Analysis of EGFR, KRAS and P53 mutations in lung cancer using cells in the curette lavage fluid obtained by bronchoscopy

Yamaguchi, Fuminori; Kugawa, Satoshi; Tateno, Hidetsugu; Kokubu, Fumio; Fukuchi, Kunihiko

doi:10.1016/j.lungcan.2012.08.014

Cited by 30 publications

(24 citation statements)

References 41 publications

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“…It is challenging to compare mutation rates due to differences in the specific exons screened, interpretation of functional mutations, patient populations, and stage of disease. However, the mutation frequency of p53 reported in the current study (40.0 %) is consistent with what has been previously reported [7,24,25]. It is also important to note that different mutations have different effects on p53 function.…”

Section: Discussionsupporting

confidence: 92%

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer

Scagliotti

Kang

Smith³

et al. 2016

Invest New Drugs

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Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

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Section: Discussionsupporting

confidence: 92%

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer

Scagliotti

Kang

Smith³

et al. 2016

Invest New Drugs

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“…The frequency of EGFR mutation in the current study is comparable to those published from Korea, Japan, Italy and USA (25-29 %) [41,48,56,59] higher than those from Canada, France, Brazil and Japan (5-21 %) [38, 47, 51, 53], while lower in comparison to Taiwan, China and Mexico (33-54 %) [43,54,57]. In comparison to recent Indian studies, our frequency was pretty much similar to some studies 23-32 % [27, 65,66], though few studies even reported a much higher mutation rate varying between 39-52 % [28, 64,67] which could be attributed to small sample size, and or clinically selected patients.…”

Section: Discussionsupporting

confidence: 87%

Molecular Spectrum of Somatic EGFR and KRAS Gene Mutations in non Small Cell Lung Carcinoma: Determination of Frequency, Distribution Pattern and Identification of Novel Variations in Indian Patients

Das¹,

Bhaumik²,

Ahmad³

et al. 2015

Pathol. Oncol. Res.

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Somatic mutations of EGFR and KRAS gene represent the most common alterations currently known in NSCLC patients. This study explored the frequency, distribution pattern of EGFR and KRAS mutations in Indian patients. The frequencies of EGFR and KRAS mutations were 29 % (116/400) and 4.5 % (6/132) respectively. Both EGFR and KRAS mutations were prevalent in females, and a trend towards higher mutation frequency was seen in patients under ≥ 60 years age. The presence of EGFR and KRAS mutations were higher in adenocarcinomas in comparison to other histological subtype. Sequencing analysis of EGFR exon 18 revealed Inframe deletion (G709_T710 > A) and missense mutation (K713R). Among exon 19 positive cases, 49.3 % (37/75) were in-frame deletions, of which E746_A750del was frequent. Similarly, ~47 % (35/75) cases showed complex mutation involving indel. Among mutations in exon 20 (N = 9), 8 were substitutions, one showed duplication, while all exon 21 mutations were of the missense types with L858R as the most recurrent type. Sequencing analysis of KRAS exon 1 revealed three different types codon 12 substitutions resulting in c34G > T (G12C) (n = 4), c.35G > A (G12D) (n = 1), and c.35G > T (G12V) (n = 1). In conclusion, the present study is an example of molecular diversity of EGFR and KRAS gene in Indian patients and further confirms that the frequency of EGFR and KRAS mutations varies considerably globally. To the best of our knowledge, this is the first Indian study to evaluate KRAS mutation. The current study also served to identify novel variations that added new insights into the genetic heterogeneity of NSCLC.

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“…The relevance of this residue for kinase activity regulation is illustrated by the EGFR exon 19 insertions leading to the L747P mutation described in patients with lung adenocarcinoma or by the L747S mutation of the EGFR, reported in patients acquiring secondary resistance to EGFR inhibitors. It is believed to shift the equilibrium toward the receptor's active conformation (27)(28)(29). Other arguments point toward the importance of the JAK ␣C helix in the regulation of the cytokine receptor dependence.…”

Section: Discussionmentioning

confidence: 99%

Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities

Losdyck

Hornakova

Springuel

et al. 2015

Journal of Biological Chemistry

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Background: JAK3, a tyrosine kinase associated to cytokine receptors, is frequently mutated in leukemia. Results: JAK3L857P induces constitutive signaling independently of cytokine receptors and JAK1, in contrast to other JAK mutants. Conclusion: Different JAK mutants signal through distinct mechanisms and show different sensitivity to JAK1-or JAK3-specific inhibitors. Significance: Depending on the JAK residue mutated, patients will require different treatments.

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Analysis of EGFR, KRAS and P53 mutations in lung cancer using cells in the curette lavage fluid obtained by bronchoscopy

Cited by 30 publications

References 41 publications

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer

Molecular Spectrum of Somatic EGFR and KRAS Gene Mutations in non Small Cell Lung Carcinoma: Determination of Frequency, Distribution Pattern and Identification of Novel Variations in Indian Patients

Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities

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