Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp

Sutani, Akihisa; Nagai, Yoshinori; Udagawa, Kiyoshi; Uchida, Yoshitaka; Koyama, Nobuyuki; Murayama, Yoshitake; Tanaka, Tomoaki; Miyazawa, Hitoshi; Nagata, Michio; Kanazawa, Minoru; Hagiwara, Koichi; Kobayashi, Kunihiko

doi:10.1038/sj.bjc.6603466

Cited by 162 publications

(121 citation statements)

References 20 publications

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“…PNA clamp primers bind to the wild-type sequence and suppress their amplification; LNA probes are designed to specifically detect mutant sequences and enhance their amplification in the presence of wild-type sequences, because PNA clamp primers competitively inhibit mutant LNA probes to bind to the wild type. 15,22,23 To detect mutations of exon18 (G719C, G719S and …”

Section: Pna-lna Pcr Clamp Methodsmentioning

confidence: 99%

Direct Comparison of 3 PCR Methods in Detecting EGFR Mutations in Patients with Advanced Non–Small-Cell Lung Cancer

Ikeda

Nakamura

Yamaguchi

et al. 2012

Clinical Lung Cancer

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Micro abstractWe compared three PCR methods (mutant-enriched PCR, PNA-LNA PCR and PCR clamp) to detect EGFR mutations in 50 patients with advanced NSCLC. Seventeen were harboring EGFR mutations, five of whom showed discrepancies between the results of different PCR methods. All five responded to gefitinib, which we consider to suggest that the discrepancies were false negatives. Clinical Practice Points• Several methods have been used to detect EGFR mutations in non-small-cell lung cancer (NSCLC): however, it is not clear which is the most suitable for use in the clinic.• We compared three PCR methods (mutant-enriched PCR, PNA-LNA PCR and PCR clamp) in 50 patients with advanced NSCLC. Seventeen of the patients were harboring EGFR mutations, five of whom showed discrepancies between the results of different PCR methods. All five patients responded to gefitinib.• We considered that all of the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reasons for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each method, a large prospective clinical trial is warranted. AbstractBackground: Epidermal growth factor receptor (EGFR) mutations are predictive of

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Section: Pna-lna Pcr Clamp Methodsmentioning

confidence: 99%

Direct Comparison of 3 PCR Methods in Detecting EGFR Mutations in Patients with Advanced Non–Small-Cell Lung Cancer

Ikeda

Nakamura

Yamaguchi

et al. 2012

Clinical Lung Cancer

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“…Based on our search criteria, we identified six reports that prospectively evaluated the effects of gefitinib monotherapy for advanced NSCLC based on the presence of an EGFR tyrosine kinase domain mutation in the patient's tumor specimens [43][44][45][46][47][48]. All trials were published between 2006 and 2007.…”

Section: Identification Of Five Prospective Trials Of Patients With Ementioning

confidence: 99%

Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers

et al. 2007

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Purpose-Epidermal growth factor receptor (EGFR) mutations have been found in the majority of gefitinib-responsive non-small cell lung cancer (NSCLC) patients from retrospective studies. We sought to compile the available phase II and prospective trials of this EGFR tyrosine kinase inhibitor (TKI) to better understand the efficacy and safety of selecting patients to receive gefitinib based on their genotype.Design-We searched published trials involving EGFR-mutant patients and gefitinib. Five reports were identified (published between June 2006 and April 2007) in which gefitinib was given in a prospective manner to EGFR mutation positive patients at a dose of 250 mg a day. Responses were determined by RECIST and toxicities by NCI-CTC.Results-A total of 101 patients were pooled from these studies. 59 received gefitinib as their first line of therapy and 42 after having received chemotherapy. The combined rate of complete and partial response (CR+PR) in the 99 measured patients was 80.8% (80/99) and only 7.1% (7/99) had progressive disease as best response. The response rate (CR+PR) for exon 19 deletion and L858R patients were 80.3% (53/66) and 81.8% (27/33), respectively. The median progression-free survival ranged from 7.7 to 12.9 months. Overall survival had not been reached in 4/5 reports and was 15.4 months in one of them. Gefitinib administration was safe (<50% of patients developed grade 1-2 skin rash or diarrhea) and interstitial lung disease was only reported in 2 patients (2%), without deaths.Conclusions-Gefitinib monotherapy leads to objective responses in most patients with EGFR mutations. Both L858R and deletion 19 mutations derived similar clinical benefits. Small molecule TKIs are the new treatment paradigm for EGFR-mutant NSCLC.

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“…Such a technique has been applied to search for K-Ras mutations in various tumour samples (Sun et al, 2002;Chen et al, 2004;Taback et al, 2004;Däbritz et al, 2005;Luo et al, 2006;Miyake et al, 2007). This method was also used to detect EGFR mutations in NSCLC (Nagai et al, 2005;Soh et al, 2006;Sutani et al, 2006;Tanaka et al, 2007;Miyanaga et al, 2008).…”

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confidence: 99%

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping

et al. 2009

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Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P <0.005), among which five in samples with low tumour cellularity. In adenocarcinoma, K-Ras mutation frequency increased from 7 out of 55 (13%) by direct sequencing to 15 out of 55 (27%) by clamped-PCR ( P <0.005). K-Ras mutations detected by these sensitive techniques lost its prognostic value. In conclusion, a rapid and sensitive PCR-clamping test avoiding macro or micro dissection could be proposed in routine analysis especially for NSCLC samples with low percentage of tumour cells such as bronchial biopsies or after neoadjuvant chemotherapy.

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Gefitinib for non-small-cell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp

Cited by 162 publications

References 20 publications

Direct Comparison of 3 PCR Methods in Detecting EGFR Mutations in Patients with Advanced Non–Small-Cell Lung Cancer

Direct Comparison of 3 PCR Methods in Detecting EGFR Mutations in Patients with Advanced Non–Small-Cell Lung Cancer

Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping

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