Guanghui Gao

Tongji University, Shanghai, Shanghai Shi, China

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Publications (12)37.65 Total impact

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    ABSTRACT: Current targeted therapy proves no effective outcomes in lung squamous cell carcinoma (SQCC). Recent studies suggested that FGFR1 would be promising. This systematic review elaborated FGFR1 amplification in lung SQCC. An electronic search was conducted on PubMed, EMBASE, Web of SCI, Google Scholar and Cochrane Library. Eligible studies regarding incidence of FGFR1 amplification in lung SQCC and correlation between FGFR1 amplification and clinicopathological features or survival were extracted and analyzed. We identified 13 eligible studies with a total of 1798 patients. The results showed about 19% of FGFR1 amplification (95% CI: 0.15-0.24; I(2)=84.5%; p=0.000). Using the same test method: FISH, definition and ethnicity, the rates were 17% (95% CI: 0.14-0.20; I(2)=53.1%; p=0.037), 21% (95% CI: 0.18-0.24; I(2)=0; p=0.615), and 16% (95% CI: 0.13-0.19; I(2)=72.1%; p=0.028), respectively. Pearson's correlation analysis suggested that smoking status was highly correlated with FGFR1 amplification (coefficient=0.961, p<0.001). FGFR1 amplification was significantly correlated with lymph node metastasis (OR: 2.27; 95% CI: 1.62-3.20; p=0.000), but not correlated with gender (OR: 1.12; 95% CI: 0.90-1.38; p=0.91), differentiation (OR: 1.02; 95% CI: 0.76-1.38; p=0.959) and stage (OR: 0.93; 95% CI: 0.73-1.19; p=0.877) in lung SQCC patients. With respect to survival, FGFR1 amplification had no influence on PFS (HR: 1.57; 95% CI: 0.85-2.30; p=0.259) and OS (HR: 1.40; 95% CI: 0.90-1.89; p=0.416) for SQCC patients. FGFR1 amplification is about 19%. Gender, stage, differentiation, ethnicities and test methods have no influence on FGFR1 amplification. FGFR1 amplification trends to correlate with lymph node metastasis and smoking. Whether FGFR1 amplification has effect on survival remains controversial. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Lung cancer (Amsterdam, Netherlands) 11/2014; · 3.14 Impact Factor
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    ABSTRACT: Several polymorphisms in the genes involved in drug metabolism or elimination are known to be associated with pharmacokinetic or pharmacodynamic variability, but their correlations with overall survival (OS) and response rate (RR) in lung cancer have been unknown. This prospective study was to investigate whether genetic polymorphisms could influence OS and RR in advanced or metastatic non-small-cell lung cancer (NSCLC) patients treated with third-generation cytotoxic chemotherapy. Three hundred and sixty-four patients with chemotherapy naïve stage IIIB or IV NSCLC, receiving standard first-line chemotherapy, were eligible for this study. The DNA samples were extracted from peripheral blood mononuclear cells before treatment and single nucleotide polymorphisms of solute carrier family 29 member 3 SLC29A3 (rs10999776), SULT1E1 (rs4149525), and TBXAS1 (rs2267703), a category of drug-metabolizing enzymes or transporters were analyzed. Statistical analyses were performed by the log-rank test and Cox proportional hazards model. Patients with SLC29A3 C/T+T/T genotype had longer overall survival (median OS 12.3 months, 95 % CI 11.0-13.6 months) than those with C/C genotype (median OS 11.0 months, 95 % CI 9.9-12.1 months, P = 0.030 for log-rank test). More evidently significant association was found between the SLC29A3 polymorphism and overall survival in patients treated with gemcitabine-based chemotherapy (C/T+T/T versus C/C: median OS 12.0 months, 95 % CI 10.5-13.5 months versus median OS 10.0 months, 95 % CI 9.0-11.0 months, P = 0.027 for log-rank test). No association between the other two genetic polymorphisms and OS was observed. Genes involved in the drug metabolism or elimination (SLC29A3) may be new prognostic biomarkers for patients with advanced NSCLC who receive gemcitabine as the first-line chemotherapy and may unveil an unexplored molecular pathway correlated with the drug response and further may be predictive biomarkers for these patients.
    Medical Oncology 04/2014; 31(4):865. · 2.14 Impact Factor
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    ABSTRACT: Epithelial to mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Nowadays there is still no predictive biomarker identified for the use of EGFR-TKIs in non-small cell lung cancer (NSCLC) patients with wild-type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR-TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from Jun 2008 to Sep 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E-cadherin, fibronectin, N-cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (P=0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5% vs 11.1% vs 0.0% vs 2.4% p=0.011), longer PFS (4.4 vs 1.9 vs 1.7 vs 1.0 months, P<0.001) and longer OS (11.5 vs 8.9 vs 4.5 vs 4.9 months, P<0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild-type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild-type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR-TKI therapy in this population. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2014; · 6.20 Impact Factor
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    ABSTRACT: Background and purpose Continuous EGFR-TKI treatment beyond progression has shown promising benefit for some patient with acquired resistance to EGFR-TKIs. The aim of this study was to investigate the association of secondary T790 M mutation at the time of progression with the efficacy of EGFR-TKI treatment beyond progression. Methods From Mar 2011 to Mar 2013, patients with advanced NSCLC who developed acquired resistance to EGFR-TKI and where a re-biopsy was performed in Tongji University Cancer Institute were included into this study. Scorpion ARMS was used to detect EGFR mutation status. Results 54 patients were enrolled in this study with a median progression-free survival time (PFS1) of 10.9 months according to RECIST criteria. 53.7% (29/54) had T790 M mutation after the failure of EGFR-TKIs, PFS1 was not statistically significantly different between patient with T790 M mutation and without (13.0 vs10.5 months, p = 0.894). 41 patients received TKI treatment beyond progression, including 22 with local progression to receive additional local therapy and 19 with gradual progression to receive additional chemotherapy. The median progression-free survival time (PFS2) of patients who received EGFR-TKI beyond progression treatment was 3.5 months (95% CI 2.689-4.311). Patients with T790 M mutation had significantly longer PFS2 (6.3 vs2.6 months, p = 0.002) and overall survival(39.8vs 23.2 months, p = 0.044) than those without. Conclusion Patients with secondary T790 M mutation at time of progression having gradual or local progressionafter acquired resistance to EGFR-TKI benefit more from EGFR-TKI treatment beyond progression compared to those without T790 M mutation
    Lung cancer (Amsterdam, Netherlands) 01/2014; · 3.14 Impact Factor
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    ABSTRACT: BACKGROUND: Epidermal growth factor receptor (EGFR) activating mutation is an important predictive biomarker of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), while family history of cancer also plays an important role in the neoplasia of lung cancer. This study aimed to investigate the association between family history of cancer and EGFR mutation status in NSCLC population. METHODS: From February 2008 to May 2012, 538 consecutive NSCLC patients with known EGFR mutation status were included into this study. Amplification refractory mutation system (ARMS) method was used to detect EGFR mutation. The associations between EGFR mutation and family history of cancer were evaluated using logistic regression models. RESULTS: EGFR activating mutation was found in 220 patients and 117 patients had family cancer histories among first-degree relatives. EGFR mutation was more frequently detected in adenocarcinoma patients (p<0.001), never-smoker (p<0.001) and with family history of cancer (p=0.031), especially who had family history of lung cancer (p=0.008). In multivariate analysis, the association of EGFR mutation with family history of cancer also existed (p=0.027). CONCLUSIONS: NSCLC patients with family history of cancer, especially family history of lung cancer, might have a significantly higher incidence of EGFR activating mutation.
    Lung cancer (Amsterdam, Netherlands) 05/2013; · 3.14 Impact Factor
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    ABSTRACT: Background and Purpose With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in patients with advanced non-small cell lung cancer (NSCLC), its acquired resistance has become a major clinical problem. Recent studies revealed that miR-21 was involved into the resistance of cytotoxic agents. The aim of this study was to investigate its role in the acquired resistance of NSCLC to EGFR-TKI. Methods EGFR-TKI-sensitive human lung adenocarcinoma cell line PC9 and the acquired resistant cell line, PC9R, were used. Lentiviral vectors were used to infect PC9 or PC9R to regulate the miR-21 expression. The expression of targeted proteins PTEN and PDCD4 was controlled by RNA interference. MicroRNA array, RT-PCR and TaqMan MicroRNA Assays were used to detect miR-21 expression. The MTT and Annexin V assays were used to determine proliferation and apoptosis. Western Blot and immunohistochemistry were used to analyze target protein expression (PTEN, PDCD4, Akt, p-Akt). We also constructed PC9R xenograft tumor model to observe the relationship between miR-21 and EGFR-TKI resistance in vivo and validated it in the clinical serum specimens of NSCLC patients treated with EGFR-TKI. Result MiR-21 was overexpressed in the EGFR-TKI resistant cell line PC9R relative to PC9. The level of miR-21 was reversely correlated with the expression of PTEN and PDCD4 and positive correlated with PI3 K/Akt pathway. Inhibiting miR-21 with lentivirus vector induces apoptosis in PC9R cell line and inhibiting miR-21with ASO suppressed tumor growth in nude mice treated with EGFR-TKI. Furthermore, serum miR-21 expression in NSCLC patients treated with EGFR-TKI was significantly higher at the time of acquiring resistance than at baseline (p < 0.01). Conclusion miR-21 is involved in acquired resistance of EGFR-TKI in NSCLC, which is mediated by down-regulating PTEN and PDCD4 and activating PI3 K/Akt pathway.
    Lung cancer (Amsterdam, Netherlands) 01/2013; · 3.14 Impact Factor
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    ABSTRACT: Overexpression of COX-2 is proved to contribute to tumor promotion and carcinogenesis through stimulating cell proliferation, inhibiting apoptosis and enhancing the invasiveness of cancer cells. Apoptosis-related molecules are potential predictive markers for survival and toxicity in platinum treatment. This study aimed at investigating the association between COX-2 polymorphisms and the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Two hundred and twelve patients with inoperable stage IIIB-IV NSCLC received first-line chemotherapy between 2007 and 2009 were recruited in this study. Four functional COX-2 polymorphisms were genotyped by PCR-based restriction fragment length polymorphism (RFLP) methods. The incidence of grade 3 or 4 hematologic toxicity was significantly higher in G allele carriers of the COX-2 rs689466 (-1195G/A) polymorphism compared with wild-type homozygotes AA (P value = 0.008; odds ratio, 2.47; 95% confidence internal, 1.26-4.84) and the significance still existed after the Bonferroni correction. Statistically significant difference was also found in grade 3 or 4 leukopenia (P value = 0.010; OR = 2.82; 95%CI = 1.28-6.20). No other significant association was observed between genotype and toxicity in the study. The haplotype analysis showed that the haplotype AGG was associated with a reduced risk of grade 3 or 4 hematologic and leukopenia toxicity (P value = 0.009; OR = 0.59; 95%CI = 0.39-0.88 and P value = 0.025; OR = 0.61; 95%CI = 0.39-0.94, respectively) while the haplotype GGG was associated with an increased risk of grade 3 or 4 hematologic and leukopenia toxicity (P value = 0.009; OR = 1.71; 95%CI = 1.14-2.56 and P value = 0.025; OR = 1.65; 95%CI = 1.06-2.57, respectively). This investigation for the first time suggested that polymorphism in COX-2 rs689466 may be a potent bio-marker in predicting severe hematologic toxicity in NSCLC patients after platinum-based chemotherapy.
    PLoS ONE 01/2013; 8(4):e61585. · 3.53 Impact Factor
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    ABSTRACT: One of the target genes of pemetrexed (PEM), thymidylate synthase (TS), has been shown to have a close association with its efficacy. TS gene polymorphisms have been shown to be associated with the efficacy of antifolate treatment in enteron tumors. The purpose of this study was to investigate the clinical significance of TS gene polymorphisms in patients with advanced NSCLC receiving PEM-based treatment. The variable nucleoid tandem repeat in the 5'-UTR region was amplified and detected using fluorescently labeled multiplex short tandem repeat polymerase chain reaction. The polymorphism in the 3'-UTR region of the TS gene was detected using the Taqman probe. Efficacy of PEM was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. None of the genotypes were associated with gender, smoking status and age. Disease control rate (DCR), objective response rate (ORR) and progression-free survival (PFS) were similar between patients harboring 2R and 3R alleles (PFS, p=0.518; DCR, p=0.631; ORR, p=0.541), as well as those with a 6-bp insertion and 6-bp deletion (PFS, p=0.776; DCR, p=0.626; ORR, p=0.330). To study the combined effect of TS polymorphisms, the study population was divided into three groups: 2R&6 del, 2R&6 ins and 3R&6 del. No significant differences were observed among the different groups according to DCR (p=0.517), ORR (p=0.611) and PFS (p=0.938). In conclusion, polymorphisms of the TS gene do not appear to be a prognostic marker for advanced NSCLC patients receiving PEM-based treatment.
    Experimental and therapeutic medicine 12/2012; 4(6):1010-1016. · 0.34 Impact Factor
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    ABSTRACT: Erlotinib is an agent of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors which are used for non-small cell lung cancer. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). ILD induced by gefitinib been often described, but the ILD induced by erlotinib is relatively less well known. We here describle four cases of ILD related to erlotinib and review recent literatures to help physicians earlier alert erlotinib-induced ILD. It is important to carefully monitor pulmonary symptoms in all patients who are receiving erlotinib. Early diagnosis and timely intervention is critical in the treatment of drug-induced ILD.
    Zhongguo fei ai za zhi = Chinese journal of lung cancer 08/2012; 15(8):494-8.
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    ABSTRACT: The published data on the curative effects of comparing the once weekly paclitaxel-based chemotherapies (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies (S-paclitaxel) in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed. Medical databases and conference proceedings were searched for randomized controlled trials which compared W-paclitaxel with S-paclitaxel in patients with first-line treatment of advanced NSCLC. The following keywords were used: "paclitaxel", "weekly schedule" and "non-small cell lung cancer". Reference lists of original articles and review articles were also examined. The published languages and years were not limited. Endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Five eligible trials involved 940 patients were identified. They were all published as full-text articles. The intention to treatment (ITT) analysis demonstrated that the ORR of W-paclitaxel regimens patients was 30.89% (143/463), whereas the ORR of S-paclitaxel regimens patients was 27.09% (123/454). The overall pooled relative ratio (RR) for ORR was 1.24 (95% confidence intervals (CI)=0.93-1.66; P=0.14) when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. Although the patients with W-paclitaxel regimens had an similar OS and PFS in comparison with S-paclitaxel regimens (median OS was 9.8 versus 10.7 months; hazard ratio (HR)=1.00; 95%CI=0.86-1.17; P=0.99; median PFS was 5.2 versus 4.7 months; HR=0.90; 95%CI=0.79-1.03; P=0.13, respectively), the W-paclitaxel regimens led to significantly less frequent adverse events of hematological toxicities and nonhematological toxicities. These results suggest that the W-paclitaxel is not superior than S-paclitaxel regimens. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens. For patients, especially for the elder or the people with poor conditions who cannot tolerate the standard regimen, the weekly schedule can be considered.
    Lung cancer (Amsterdam, Netherlands) 01/2012; 76(3):380-6. · 3.14 Impact Factor
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    ABSTRACT: New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying non-small-cell lung cancer (NSCLC) could influence chemosensitivity. In this study, we assessed whether polymorphisms in genes of nucleotide excision repair (NER) pathway, including ERCC5, ERCC6, MMS19L, CCNH, XPC, RRM1, can affect the tolerability of platinum-based chemotherapy in NSCLC patients. We used AllGloTM probe to assess genotyping and polymorphisms in 388 stage IIIB and IV NSCLC patients treated with platinum-based chemotherapy. MMS19L might be associated with the adverse events of chemotherapy in NSCLC, especially for all grade leucopenia (P = 0.020), all grade jaundice (P = 0.037) and all grade creatinine increasing (P = 0.013). In terms of grade 3/4 adverse events, MMS19L was related with total grade 3/4 adverse events (P = 0.024) and grade 3/4 thrombocytopenia (P = 0.035), while RRM1 was related with total grade 3/4 adverse events (P = 0.047) and grade 3/4 vomiting (P = 0.046). ERCC5 was related with more infection (P = 0.017). We found that some SNPs in NER pathway genes were correlated with toxicity treated with double chemotherapy in advanced NSCLC patients, especially for SNPs of MMS19L, RRM1 and ERCC5.
    PLoS ONE 01/2012; 7(10):e48350. · 3.53 Impact Factor
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    ABSTRACT: Gefiinib and erlotinib are two similar small molecules of selective and reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which have been approved for second-line or third-line indication in previously treated advanced Non-small-cell lung cancer (NSCLC) patients. The results of comparing the EGFR-TKI with standard platinum-based doublet chemotherapy as the first-line treatment in advanced NSCLC patients with activated EGFR mutation were still controversial. A meta-analysis was performed to derive a more precise estimation of these regimens. Finally, six eligible trials involved 1,021 patients were identified. The patients receiving EGFR-TKI as front-line therapy had a significantly longer progression-free survival (PFS) than patients treated with chemotherapy [median PFS was 9.5 versus 5.9 months; hazard ratio (HR)=0.37; 95% confidence intervals (CI)=0.27-0.52; p<0.001]. The overall response rate (ORR) of EGFR-TKI was 66.60%, whereas the ORR of chemotherapy regimen was 30.62%, which was also a statistically significant favor for EGFR-TKI [relative risk (RR)=5.68; 95% CI=3.17-10.18; p<0.001]. The overall survival (OS) was numerically longer in the patients received EGFR-TKI than patients treated by chemotherapy, although the difference did not reach a statistical significance (median OS was 30.5 vs. 23.6 months; HR=0.94; 95% CI=0.77-1.15; p=0.57). Comparing with first-line chemotherapy, treatment of EGFR-TKI achieved a statistical significantly longer PFS, higher ORR and numerically longer OS in the advanced NSCLC patients harboring activated EGFR mutations, thus, it should be the first choice in the previously untreated NSCLC patients with activated EGFR mutation.
    International Journal of Cancer 12/2011; 131(5):E822-9. · 6.20 Impact Factor