1.Influence of Different Therapies on EGFR Mutants by Circulating Cell-free DNA of Lung Adenocarcinoma and Prognosis.
Fei SU ; Ke ZHENG ; Yiyun FU ; Qian WU ; Yuan TANG ; Weiya WANG ; Lili JIANG
Chinese Journal of Lung Cancer 2018;21(5):389-396
BACKGROUND:
Epidermal growth factor receptor (EGFR) gene mutation is closely related to the EGFR-TKI target treatment and prognosis of lung adenocarcinoma patients. The mutation status of EGFR is limited by tissue detection. The purpose of this study was to investigate the difference of EGFR mutants in plasmacirculating cell-free DNA (cfDNA) obtained from patients with non-small cell lung cancer (NSCLC) in three groups: pre-therapy, after traditional chemotherapy and targeted therapy. The aim of this study was to analyze whether the plasma cfDNA could effectively determine the EGFR mutations and monitor the drug resistant gene T790M, as well as its prognostic prediction value in patients with targeted therapy.
METHODS:
ARMS (amplification refractory mutation system)-PCR was used to detect EGFR mutations in 107 (50 of pre-therapy, 29 after traditional chemotherapy and 28 after targeted therapy) cases of paired plasma and tumor tissue specimens, followed by comparing their concordance. The sensitivity, specificity and the prognostic value of plasma cfDNA detection were also observed.
RESULTS:
The total rate of EGFR mutation was 56% (60/107) in all plasma samples and 77.6% (83/107) in corresponding tumor tissues. Completely the same mutants and wild-type EGFR were found in 68.2% cases of paired specimens. The sensitivity of plasma cfDNA detection was 72.3% and the specificity was up to 100%. Patients were sub-categorized according to therapy. The results showed that the highest consistent rate of cfDNA and tumor tissues was found in the group of pre-therapy (74%, 37/50). Whereas, the lowest consistent rate was observed in the targeted therapy group (57.1%, 16/28). It indicated that the targeted treatment could change the EGFR status in plasma cfDNA. Further analyses on inconsistent cases in this group revealed that 50% of them were compound EGFR mutations with T790M. Thereby, it suggested that targeted therapy might induce the emergence of drug resistance gene T790M. This speculation was confirmed by survival analyses. Based on plasma cfDNA results, patients with T790M mutant had significantly worse progression-free survival (PFS) and overall survival (OS).
CONCLUSIONS
For EGFR testing, ARMS-PCR on plasma cfDNA is a promising methodology with the highest specificity and effective sensitivity. It is useful for EGFR testing in patients before treatment, especially the late-stage patients. Simultaneously, plasma cfDNA could be used to monitor the drug resistant mutation, T790M status and predict prognosis after targeted therapy.
Adenocarcinoma
;
blood
;
drug therapy
;
genetics
;
mortality
;
Adenocarcinoma of Lung
;
Adult
;
Aged
;
Aged, 80 and over
;
Cell-Free Nucleic Acids
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blood
;
ErbB Receptors
;
genetics
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Female
;
Humans
;
Lung Neoplasms
;
blood
;
drug therapy
;
genetics
;
mortality
;
Male
;
Middle Aged
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Molecular Targeted Therapy
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Mutation, Missense
;
Prognosis
2.Association between polymorphisms of ERCC1 and response in patients with advanced non-small cell lung cancer receiving cisplatin-based chemotherapy.
Jinghui WANG ; Quan ZHANG ; Hui ZHANG ; Qunhui WANG ; Xinjie YANG ; Yanfei GU ; Shucai ZHANG
Chinese Journal of Lung Cancer 2010;13(4):337-341
BACKGROUND AND OBJECTIVEResults of studies on genetic polymorphisms of ERCC1 gene in DNA repair pathway which may affect response to platinum-based chemotherapy and survival in patients with non-small cell lung cancer are conflicting. The aim of this study is to prospectively assess the association between single nucleotide polymorphisms of C8092A and codon118 in ERCC1 and drug response in 90 patients with advanced non-small cell lung cancer treated with cisplatin-based chemotherapy.
METHODSAll patients were treated with cisplatin-based chemotherapy. Genotypes of ERCC1 C8092A and codon118 were examined by sequencing, and the association between genotypes and response was evaluated.
RESULTSGenotype frequencies of ERCC1 C8092A were CC 40.0% (36/90), CA 48.9% (44/90) and AA 11.1% (10/90), frequencies of codon118 were CC 58.9% (53/90), CT 34.4% (31/90) and TT 6.7% (6/90). There was no significant difference in response rate of patients carrying with CC, compared with CA plus AA in C8092A (33.3% vs 29.6%, P = 0.71). Response rate of patients carrying with CC in ERCC1 118 was 32.1%, 24.3% with CT plus CC (P = 0.43). There was no difference in progression free survival between patients carrying with CC and CT plus TT in C8092A (5.2 months vs 5.4 months, P = 0.62). There was no difference in progression free survival between patients carrying with CC and CA plus AA (5.5 months vs 5.3 months, P = 0.59).
CONCLUSIONThe results suggest that there is no association between polymorphisms in ERCC1 C8092A and codon118 and response in patients with advanced non-small cell lung cancer receiving cisplatin-based chemotherapy.
Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; mortality ; Cisplatin ; therapeutic use ; DNA-Binding Proteins ; genetics ; Disease-Free Survival ; Endonucleases ; genetics ; Female ; Genotype ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; mortality ; Male ; Middle Aged ; Polymorphism, Genetic ; genetics ; Prospective Studies
3.Transglutaminase 2 Expression Predicts Progression Free Survival in Non-Small Cell Lung Cancer Patients Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor.
Jae Heon JEONG ; Byoung Chul CHO ; Hyo Sup SHIM ; Hye Ryun KIM ; Sun Min LIM ; Se Kyu KIM ; Kyung Young CHUNG ; S M Bakhtiar Ul ISLAM ; Jae Jin SONG ; Soo Youl KIM ; Joo Hang KIM
Journal of Korean Medical Science 2013;28(7):1005-1014
Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and in the constitutive activation of nuclear factor kappa B (NF-kappaB). We investigated the association of non-small cell lung cancer (NSCLC) treatment efficacy with TG2 and NF-kappaB expression in 120 patients: 102 with adenocarcinoma and 18 with other histologic types. All patients underwent surgery; 88 received adjuvant chemotherapy, with 28 receiving platinum-based doublet chemotherapy as first-line treatment and 29 receiving epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Patients' TG2 and NF-kappaB expression values were calculated semiquantitatively. The median TG2 value was 50 (range, 0-300) and the median NF-kappaB value was 20 (range, 0-240). Disease-free survival did not differ between the low- and high-TG2 groups. Among patients who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was longer in the low-TG2 group than in the high-TG2 group (11.0 vs. 7.0 months; P=0.330). Among those who received EGFR-TKI therapy, PFS was also longer in the low-TG2 group than in the high-TG 2 group (11.0 vs. 2.0 months; P=0.013). Similarly, in EGFR wild-type patients treated with EGFR-TKI, PFS was longer in patients with low TG2 expression (9.0 vs. 2.0 months; P=0.013). TG2 expression levels can predict PFS in patients with NSCLC treated with EGFR-TKI.
Adenocarcinoma/*drug therapy/mortality/surgery
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Adult
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Aged
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Aged, 80 and over
;
Antineoplastic Agents/therapeutic use
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Carcinoma, Non-Small-Cell Lung/*drug therapy/mortality/surgery
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Disease-Free Survival
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Female
;
GTP-Binding Proteins/*biosynthesis
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Humans
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Lung Neoplasms/*drug therapy/mortality/surgery
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Male
;
Middle Aged
;
NF-kappa B/biosynthesis
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Protein Kinase Inhibitors/therapeutic use
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Receptor, Epidermal Growth Factor/*antagonists & inhibitors/genetics
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Transglutaminases/*biosynthesis
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Treatment Outcome
4.Pharmacogenomic Assessment of Outcomes of Pemetrexed-Treated Patients with Adenocarcinoma of the Lung.
Minkyu JUNG ; Chul Ho LEE ; Hyung Soon PARK ; Ji Hyun LEE ; Young Ae KANG ; Se Kyu KIM ; Joon CHANG ; Dae Joon KIM ; Sun Young RHA ; Joo Hang KIM ; Byoung Chul CHO
Yonsei Medical Journal 2013;54(4):854-864
PURPOSE: The main objective of this study was to evaluate the association between polymorphisms of the target genes of pemetrexed and clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with pemetrexed. MATERIALS AND METHODS: We assessed polymorphisms at 8 sites in 4 genes [thymidylate synthase (TS), dihydrofolate reductase (DHFR; 1610, 680, 317, intron 1), methylenetetrahydrofolate reductase (MTHFR; 677, 1298), glycinamide ribonucleotide formyl transferase (GARFT; 2255)] associated with pemetrexed metabolism using polymerase chain reaction, gene scanning, and restriction fragment length polymorphism analysis in 90 patients with adenocarcinoma of the lung. RESULTS: Survival was significantly longer with pemetrexed in patients with TS 3RGCC/3RGCC or 3RGGC/3RGGC compared with the other groups (PFS; 5.2 months vs. 3.7 months, p=0.03: OS; 31.8 months vs. 18.5 months, p=0.001). Patients with DHFR 680CC experienced fatigue more frequently (50% vs. 8.6%, p=0.008). Polymorphisms of MTHFR and GARFT were not significantly associated with clinical outcomes of pemetrexed. CONCLUSION: The TS genotype was associated with survival and one DHFR polymorphism was associated with fatigue in NSCLC patients treated with pemetrexed. Further large prospective studies are required to identify other biomarkers that affect patients being treated with pemetrexed for adenocarcinoma of the lung.
Adenocarcinoma/*drug therapy/*genetics/mortality
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Adult
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Aged
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Aged, 80 and over
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Antimetabolites, Antineoplastic/pharmacology/*therapeutic use/toxicity
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Female
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Glutamates/pharmacology/*therapeutic use/toxicity
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Guanine/*analogs & derivatives/pharmacology/therapeutic use/toxicity
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Humans
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Lung Neoplasms/*drug therapy/*genetics/mortality
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Male
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Methylenetetrahydrofolate Reductase (NADPH2)/genetics
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Middle Aged
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Pharmacogenetics
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Phosphoribosylglycinamide Formyltransferase/genetics
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*Polymorphism, Single Nucleotide
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Tetrahydrofolate Dehydrogenase/genetics
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Thymidylate Synthase/genetics
5.Clinical Predictive Factors associated with First Line EGFR-TKI Efficacy in Advanced NSCLC Patients with EGFR Mutations.
Minjiang CHEN ; Yan XU ; Jing ZHAO ; Wei ZHONG ; Mengzhao WANG
Chinese Journal of Lung Cancer 2019;22(2):99-104
BACKGROUND:
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated some dramatic efficacy in advanced non-small-cell lung cancer (NSCLC) patients with activating EGFR mutation. However, progression-free survivals (PFS) among those patients who were treated with first line EGFR TKIs were inconsistent. The aim of this study is to explore the association of clinical prognostic factors with EGFR-TKI efficacy in advanced NSCLC patients.
METHODS:
The demographic and clinical characteristics of 203 patients with activating EGFR mutation treated with first generation TKI as a first-line therapy were retrospectively reviewed.
RESULTS:
Of the 203 patients enrolled in this study, 139 patients had progression of disease and 63 patients died. The subjects had a median follow up duration of 21.1months and a median PFS of 14.3 months. Partial response (PR) was achieved in 127 (66.1%) patients and stable disease (SD) rate was achieved in 55 (28.6%) patients. In univariate analysis, patients with 2 or higher ECOG score (5.1 vs 16 months, P=0.033), SD as best overall response (9.5 vs 17.9 months, P=0.030), extrathoracic metastasis (11.7 vs 27.5 months, P=0.004), liver metastasis (4.1 vs 16.0 months, P=0.000), bone metastasis (13.3 vs 21.5months, P=0.027) and pulmonary embolism (5.5 vs 16.6 months, P=0.005) had shorter PFS than those without the listed factors. Multivariable Cox regression analysis showed best overall response (HR=1.825, 95%CI: 1.107-3.008, P=0.018) and liver metastasis (HR=1.694, 95%CI: 1.146-5.756, P=0.022) were independent predictive factors of shorter PFS.
CONCLUSIONS
Despite the high efficacy of EGFR-TKI, SD as best overall response and liver metastasis predicts poorer PFS in advanced NSCLC patients with EGFR gene mutations receiving first-line therapy treatment.
Adult
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Aged
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Antineoplastic Agents
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administration & dosage
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Carcinoma, Non-Small-Cell Lung
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drug therapy
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enzymology
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genetics
;
mortality
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ErbB Receptors
;
genetics
;
metabolism
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Female
;
Humans
;
Lung Neoplasms
;
drug therapy
;
enzymology
;
genetics
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Middle Aged
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Mutation
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Protein Kinase Inhibitors
;
administration & dosage
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Retrospective Studies
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Treatment Outcome
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Young Adult
6.Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer.
Jaemin JO ; Se Hyun KIM ; Yu Jung KIM ; Juhyun LEE ; Miso KIM ; Bhumsuk KEAM ; Tae Min KIM ; Dong Wan KIM ; Dae Seog HEO ; Jin Haeng CHUNG ; Yoon Kyung JEON ; Jong Seok LEE
Yonsei Medical Journal 2018;59(2):202-210
PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p < 0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p < 0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.
Adult
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Aged
;
Antineoplastic Agents/*therapeutic use
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Carcinoma, Non-Small-Cell Lung/*drug therapy/enzymology/mortality
;
Disease-Free Survival
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Female
;
Humans
;
Lung Neoplasms/*drug therapy/enzymology/mortality
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Male
;
Middle Aged
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Mutation
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Pemetrexed/*therapeutic use
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Receptor Protein-Tyrosine Kinases/genetics
;
Retrospective Studies
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Survival Rate
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Treatment Outcome