ERCC1 mRNA Levels Research Articles

Characterizing excision repair cross-complementing family genes as drug resistance biomarkers in breast cancer

BackgroundExcision repair cross-complementing (ERCC) genes are important regulators of DNA repair processes, the aberrant expression of which may lead to treatment failures of breast cancer. The prognostic significance of the ERCC genes in several cancers has been investigated, except for breast cancer; therefore, we explored the ERCC genes, including ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, and ERCC8 in breast cancer, particularly during drug resistance processes.ResultsUsing the 2021 provisional study of The Metastatic Breast Cancer Project from cBioPortal, we identified ERCC genetic alterations in 8–36% of patients, where most alterations were considered amplifications followed by deep deletions. Pathway enrichment analyses identified Wnt signaling enrichment which contributed to cell proliferation. ERCC2 had the highest epigenetic alteration levels at 7 DNA methylation sites. Also, the mRNA levels of ERCC1, ERCC2, ERCC4, ERCC6, and ERCC8 were higher in patients with breast cancer when compared to normal breast tissues, with higher ERCC2 but lower ERCC8 levels in metastatic breast tissues. Breast cancer patients with low ERCC6 levels had better overall survival rates than the groups with higher ERCC6 levels. ERCC1, ERCC2, and ERCC4 were identified as endocrine therapy response predictors. ERCC1 was specifically an antihuman epidermal growth factor receptor therapy predictor, and ERCC1, ERCC2, ERCC6, and ERCC8 were chemotherapy response predictors.ConclusionWe used bioinformatics to investigate and identify the roles of ERCC genes in breast cancer resistant cells, in particular ERCC1, ERCC2, and ERCC6. We also showed how the Wnt pathway and DNA repair processes had a role in drug resistance in breast cancer cells, but further studies are required to validate those results.

Fabrication and evaluation of a dual-targeting nanoparticle mediated CRISPR/Cas9 delivery to combat drug resistance in breast cancer cells

Breast cancer treatment is hampered by drug resistance which leads to recurrence and metastasis. Alteration of specific gene expression such as ERCC1 evidently acquires drug resistance in breast cancer patients. The genome-editing technique known as the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated Cas9 system (CRISPR-Cas9) has shown promise in targeting genes. The current study aimed to design and characterize an efficient cargo through a safe and noninvasive dual-targeted polyplex for CRISPR/Cas9 delivery to downregulate the ERCC1 gene expression, which is overexpressed in MCF-7 cisplatin-resistant cells. In this manner, a carrier based on chitosan (CS) polyplex was modified with hyaluronic acid conjugated triptorelin (HA-LHRH) as dual-targeting agents and loaded with CRISPR/Cas9 plasmids. CS/HA-LHRH/pCRISPR exhibited negligible toxicity and comparable transfection efficiency with Lipofectamine™ 3000. Dual-targeted polyplexes have boosted gene transfer by nearly two times that of single-targeted polyplexes (CS/HA/pCRISPR). Also, the dual-targeted polyplexes carrying plasmids of CRISPR/Cas9 enhanced drug sensitivity and decreased ERCC1 mRNA levels in MCF-7 cisplatin-resistant cell line, significantly. Our results suggest that CS/HA-LHRH/pCRISPR-mediated targeting of ERCC1 is practicable and could be potentially adopted as a novel therapeutic tool for removing platinum drug resistance in breast cancer cells.

ERCC1 polymorphism and its expression associated with ischemic stroke in Chinese population.

Excision repair cross-complementing group 1 (ERCC1) was considered a potential candidate gene for ischemic stroke, and its polymorphisms might be associated with the susceptibility to ischemic stroke. A total of 513 patients with ischemic stroke and 550 control subjects were recruited. The expression levels of ERCC1 messenger RNA (mRNA) in peripheral blood mononuclear cells and its protein in plasma were detected by quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Rs3212986 polymorphism of ERCC1 was detected by PCR-restriction fragment length polymorphism (RFLP-PCR) and was confirmed by sequencing. The association between the ERCC1 rs3212986 polymorphism or its expression and ischemic stroke was further analyzed. The ERCC1 mRNA level in patients with ischemic stroke was lower than that in the control group (P < 0.05). However, the ERCC1 protein level in patients with ischemic stroke was higher than that in the control group (P < 0.05). The A allele of rs3212986 was associated with increased ischemic stroke risk (OR = 1.287, 95% CI = 1.076-1.540, P = 0.006). The association between rs3212986 polymorphism and ischemic stroke susceptibility was found in both recessive (OR = 2.638, 95% CI = 1.744-3.989, P < 0.001) and additive models (OR = 1.309, 95% CI = 1.028-1.667, P = 0.031), respectively. Similar results were obtained in the recessive model (OR = 2.015, 95% CI = 1.087-3.704, P = 0.026) after adjusting for demographic information and other variables. Additionally, the level of ERCC1 mRNA in the CC/CA genotype was higher than that in the AA genotype (P < 0.05). It was suggested that the ERCC1 rs3212986 polymorphism was associated with ischemic stroke susceptibility in a Chinese Han population and that an A allele of rs3212986 was related to increased ischemic stroke risk. The altered ERCC1 expression level caused by the rs3212986 polymorphism might participate in the pathophysiological process of ischemic stroke.

PAICS is related to glioma grade and can promote glioma growth and migration.

Glioma is a common malignant tumour of the brain. In this study, we aimed to investigate diagnostic biomarkers and its role in glioma. Weighted gene co‐expression network analysis (WGCNA) and Cytoscape software were used to screen the marker genes in glioma. RT‐qPCR and Western blotting methods were performed to determine the expression of PAICS, ERCC1 and XPA genes in glioma tissues. Expression level of PAICS in different grades of glioma was examined by immunohistochemistry. CCK8 and Colony formation assays were used to detect cell proliferation. Cell adhesion assay was used to detect adhesion ability. Wound healing and transwell tests were used to detect cell migration ability. Flow cytometry was used to detect cell cycle and apoptosis. According to the predicted co‐expression network, we identified the hub gene PAICS. Furthermore, we observed that PAICS expression level was up‐regulated in glioma tissues compared with normal tissues, and the expression level was correlated with the grade of glioma. Moreover, we found PAICS can promote glioma cells proliferation and migration in vitro. Flow cytometry results showed that si‐PAICS cells were stalled at the G1 phase compared with the si‐NC cells and knocking down PAICS expression can increase apoptotic rate. PAICS can regulate the mRNA and protein levels of nucleotide excision repair pathway core genes ERCC1 and XPA. l‐aspartic acid can affect the expression of PAICS and then inhibit glioma cell proliferation. Our results indicated that PAICS can promote glioma proliferation and migration. PAICS may act as a potential diagnostic marker and a therapeutic target for glioma.

Predictive Value of ERCC1 mRNA Level from Receiver-Operator Characteristic and Pretreatment EBV-DNA Virus Load in Stage II Nasopharyngeal Carcinoma Patients Receiving Intensity-Modulated Radiotherapy with Concurrent Cisplatin.

Background: The molecular mechanisms underlying chemoresistance are still poorly understood in nasopharyngeal cancer. The protein expression of ERCC1 in DNA repair genes has been reported related to resistance platinum and predicting treatment outcomes in various malignant carcinomas, but the benefit for predicting outcomes with optimal cutoff value of ERCC1mRNA is controversial. The level of plasma Epstein-Barr virus (EBV) DNA is positively correlated with clinical stages of nasopharyngeal carcinoma (NPC). The predictive value of ERCC1mRNA from receiver-operator characteristic (ROC) and EBV-DNA level for stratified treatment with stage II NPC is exactly unclear. This study aims to assess the predictive value of combined EBV-DNA and ERCC1 in stage II nasopharyngeal cancer (NPC) patients treated with intensity-modulated radiotherapy (IMRT) with concurrent cisplatin, and provide guidance for future stratified treatment. Methods: A total of 86 stage II NPC patients who received IMRT and concurrent cisplatin-based chemotherapy with or without cisplatin-based adjuvant chemotherapy had measurements of ERCC1 mRNA, and pretreatment EBV-DNA levels were analyzed by real-time PCR (RT-PCR). Associations of ERCC1 mRNA and pretreatment EBV-DNA levels with clinical characteristics and survivals were evaluated. Results: Cutoff value of ERCC1 mRNA obtained from ROC curve was used, and there were significant differences in progression-free survival (PFS) and overall survival (OS) and overall response rate (ORR) between high expression group and low expression group (p = 0.021 and 0.030 and 0.000, respectively). Patients with pretreatment EBV-DNA <2000 copies/mL had significantly better PFS and ORR (p = 0.024 and 0.043, respectively) and a marginally significant impact on OS (p = 0.062) than those with pretreatment EBV-DNA ≥2000 copies/mL. Patients were divided into three groups by combination of ERCC1 mRNA and EBV-DNA level: ERCC1 mRNA low expression/pre-EBV-DNA <2000 copies/mL, ERCC1 mRNA low expression/pre-EBV-DNA ≥2000 copies/mL, and ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL. There were significant differences in ORR among the three groups (p = 0.005). The median follow-up was 62 months (range 22-84) with a follow-up rate of 90.70%. In these groups by combination of ERCC1 mRNA and EBV-DNA level, 1, 3, 5-year OS were 100%, 100%, 100%; 100%, 94.1%, 90.9%; and 100%, 85%, 72.9%, respectively (p = 0.038); 1, 3, 5-year PFS were 100%, 100%, 100%; 97.1%, 91.2%, 84.8%; and 95%, 85%, 71.4%, respectively (p = 0.028). Multivariate analysis showed that combination of ERCC1 mRNA and EBV-DNA levels remained independent prognostic factor but not ERCC1 mRNA and EBV-DNA alone. Conclusions: Combined ERCC1 mRNA and pre-EBV-DNA is a better prognostic biomarker in stage II NPC patients treated with concurrent chemoradiation. Patients with ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL may benefit from more aggressive treatment.

Bioactive Hexapeptide Reduced the Resistance of Ovarian Cancer Cells to DDP by Affecting HSF1/HSP70 Signaling Pathway.

Ovarian cancer is the leading cause of death in gynecologic malignancies. Ovarian cancer as a metastatic malignant tumor is highly recurrent and prone to drug resistance. Bioactive peptides are an emerging area of biomedical research in reducing resistance of tumor cell to drugs. In this paper, we investigated the effects and mechanisms of bioactive hexapeptide (PGPIPN) derived in milk protein on the sensitivity of ovarian cancer cells to cis-dichlorodiammine platinum (DDP). Human ovarian cancer cell lines (SKOV3 and COC1), their DDP-resistant sublines (SKOV3/DDP and COC1/DDP) and human primary ovarian cancer cells were cultured in vitro under the combined treatment of DDP (close to IC50) and different concentrations of PGPIPN. The viabilities, apoptosis and cell cycle changes were respectively measured by WST-8 and flow cytometry. The mRNA and protein expression levels of HSF1, HSP70, MDR1, ERCC1 and β-actin gene were respectively assayed by RT-qPCR and western blotting. The results showed that PGPIPN significantly increased the sensitivity of human ovarian cancer cells to DDP in inhibiting viability and inducing apoptosis in vitro. But the effects in sensitive cells were lower than DDP-resistant cells. PGPIPN significantly changed the cell cycles in all human ovarian cancer cells, which leaded to a significant increase in the percentage of cells blocked at G2/M phase and decrease the percentage of cells at G1 phases in a dose-dependent manner. PGPIPN affected the expression levels of HSF1, HSP70, MDR1 and ERCC1 genes. Compared with cells in DDP treatment alone, the expression levels of HSF1 and HSP70 in human ovarian cancer cells treated with DDP and PGPIPN together significantly decreased in dose-dependent manner. PGPIPN significantly decreased MDR1 and ERCC1 of drug-resistant ovarian cancer cell lines and human primary ovarian cancer cell in a dose-dependent manner. Pifithrin-μ (PFTμ, HSP70 inhibitor) decreased or removed the effects of peptide in increasing the sensitivity of ovarian cancer cells to DDP. This suggests that PGPIPN enhanced the sensitivity of ovarian cancer cells to DDP partially via reducing the activity of HSF1/HSP70 signaling pathway, thus inducing cell apoptosis and decreasing repairment of DNA damage.

Expression and Clinical Significance of ERCC1 and XPF in Human Hepatocellular Carcinoma.

ObjectiveTo investigate the correlation between the ERCC1 and XPF expression and the clinicopathological parameters of hepatocellular carcinoma (HCC) patients through assessment of the expression of the DNA repair genes ERCC1 and XPF.MethodsERCC1 and XPF mRNA expression in HCC (n= 177) and adjacent para-cancer tissues (n=21) were assessed by RT-PCR. The correlation between ERCC1 and XPF expression, clinicopathological features and HCC prognosis were compared.ResultsERCC1 expression in liver cancer tissues was significantly lower than that of adjacent tissues (9.5% (2/21) vs 38.1% (8/21); P<0.05). The positive expression rates of XPF in liver cancer tissues was lower than that of adjacent tissues (14.3% (3/21) vs 71.4% (15/21); P<0.05). ERCC1 and XPF expression were associated with hepatic capsular invasion and microvascular invasion. HCC patients with hepatic capsular invasion and microvascular tumor embolus formation had significantly lower levels of ERCC1 and XPF mRNA than those without hepatic capsular invasion and microvascular tumor embolus formation (P<0.05). In addition, ERCC1 expression was associated with TNM staging of HCC. The expression of ERCC1 mRNA in patients with stage II and III HCC were lower than that of patients with stage I HCC (P<0.05). The low levels of ERCC1 and XPF mRNA significantly correlated with relapse-free survival times (RFS) in HCC patients. The median RFS of the low ERCC1 expression group and low XPF expression group were shorter than those of the high expression group (15.0 months vs 32.0 months, P<0.05) and (19.0 months vs 33.0 months, P<0.05). The decrease in XPF mRNA expression was significantly associated with the overall survival (OS) of HCC patients. The median OS in the low XPF expression group was shorter than that of the high expression group (46.0 months vs 78.0 months, P<0.05). However, no significant difference in OS between the low ERCC1 expression group and the high ERCC1 expression groups were observed (63.0 months vs 64.0 months, P>0.05). Multivariate analysis showed that tumor size and the extent of differentiation were independent factors affecting the RFS in HCC patients (P<0.05). The extent of differentiation and XPF were independent factors affecting the OS in HCC (P<0.05).ConclusionThe expression in ERCC1 and XPF were low in HCC and associated with early relapse after HCC surgery. Low XPF expression may be a potential indicator of a high risk of death.

Transcription Factor ZNF326 Upregulates the Expression of ERCC1 and HDAC7 and its Clinicopathologic Significance in Glioma.

Previous reports that we have coauthored have shown that transcription factor ZNF326 can upregulate the expression of ERCC1 and HDAC7, and downregulate the expression of LTBP4 and ZNF383 in lung-cancer cells. However, whether tissue-specificity of the ZNF326 function exists in glioma tissue remains unclear. In this study, overexpression or knockdown of ZNF326 in glioma cells caused upregulation or downregulation, respectively, of the protein and micro RNA (mRNA) levels of ERCC1 and HDAC7. The levels of LTBP4 and ZNF383 were not significantly changed. Immunohistochemical results showed that ZNF326 was not only highly expressed in glioma but was also positively correlated with the expression of ERCC1 and HDAC7. Moreover, the expression of ERCC1 and HDAC7 was enhanced with the increase in tumor grade. However, there was no correlation between ZNF326 and the expression of LTBP4 and ZNF383. Therefore, the detection of ZNF326, ERCC1, and HDAC7 expressions was useful for identifying different grades of glioma.

A Preliminary Study of NER and MMR Pathways Involved in Chemotherapy Response in Bladder Transitional Cell Carcinoma: Impact on progression-free survival.

One of the main genotoxic drugs used in bladder cancer chemotherapy is cisplatin. While it is applied in most types of cancers, resistance to cisplatin is wildly common. In order to overcome drug resistance, it is necessary to determine a predictive marker. This study was conducted to provide basic data for selecting and designing a gene profile for further cohort and RCT studies in the future to improve response to treatment in bladder cancer. The expression levels of ERCC1, MLH1, MSH2, and CTR1 mRNA were determined in the tumor tissue using real-time q-PCR. Progression-free survival (PFS) was analyzed in term of the level of genes expression. The results revealed that the level of ERCC1 mRNA expression was higher in the recurrence (R) group compared to the no recurrence (NR) group. Moreover, the PFS time was increased in the patients with an ERCC1 expression level of below 1.57. The level of MLH1 and MSH2 mRNA expression was lower in the R group compared to the NR group; therefore, PFS time was increased in the patients with MLH1 and MSH2 gene expression levels above the cutoff point. While the level of CTR1 mRNA expression was higher in the R group versus the NR group, the PFS time was longer in the patients with CTR1 expression levels of below 1.265 compared to the patients with high levels of CTR1 expression. It can be concluded that the level of ERCC1, MLH1, MSH2, and CTR1 mRNA expression may be associated with PFS time as possible therapeutic targets for decreasing cisplatin resistance.

PREDICTORS OF CHEMORESISTANCE TO PLATINUM-CONTAINING NEOADJUVANT CHEMOTHERAPY IN ADVANCED OVARIAN CANCER

Chemoresistance is one of the main causes of treatment failure in advanced ovarian cancer (OC). In order to identify predictors of chemoresistance, 30 patients with ascitic form of OC, who received neoadjuvant chemotherapy (NACT) according to AP regimen, were examined. In the epithelial cells of ascites and in tumor tissue after NACT, expression of the VEGFa, ABCB1 and ERCC1 genes was assessed by PCR-RT. The effectiveness of NACT was assessed using the criteria of therapeutic pathomorphosis, survival - using the Kaplan-Meier criterion, the relationship of clinical and molecular parameters - using the Mann-Whitney criterion. Results. We established that in 43% of patients the response to NACT was absent (CRS1), the significant response (CRS2) was in 35% of cases, and the complete response (CRS3) was in 21% of cases. VEGFa expression was increased in ascites in 17% of cases, in tumor tissue - in 33% in the CRS1 group. In groups with CRS 2,3, overexpression of VEGFa in ascites was detected in 25% of cases, in tumor tissue in 37.5%. ABCB1 mRNA expression was increased after NACT in 50% of cases in the CRS1 group and in 25% of cases in the CRS 2,3 group. Thus, platinum-based NACT initiates an increase in the expression of VEGFa and ABCB1 in tumor tissue. We established that in case of high expression (ERCC + / VEGF + / ABCB1 +) in ascites, there is a statistically significant increase in relapse-free survival compared with the group with low or absent expression (p = 0.012). The overall survival rate was 41.8 months in patients with overexpression of the studied genes in the tissue of the primary tumor after NACT and 25.3 months in patients with low expression (p = 0.058). Conclusion. The levels of ERCC1, VEGFa and ABCB1 mRNA in ascitic cells before NACT and in the primary tumor after NACT according to the AP scheme can serve as a predictor of the effectiveness of this treatment in ascitic OC.

Low-power laser alters mRNA levels from DNA repair genes in acute lung injury induced by sepsis in Wistar rats.

Acute lung injury (ALI) is defined as respiratory failure syndrome, in which the pathogenesis could occur from sepsis making it a life-threatening disease by uncontrolled hyperinflammatory responses. A possible treatment for ALI is the use of low-power infrared lasers (LPIL), whose therapeutical effects depend on wavelength, power, fluence, and emission mode. The evaluation mRNA levels of repair gene related to oxidative damage after exposure to LPIL could provide important information about the modulation of genes as treatment for ALI. Thus, the aim of this study was to evaluate the mRNA levels from OGG1, APEX1, ERCC2, and ERCC1 genes in lung tissue from Wistar rats affected by ALI and after exposure to LPIL (808nm; 100mW). Adult male Wistar rats (n = 30) were randomized into six groups (n = 5, for each group): control, 10J/cm2 (2J), 20J/cm2 (5J), ALI, ALI + LPIL 10J/cm2 and ALI + LPIL 20J/cm2. ALI was induced by intraperitoneal E. coli lipopolysaccharide injection (10mg/kg). Lungs were removed, and samples were withdrawn for total RNA extraction, cDNA synthesis, and mRNA levels were evaluated by RT-qPCR. Data normality was verified by Kolmogorov-Smirnov, comparisons among groups were by Student's t test, Mann-Whitney test, one-way ANOVA, Kruskal-Wallis followed by post-tests. Data showed that OGG1 (0.39 ± 0.10), ERCC2 (0.67 ± 0.24), and ERCC1 (0.60 ± 0.19) mRNA levels are reduced in ALI group when compared with the control group (1.00 ± 0.07, 1.03 ± 0.25, 1.01 ± 0.16, respectively) and, after LPIL, mRNA relative levels from DNA repair genes are altered when compared to non-exposed ALI group. Our research shows that ALI alter mRNA levels from genes related to base and nucleotide excision repair genes, suggesting that DNA repair is part of cell response to sepsis, and that photobiomodulation could modulate the mRNA levels from these genes in lung tissue.

Expression of nucleotide excision repair in Alzheimer’s disease is higher in brain tissue than in blood

Age-related changes are increased in patients with Alzheimer’s disease (AD), including oxidative stress and DNA damage. We propose that genotoxic stress and DNA repair responses influence neurodegeneration in the pathogenesis of AD. Here, we focus on nucleotide excision repair (NER). Real-time qPCR and mass spectrometry were employed to determine the expression levels of selected NER components. The mRNA levels of the genes encoding the NER proteins RAD23B, RPA1, ERCC1, PCNA and LIG3 as well as the NER-interacting base excision repair protein MPG in blood and brain tissue from four brain regions in patients with AD or mild cognitive impairment and healthy controls (HC), were assessed. NER mRNA levels were significantly higher in brain tissue than in blood. Further, LIG3 mRNA levels in the frontal cortex was higher in AD versus HC, while mRNA levels of MPG and LIG3 in entorhinal cortex and RPA1 in the cerebellum were lower in AD versus HC. In blood, RPA1 and ERCC1 mRNA levels were lower in AD patients than in HC. Alterations in gene expression of NER components between brain regions were associated with AD, connecting DNA repair to AD pathogenesis and suggesting a distinct role for NER in the brain.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

P2.03a-007 Pem/CBP/Bev Followed by Pem/Bev in Hispanic Patients with NSCLC: Outcomes According to Combined Score of TS, ERCC1 and VEGF Expression

To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS), ERCC1 and VEGF mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance pemetrexed and bevacizumab was administered until disease progression or unacceptable toxicity. One hundred forty-four Hispanic patients with a median follow-up of 13.8 months and a median number of maintenance cycles of 6 (range, 1- 32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median progression-free and overall survival (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. Median TS, ERCC1 and VEGF mRNA levels were 1.45 (range, 0.17–2.52), 0.58 (range, 0.44-1.20), and 2.72 (range, 1.84-3.21), respectively. OS was significantly higher in patients with the lowest TS mRNA levels [29.6 months (95% CI 26.2-32.9) compared with those with higher levels 9.3 months (95% CI 6.6-12.0); p=0.0001]. ERCC1 mRNA levels also influenced the OS [median for ERCC1 mRNA˂0.58 28.7 months (95% CI 26.3-31.2) vs. ERCC1 mRNA˃0.58 11.1 months (95% CI 9.6-12.7); p=0.0001] as well as VEGF mRNA levels [median OS for VEGF mRNA˂2.72 26.4 months (95% CI 22.8-30.0) vs. VEGF mRNA˃2.72 18.2 months (95% CI 8.4-27.9); p=0.009]. TS mRNA did not influence treatment response, however the ORR was significantly higher in patients with low levels of ERCC1 (p = 0.003) and elevated VEGF (p = 0.005). Multivariate analysis found that TS mRNA levels (p=0.0001), VEGF mRNA levels (p=0.007) and PS (p=0.014) were independent prognostic factors. Overall, PCB followed by maintenance pemetrexed and bevacizumab was in Hispanic patients with non-squamous NSCLC. This regimen was associated with prolonged OS, particularly in patients with low TS, ERCC1 and VEGF mRNA expression. These biomarkers alone or in combination may be useful to assess the prognosis of patients with NSCLC treated with CBP/Pem/Bev.

ERCC1_202 Is A Prognostic Biomarker in Advanced Stage Non-Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

Purpose: To develop a qPCR method to examine the 202 isoform of excision repair cross-complementation group 1 (ERCC1_202) and to evaluate its clinical utility as a predictive biomarker for platinum-based chemotherapy in non-small cell lung cancer (NSCLC).Methods: The relative complementary DNA (cDNA) quantification for ERCC1_202 was conducted using a fluorescence-based, real-time detection method and β-actin was used as a reference gene.Results: A strong correlation was observed between ERCC1_202 mRNA and ERCC1 mRNA levels in NSCLC cells (P < 0.001). 28 patients completed this research. Our results implied that as ERCC1_202 levels increased, the risk of progression (HR = 4.296, P = 0.011) and death (HR = 6.503, P = 0.001) increased. At multivariate analysis, high expression of ERCC1_202 was shown to be an independent predictive factor for time to progression (P = 0.047), and progression-free survival (P = 0.014). However, the high expression of ERCC1_202 was not an independent predictive factor for response (P = 0.324).Conclusions: This study suggests that the efficacy of platinum-based chemotherapy can be improved when customized according to the expression of ERCC1_202.

642P - Plasma mRNA as liquid biopsy in individualized chemotherapy of gastric cancer

Biomarker from blood could be a useful and non-invasive tool to provide real-time information in the procedure of treatment. To further understand the role of plasma mRNA in chemo-efficiency prediction, several mRNA levels were assessed in plasma and paired FFPE tumor tissues, and were correlated with chemosensitivity. In the 133 patients with locally advanced gastric cancer (Stage III), significant correlations were observed between plasma and tumor mRNA levels of BRCA1(rho = 0.532, P < 0.001), ERCC1(rho = 0.570, P < 0.001), TS(rho = 0.506, P = 0.002), Topo1 (rho = 0.310, P = 0.031), and APTX (rho = 0.561, P < 0.001). Correlations were also observed between the mRNA expression of plasma/tumor BRCA1 levels and docetaxel sensitivity (P < 0.001), plasma/tumor TS and pemetrexed sensitivity (P < 0.001), plasma/tumor BRCA1 and platinum sensitivity (plasma, P = 0.016; tumor, P < 0.001), and plasma/tumor Topo1 and irinotecan sensitivity (plasma, P = 0.015; tumor, P = 0.011). Among another 64 patients with advanced cancer (Stage IV), 55 patients were in the test group receiving chemotherapy according to plasma gene detection, and 9 patients were in the control. The median overall survival of test group was 15.5 months (95% CI = 10.1 to 20.9 months), the progress free survival was 9.1 months (95% CI = 8.0 to 10.2 months), which were significant longer than the control (P = 0.047 for OS, P = 0.038 for PFS). The risk of mortality was higher in the control than patients treated according to the plasma gene detection (HR in the control = 2.34, 95% CI = 0.93 to 5.88, P = 0.071). Plasma mRNA expression levels mirror those in the tumor and can be used as promising predictive biomarkers to predict chemo-efficiency.

Changes in expression levels of ERCC1, DPYD, and VEGFA mRNA after first-line chemotherapy of metastatic colorectal cancer: results of a multicenter study.

Our previous study showed that administering oxaliplatin as first-line chemotherapy increased ERCC1 and DPD levels in liver colorectal cancers (CRCs) metastases. Second, whether the anti-VEGF monoclonal antibody bevacizumab alters tumoral VEGFA levels is unknown. We conducted this multicenter observational study to validate our previous findings on ERCC1 and DPD, and clarify the response of VEGFA expression to bavacizumab administration. 346 CRC patients with liver metastases were enrolled at 22 Japanese institutes. Resected liver metastases were available for 175 patients previously treated with oxaliplatin-based chemotherapy (chemotherapy group) and 171 receiving no previous chemotherapy (non-chemotherapy group). ERCC1, DPYD, and VEGFA mRNA levels were measured by real-time RT-PCR. ERCC1 mRNA expression was significantly higher in the chemotherapy group than in the non-chemotherapy group (P = 0.033), and were significantly correlated (Spearman's correlation coefficient = 0.42; P < 0.0001). VEGFA expression level was higher in patients receiving bevacizumab (n = 51) than in those who did not (n = 251) (P = 0.007). This study confirmed that first-line oxaliplatin-based chemotherapy increases ERCC1 and DPYD expression levels, potentially enhancing chemosensitivity to subsequent therapy. We also found that bevacizumab induces VEGFA expression in tumor cells, suggesting a biologic rationale for extending bevacizumab treatment beyond first progression.

ERCC1 SNPs as Potential Predictive Biomarkers in Non-Small Cell Lung Cancer Patients Treated With Platinum-Based Chemotherapy

Polymorphisms in ERCC1, XPD, and XRCC1 were examined for (a) association with the clinical outcome of 107 non-small cell lung cancer patients receiving front-line platinum-based chemotherapy, and (b) correlation with the ERCC1 mRNA levels of 176 chemo-naive primary tumors. The ERCC1-C8092 allele and the number of ERCC1 polymorphic variants (C8092A and Asn118Asn) were associated with progression-free survival. In non-squamous histology, tumoral ERCC1 mRNA levels were lower in patients homozygous for ERCC1-C8092 as compared with the patients carrying the A allele (p = .024). These findings merit investigation in larger cohorts of patients treated with uniform regimens.

Association between ERCC1 and TS mRNA levels and disease free survival in colorectal cancer patients receiving oxaliplatin and fluorouracil (5-FU) adjuvant chemotherapy.

BackgroundAim was to explore the association of ERCC1 and TS mRNA levels with the disease free survival (DFS) in Chinese colorectal cancer (CRC) patients receiving oxaliplatin and 5-FU based adjuvant chemotherapy.MethodsTotal 112 Chinese stage II-III CRC patients were respectively treated by four different chemotherapy regimens after curative operation. The TS and ERCC1 mRNA levels in primary tumor were measured by real-time RT-PCR. Kaplan–Meier curves and log-rank tests were used for DFS analysis. The Cox proportional hazards model was used for prognostic analysis.ResultsIn univariate analysis, the hazard ratio (HR) for the mRNA expression levels of TS and ERCC1 (logTS: HR = 0.820, 95% CI = 0.600 - 1.117, P = 0.210; logERCC1: HR = 1.054, 95% CI = 0.852 - 1.304, P = 0.638) indicated no significant association of DFS with the TS and ERCC1 mRNA levels. In multivariate analyses, tumor stage (IIIc: reference, P = 0.083; IIb: HR = 0.240, 95% CI = 0.080 - 0.724, P = 0.011; IIc: HR < 0.0001, P = 0.977; IIIa: HR = 0.179, 95% CI = 0.012 - 2.593, P = 0.207) was confirmed to be the independent prognostic factor for DFS. Moreover, the Kaplan-Meier DFS curves showed that TS and ERCC1 mRNA levels were not significantly associated with the DFS (TS: P = 0.264; ERCC1: P = 0.484).ConclusionThe mRNA expression of ERCC1 and TS were not applicable to predict the DFS of Chinese stage II-III CRC patients receiving 5-FU and oxaliplatin based adjuvant chemotherapy.

Relevance of ERCC1, RRM1 and BRCA1 in surgically treated non-small cell lung cancer patients

Scientific objectives Chemotherapy has been an important modality of treatment of NSCLC. Recent studies have shown that assessment of predictive molecular markers could be helpful for estimation of response rate to chemotherapy. The aim of our study was to assess relation of mRNA levels of DNA repair genes ERCC1, RRM1 and BRCA1 in surgically resected tumor tissue in patients who received adjuvant chemotherapy to disease free interval (DFI) and overall survival (OS). We investigated if potential residual tumor cells after resection reflect properties of a primary tumor and response to chemotherapy according to level of predictive markers with the respect to current knowledge.