Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer

Sun, Wanqing; Song, Liping; Ai, Ting; Zhang, Yingbin; Gao, Ying; Cui, Jie

doi:10.7555/jbr.27.20130004

Cited by 34 publications

(37 citation statements)

References 40 publications

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“…This indicates that the tivantinib/erlotinib combination presents superior efficacy in EGFR-resistant patients with high expression of c-Met high or HGF high, both reported as poor prognostic factors. [8][9][10][11] Interestingly, similar superior efficacy in a poor prognosis population (ie, c-Met high and/or HGF high) was observed in previous phase III studies testing the tivantinib/erlotinib combination, even though those studies enrolled patients with NSCLC with backgrounds different from this study. The MARQUEE study enrolled EGFR-TKI-naive Caucasian patients including about 10% EGFR mutation-positive patients, and resulted in longer OS in c-Met high; HR was 0.70 (95% CI 0.49 to 1.01, vs placebo) in c-Met high, and 0.90 (95% CI 0.64 to 1.26, vs placebo) in c-Met low.…”

Section: Discussionsupporting

confidence: 76%

“…Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, which is reported as a poor prognostic factor in NSCLC, [8][9][10][11] may define a patient subset associated with longer survival by treatment using the tivantinib/erlotinib combination. It will be interesting to evaluate the efficacy of tivantinib alone in patients with activated HGF/c-Met signalling in the future.…”

Section: Discussioncontrasting

confidence: 60%

“…7 Activation of HGF/c-Met signalling due to overexpression of HGF/c-Met is reported to be involved in tumour infiltration and metastasis, and is identified as a poor prognosis factor in NSCLC. [8][9][10][11] Tivantinib (ARQ 197) is an oral, non-ATP-competitive, low-molecular weight selective c-Met inhibitor. The primary metabolic enzyme of tivantinib, CYP2C19, is known for the gene polymorphism associated with loss of function.…”

Section: Introductionmentioning

confidence: 99%

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Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

et al. 2016

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BackgroundPatients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs.MethodsThis study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples.ResultsThe ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone.ConclusionsAlthough this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination.Trial registration numberNCT01580735.

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Section: Discussionsupporting

confidence: 76%

Section: Discussioncontrasting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

et al. 2016

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“…There was heterogeneity between studies for both univariate ( I 2 = 58.0%, p = 0.008) and multivariate ( I 2 = 71.5%, p <0.001) analyses (Figure 2). Further analysis showed that the observed heterogeneity reflected the inclusion of the studies by Sun et al [13] and Dziadziuszko et al [18] When these studies were excluded from the meta-analysis, less heterogeneity was observed ( I 2 = 4.2%, p = 0.400; I 2 = 0%, p = 0.488), and the pooled results remained practically unchanged (HR for univariate analysis: 1.74, 95% CI: 1.40–2.15, p <0.001; HR for multivariate analysis: 1.53, 95% CI: 1.26–1.87, p <0.001).…”

Section: Resultsmentioning

confidence: 99%

Prognostic Value of MET Gene Copy Number and Protein Expression in Patients with Surgically Resected Non-Small Cell Lung Cancer: A Meta-Analysis of Published Literatures

et al. 2014

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BackgroundThe prognostic value of the copy number (GCN) and protein expression of the mesenchymal-epithelial transition (MET) gene for survival of patients with non-small cell lung cancer (NSCLC) remains controversial. This study aims to comprehensively and quantitatively asses the suitability of MET GCN and protein expression to predict patients' survival.MethodsPubMed, Embase, Web of Science and Google Scholar were searched for articles comparing overall survival in patients with high MET GCN or protein expression with those with low level. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed.ResultsEighteen eligible studies enrolling 5,516 patients were identified. Pooled analyses revealed that high MET GCN or protein expression was associated with poor overall survival (OS) (GCN: HR = 1.90, 95% CI 1.35–2.68, p<0.001; protein expression: HR = 1.52, 95% CI 1.08–2.15, p = 0.017). In Asian populations (GCN: HR = 2.22, 95% CI 1.46–3.38, p<0.001; protein expression: HR = 1.89, 95% CI 1.34–2.68, p<0.001), but not in the non-Asian subset. For adenocarcinoma, high MET GCN or protein expression indicated decreased OS (GCN: HR = 1.49, 95% CI 1.05–2.10, p = 0.025; protein expression: HR = 1.69, 95% CI 1.31–2.19, p<0.001). Results were similar for multivariate analysis (GCN: HR = 1.61, 95% CI 1.15–2.25, p = 0.005; protein expression: HR = 2.18, 95% CI 1.60–2.97, p<0.001). The results of the sensitivity analysis were not materially altered and did not draw different conclusions.ConclusionsIncreased MET GCN or protein expression was significantly associated with poorer survival in patients with surgically resected NSCLC; this information could potentially further stratify patients in clinical treatment.

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“…For example, EGFR gene amplification was shown to significantly correlate with CCND1 amplification [25], while its mutations were associated with CCND1 expression [47]. Changes in expression and gene copy number of MET oncogene were also found to coexist with aberrant cyclin D1 expression in NSCLC patients and these co-alterations had significantly adverse effect on patients' outcome [48].…”

Section: Discussionmentioning

confidence: 97%

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

et al. 2015

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Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.

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Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer

Cited by 34 publications

References 40 publications

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

Phase II study of erlotinib plus tivantinib (ARQ 197) in patients with locally advanced or metastatic EGFR mutation-positive non-small-cell lung cancer just after progression on EGFR-TKI, gefitinib or erlotinib

Prognostic Value of MET Gene Copy Number and Protein Expression in Patients with Surgically Resected Non-Small Cell Lung Cancer: A Meta-Analysis of Published Literatures

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

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