of 140 patients 102 received platinum and pemetrexed (in single or in combination), the remaining were untreated due to bad performance status, advanced age or refusing therapy. Statistically significant correlation was found between the lack of protein expression of ERCC1 and DSS in the whole cohort (P = .03). Low levels of TS mRNA were significantly correlated with the DSS in the whole cohort (P = .01) and in the untreated subgroup (including patients not receiving pemetrexed) (P = .04), whereas did not in the subgroup of pemetrexed treated patients Conclusions: ERCC1 protein expression, scored by IHC, and TS gene expression, evaluated by mRNA analysis, seem both important prognostic markers; we suggest their evaluation in routine biopsies from patients with MPM. Disclosure: All authors have declared no conflicts of interest.

Immunohistochemistry to Enhance Prognostic Allocation and Guide Decision-Making of Patients With Advanced Urothelial Cancer Receiving First-Line Chemotherapy

BackgroundKnowledge of the expression of molecular drivers and potentially druggable targets might enhance prognostic classification of M UC. Materials and MethodsWe analyzed archival tissue from patients with UC who underwent first-line chemotherapy for locally advanced (LA) and M disease between the years 2000 and 2013. The following biomarkers were evaluated using IHC: excision repair cross complementation (ERCC) group 1 (ERCC1), epidermal growth factor receptor (EGFR), HER2, VEGFR-3, PDGFRα, p53, and p63. Expression of ERCC1, EGFR, and HER2 was dichotomized as positive (2+, 3+) or negative (≤ 1+). Cox regression models were used to evaluate the association of biomarker expression with progression-free (PFS) and overall survival (OS), after controlling for known prognostic factors. ResultsSince June of 2009, tissues of 88 cases (27 LA, 61 M) were stained. Rates of positive IHC/number evaluable were as follows: ERCC1: 30 of 66 (45%); HER2: 24 of 52 (46%); EGFR: 31 of 54 (57%); VEGFR-3: 50 of 66 (76%); PDGFRα: 10 of 63 (16%); p53: 25 of 56 (45%); and p63: 46 of 53 (87%). In the multivariable model, PDGFRα was significantly prognostic for poorer PFS (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.37; P = .047) and trended to significance for poorer OS (HR, 2.66; 95% CI, 0.96-7.42; P = .060) and VEGFR-3 was significantly prognostic for better PFS (HR, 0.33; 95% CI, 0.15-0.74; P = .007) and OS (HR, 0.36; 95% CI, 0.15-0.85; P = .019). The c-index of the model was 0.67 and 0.68 for the 2 end points, respectively. ConclusionTumor VEGFR-3 and PDGFRα expression appeared to confer a divergent prognostic effect. These data underscore the hurdles in defining the role of angiogenesis as a molecular driver and therapeutic target, and the controversial role of IHC to guide therapeutic decision-making.

Predictive value of excision repair cross-complementation group 1 expression for platinum-based chemotherapy and survival in gastric cancer: a meta-analysis.

The predictive value of excision repair cross-complementation group 1 (ERCC1) gene for survival and response to platinum-based chemotherapy in gastric cancer (GC) remains controversial. We performed a meta-analysis to clarify the precise estimation of the prognostic and predictive effect of ERCC1. A systematic literature search was conducted using PubMed, ScienceDirect, Wiley and American Society of Clinical Oncology (ASCO) before March 2014. Studies analyzing survival data and/or chemotherapy response in GC by ERCC1 status were identified. The principal outcome measures were hazard ratios (HRs) for survival and relative risks (RRs) for chemotherapy response. Pooled HRs and RRs were calculated using fixed- or random-effects models according to the heterogeneity. Twenty-one studies involving 1,628 patients met our inclusion criteria. High ERCC1 expression was significantly associated with shorter overall survival (OS) and lower response to chemotherapy in advanced GC patients receiving palliative chemotherapy (HR 1.83; 95% CI 1.45-2.31; P<0.001; RR 0.49; 95% CI 0.38-0.62; P<0.001). There was no significant difference in survival between high and low ERCC1 expression in adjuvant setting (OS: HR 1.38; 95% CI 0.77-2.45; P=0.276; EFS 0.72; 95% CI 0.38-1.33; P=0.291). Some evidence of heterogeneity and possible publication bias were discovered in few meta-analyses. High ERCC1 expression might be an adverse prognostic and a drug-resistance predictive factor for advanced GC patients. However, further studies with consistent ERCC1 assessment methodology are needed.

Prognostic significance of ERCC1 expression in postoperative patients with gastric cancer.

This study explored the correlation between the expression of excision repair cross-complementation group 1 (ERCC1) and the prognosis of gastric cancer patients. From January 2005 to December 2008, 605 patients who underwent radical surgery in The First Affiliated Hospital of Nanjing Medical University were enrolled. We conducted the follow-up every 6 months and its contents included a comprehensive medical history, tumor markers and abdominal ultrasound or CT and other imaging findings. Deadline was April 30, 2013 and follow-up time between 51 to 91 months. Survival time is calculated from the date of diagnosis to death or last follow-up date. Immunohistochemistry (IHC) was used to assess the expression of ERCC1 in resected samples. The relationship between ERCC1 expression and survival of patients was investigated. The comparison of count data were analyzed by Chi-square test. Median survival time (MST) and the 5-year survival rate were calculated by life table analysis. The Kaplan-Meier curves were used for survival analysis. ERCC1 expression was positive in 412 patients (68.1%). There is no significant difference between ERCC1-positive group and ERCC1-negative group in terms of the MST and 5-year survival rate (P=0.455). The MST and 5-year survival rate have no significant difference (P=0.162) between group with chemotherapy and group with no chemotherapy in patients with ERCC1-positive expression. However, the MST and 5-year survival rate in patients with ERCC1-negative expression benefited more from with chemotherapy (P=0.019). The ERCC1-positive patients survived longer than those ERCC1-negative patients (P=0.183) in subgroup with no adjuvant chemotherapy. In the subgroup analysis, ERCC1 expression had no significant relationship with overall survival in patients with stage II or III gastric cancer (P>0.05). ERCC1 might be a good prognostic factor for the patients of gastric cancer after radical resection. Patients with ERCC1-negative expression could benefit more from adjuvant chemotherapy.

Involvement of ERCC1 in the pathogenesis of osteoarthritis through the modulation of apoptosis and cellular senescence.

DNA damage is a cause of age related pathologies, including osteoarthritis (OA). Excision repair cross complementation group 1 (ERCC1) is an endonuclease required for DNA damage repair. In this study we investigated the function of ERCC1 in chondrocytes and its association with the pathophysiology of OA. ERCC1 expression in normal and osteoarthritic cartilage was assessed, as were changes in ERCC1 expression in chondrocytes under catabolic stress. Inhibiting ERCC1 in chondrocytes under interleukin-1β stimulation using small interfering RNA (siRNA) was also evaluated. Finally, cellular senescence and apoptosis were examined in relation to ERCC1 function. ERCC1 expression was decreased in OA cartilage and increased within 4 h of exposure to interleukin (IL)-1β, but decreased after 12 h. The inhibition of ERCC1 by siRNA increased the expression of matrix metallopeptidase 13 and decreased collagen type II. ERCC1 inhibition also increased the number of apoptotic and senescent cells. The inhibition of ERCC1 in chondrocytes increased their expression of OA related proteins, apoptosis, cellular senescence, and hypertrophic-like changes which suggest that ERCC1 is critical for protecting human chondrocytes (HCs) from catabolic stresses and provides insights into the pathophysiology of OA and a potential target for its treatment. (191)

Expression of ERCC1 and class III β-tubulin in locally advanced cervical squamous cell carcinoma and its correlation with different therapeutic regimens.

e16505 Background: Several studies in solid tumors have shown that the excision repair cross-complementation group 1 (ERCC1) and class III β-tubulin (TUBB3) expressions can predict response to chem...