Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations

Wu, Jo‐Hsuan; Wu, Shang‐Gin; Yang, Chih-Hsin; Chang, Yih‐Leong; Chang, Yeun‐Chung; Hsu, Ya‐Chieh; Shih, Jin‐Yuan; Yang, Pan‐Chyr

doi:10.1016/j.lungcan.2010.08.013

Cited by 68 publications

(55 citation statements)

References 32 publications

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“…Both drugs are reversible TKI with a similar mechanism of action (32,33). In the present study, data were pooled, as no differences in 18 F-FLT kinetics were observed between the 2 treatment regimens.…”

Section: Discussionmentioning

confidence: 93%

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

et al. 2014

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3′-deoxy-3′-18 F-fluorothymidine ( 18 F-FLT) PET/CT provides a noninvasive assessment of proliferation and, as such, could be a valuable imaging biomarker in oncology. The aim of the present study was to assess the validity of simplified quantitative parameters of 18 F-FLT uptake in non-small cell lung cancer (NSCLC) patients before and after the start of treatment with a tyrosine kinase inhibitor (TKI). Methods: Ten patients with metastatic NSCLC harboring an activating epidermal growth factor receptor mutation were included in this prospective observational study. Patients underwent 15 O-H 2 O and 18 F-FLT PET/CT scanning on 3 separate occasions: within 7 d before treatment, and 7 and 28 d after the first therapeutic dose of a TKI (gefitinib or erlotinib). Dynamic scans were acquired and venous blood samples were collected during the 18 F-FLT scan to measure parent fraction and plasma and whole-blood radioactivity concentrations. Simplified measures (standardized uptake value [SUV] and tumor-to-blood ratio [TBR]) were correlated with fully quantitative measures derived from kinetic modeling. Results: Twenty-nine of thirty 18 F-FLT PET/CT scans were evaluable. According to the Akaike criterion, a reversible 2-tissue model with 4 rate constants and blood volume parameter was preferred in 84% of cases. Relative therapy-induced changes in SUV and TBR correlated with those derived from kinetic analyses (r 2 5 0.83-0.97, P , 0.001, slope 5 0.72-1.12). 18 F-FLT uptake significantly decreased at 7 and 28 d after the start of treatment compared with baseline (P , 0.01). Changes in 18 F-FLT uptake were not correlated with changes in perfusion, as measured using 15 O-H 2 O. Conclusion: SUV and TBR could both be used as surrogate simplified measures to assess changes in 18 F-FLT uptake in NSCLC patients treated with a TKI, at the cost of a small underestimation in uptake changes or the need for a blood sample and metabolite measurement, respectively.

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Section: Discussionmentioning

confidence: 93%

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

et al. 2014

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“…Acquisition of tumor specimens for testing for EGFR mutations were done before EGFR TKI treatments. Patients screened for EGFR mutations included: (i) those participating in clinical trial studies (22); (ii) those who underwent fine needle biopsy or thoracentesis for pleural effusions after July 2004, when consecutive recruitment for EGFR mutations was started at the hospital; (iii) whose resected tumors were retrospectively sequenced; and (iv) those who were recruited for retrospective NSCLC studies (6,15,(23)(24)(25)(26). Tissue sections were examined for adequacy by microscopy with hematoxylin and eosin staining; tissue samples that consisted of more than 80% tumor content, were selected for the study.…”

Section: Mutational Analysis Of Egfrmentioning

confidence: 99%

Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer

Yu²,

Chang³

et al. 2011

Clinical Cancer Research

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Purpose: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance.Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations.Results: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months).Conclusions: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed. Clin Cancer Res; 17(11); 3812-21. Ó2011 AACR.

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“…In addition, it is now clear that some molecularly targeted agents are more efficacious in specific, molecularly defined subsets of patients (6). The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, erlotinib, induces striking clinical responses in patients with activating mutations in the EGFR kinase domain (7); however, there is evidence that a subset of patients with EGFR wild-type tumors also derive benefit from erlotinib therapy (8)(9)(10). Recent efforts have therefore focused on identifying molecular biomarkers that identify further subsets of patients that may derive benefit from erlotinib.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Profiling Defines Clinically Relevant Biological Subsets of Non–Small Cell Lung Cancer

Walter¹,

Holcomb²,

Januario³

et al. 2012

Clinical Cancer Research

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Purpose: Non-small cell lung cancers (NSCLC) comprise multiple distinct biologic groups with different prognoses. For example, patients with epithelial-like tumors have a better prognosis and exhibit greater sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) pathway than patients with mesenchymal-like tumors. Here, we test the hypothesis that epithelial-like NSCLCs can be distinguished from mesenchymal-like NSCLCs on the basis of global DNA methylation patterns.Experimental Design: To determine whether phenotypic subsets of NSCLCs can be defined on the basis of their DNA methylation patterns, we combined microfluidics-based gene expression analysis and genomewide methylation profiling. We derived robust classifiers for both gene expression and methylation in cell lines and tested these classifiers in surgically resected NSCLC tumors. We validate our approach using quantitative reverse transcriptase PCR and methylation-specific PCR in formalin-fixed biopsies from patients with NSCLC who went on to fail front-line chemotherapy.Results: We show that patterns of methylation divide NSCLCs into epithelial-like and mesenchymal-like subsets as defined by gene expression and that these signatures are similarly correlated in NSCLC cell lines and tumors. We identify multiple differentially methylated regions, including one in ERBB2 and one in ZEB2, whose methylation status is strongly associated with an epithelial phenotype in NSCLC cell lines, surgically resected tumors, and formalin-fixed biopsies from patients with NSCLC who went on to fail frontline chemotherapy.Conclusions: Our data show that patterns of DNA methylation can divide NSCLCs into two phenotypically distinct subtypes of tumors and provide proof of principle that differences in DNA methylation can be used as a platform for predictive biomarker discovery and development.

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Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations

Cited by 68 publications

References 32 publications

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer

DNA Methylation Profiling Defines Clinically Relevant Biological Subsets of Non–Small Cell Lung Cancer

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Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations

Cited by 68 publications

References 32 publications

Assessment of Simplified Methods to Measure 18F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

Assessment of Simplified Methods to Measure 18F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

Effectiveness of Tyrosine Kinase Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer

DNA Methylation Profiling Defines Clinically Relevant Biological Subsets of Non–Small Cell Lung Cancer

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Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment

Assessment of Simplified Methods to Measure ¹⁸F-FLT Uptake Changes in EGFR-Mutated Non–Small Cell Lung Cancer Patients Undergoing EGFR Tyrosine Kinase Inhibitor Treatment