Relative Abundance of <i>EGFR</i> Mutations Predicts Benefit From Gefitinib Treatment for Advanced Non–Small-Cell Lung Cancer

Zhou, Qing; Zhang, Xuchao; Chen, Zhihong; Yin, Xiaolu; Yang, Jin-Ji; Xu, Chong-Rui; Yan, Hong‐Hong; Chen, Hua-Jun; Su, Jian; Zhong, Wen‐Zhao; Yang, Xue‐Ning; An, Shejuan; Wang, Bin-Chao; Huang, Yi; Wang, Zhen; Wu, Yi‐Long

doi:10.1200/jco.2010.33.3757

Cited by 216 publications

(187 citation statements)

References 23 publications

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“…Differences in overall survival and objective response rate in patients with high and low abundances of EGFR mutations were not significant. 227 This study also pointed out that heterogeneity caused by factors other than EGFR mutation could also affect EGFR TKI response. Sharma et al 228 reported detecting a small subpopulation of reversibly 'drug-tolerant' cells showing more than 100-fold reduced drug sensitivity.…”

Section: Other Genomic Alterationsmentioning

confidence: 74%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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The majority of lung adenocarcinoma patients with epidermal growth factor receptor-(EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

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Section: Other Genomic Alterationsmentioning

confidence: 74%

Molecular pathology of lung cancer: key to personalized medicine

et al. 2012

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“…The results of the present study indicate that EGFR mutations detected in both the tissue and plasma (B+/T+) was better for predicting the benefit from first-line EGFR-TKI treatment in advanced NSCLC, compared with detection in a single specimen. Recent studies that investigated the effect of intratumor EGFR mutation heterogeneity on clinical outcomes following EGFR-TKI therapy have demonstrated that an increased abundance of intratumoral EGFR mutations (implying low heterogeneity) may lead to improved clinical outcomes compared to a low abundance of EGFR mutations (20). Although the release mechanism of ctDNA from tumor tissues to peripheral blood is not well understood, ctDNA is likely derived from apoptotic and necrotic tumor cells, including primary tumors, metastatic lesions or circulating tumor cells (21).…”

Section: Discussionmentioning

confidence: 99%

Analysis of EGFR mutation status in tissue and plasma for predicting response to EGFR-TKIs in advanced non-small-cell lung cancer

Wang¹,

Duan²,

Chen³

et al. 2017

Oncology Letters

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Abstract. The detection of mutations in the epidermal growth factor receptor (EGFR) gene in tumor tissues has been established as the gold standard for predicting the efficacy of treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in advanced non-small-cell lung cancer (NSCLC). The current study aimed to investigate whether the presence of co-existing EGFR mutations in tumor tissue and in cell-free tumor DNA (ctDNA) in the plasma predicts a more favorable outcome of EGFR-TKI treatment in advanced NSCLC. A total of 287 NSCLC patients who had undergone EGFR-TKI treatment were enrolled and stratified into four subgroups: Wild-type EGFR in plasma and tissue specimens (B-/T-); mutated EGFR in plasma and tissue specimens (B+/T+); mutated EGFR in only in plasma samples (B+/T-); or mutated EGFR in only tissue specimens (B-/T+). EGFR mutations were tested using denaturing high-performance liquid chromatography and confirmed by amplification-refractory mutation system analysis. Of the 287 patients, 101 had mutations in both tissue and plasma samples and 103 had mutation in either tissue (n=65) or plasma (n=38). The median progression-free survival (mPFS) times were 9.2 and 2.0 months in the B+/T+ and B-/T-groups, respectively. The mPFS times were 7.9 months in the B-/T+ group and 11.9 months in the B+/T-group (P=0.001). Among the 187 patients with available pre-EGFR-TKI plasma samples, 70 received first-line EGFR-TKI treatment, and the mPFS in the B+/T+ group was longer than in the B-/T+ or B+/Tgroups (18.8 vs. 9.4 vs. 6.9 months; P= 0.003). In second-line setting of EGFR-TKI therapy, the groups of patients with EGFR mutation in ctDNA, regardless of the mutation status in the tissues, exhibited longer mPFS times compared with the B-/T+ group (10.0 vs. 5.8 months; P=0.044). The results suggest that co-existence of EGFR mutations in tissue and ctDNA predict longer PFS times for NSCLC patients who receive first-line EGFR-TKI therapy. In addition, real-time detection in ctDNA is an excellent predictor for the efficacy of second-or higher line EGFR-TKI therapy.

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“…Karachaliou et al (14) reported that in the patients with tumor tissue EGFR mutation, serum ex19del detected was a positive predictor for OS compared with non-serum ex19del detected patients treated with erlotinib, while serum L858R mutation was the opposite, confirming the difference between L858R mutation and ex19del (21). In a study by Zhou et al (13), high EGFR mutation abundance in tumor tissue, defined as positive in the ARMS test and gene sequencing, possessed predictive significance for benefit from gefitinib treatment for patients with NSCLC. These results revealed a similar clinical value of qualitative EGFR gene mutation status in blood compared with that in tumor tissue samples.…”

Section: Discussionmentioning

confidence: 91%

“…Theoretically, plasma EGFR mutation concentration should be associated with the EGFR mutation abundance in tumor tissues, tumor burden, and tumor necrosis or apoptosis, since tumor lysis has been considered as the main source of the cfDNA found in peripheral blood (11,12). Zhou et al (13) reported that high EGFR mutation abundance in tumor tissue, which was defined as positivity in the amplification refractory mutation system (ARMS) test and gene sequencing, predicted improved responsiveness in patients with NSCLC to gefitinib treatment. Data from the EURTAC trial demonstrated that in patients with tissue EGFR mutation, qualitatively detected L858R mutation in cfDNA, using the TaqMan assay, indicated poor overall survival (OS) while ex19del acted inversely (14).…”

Section: Association Of Mutant Egfr L858r and Exon 19 Concentration Imentioning

confidence: 99%

Association of mutant EGFR L858R and exon 19 concentration in circulating cell-free DNA using droplet digital PCR with response to EGFR-TKIs in NSCLC

et al. 2017

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Abstract. The present study aimed to determine the diagnostic concordance of plasma epidermal growth factor receptor (EGFR) mutation using droplet digital polymerase chain reaction (ddPCR) with tumor tissue samples and the predictive clinical significance of plasma EGFR mutation concentration. Plasma DNA samples from patients with non-small cell lung cancer (NSCLC) were analyzed for EGFR exon 21 codon 858 (L858R) mutation, deletion of exon 19 (ex19del) and exon 20 codon 790 (T790M) mutation using ddPCR. Firstly, the mutations in the plasma samples were compared with the matched tumor samples to determine the concordance. Secondly, image examination follow-ups were analyzed to assess the association between plasma EGFR mutation concentration and patients' response to EGFR-tyrosine kinase inhibitors (TKIs). A total of 51 patients with NSCLC were enrolled, including 48 newly diagnosed patients. Compared with tumor tissue samples, the sensitivity and specificity of ddPCR were 76.19% (16/21) and 96.55% (28/29) for mutant L858R, and 88.89% (8/9) and 100% (41/41) for ex19del, respectively. No patient exhibited the T790M mutation in the tumor tissue or plasma samples. Furthermore, 5 patients with the L858R mutation and 4 patients with ex19del in plasma and tumor tissue samples had been followed up with image examination for ≥3 months following EGFR-TKI treatment. The baseline mutant EGFR concentrations were positively correlated with a reduction in tumor burden (Spearman's r=0.7000, P=0.0358). When analyzed separately, ex19del concentrations (Spearman's r=1.0000, P<0.0001) were also positively correlated with the reduction, while mutant L858R concentrations were not (Spearman's r= 0.7000, P= 0.1881). In the present study, detection of plasma EGFR mutations using ddPCR exhibited sufficient concordance with tumor tissue sample results. Baseline plasma mutant EGFR and ex19del concentrations were significantly and positively correlated with response to EGFR-TKIs.

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Relative Abundance of EGFR Mutations Predicts Benefit From Gefitinib Treatment for Advanced Non–Small-Cell Lung Cancer

Abstract: The relative EGFR mutation abundance could predict benefit from EGFR-TKI treatment for advanced NSCLC.

Cited by 216 publications

References 23 publications

Molecular pathology of lung cancer: key to personalized medicine

Molecular pathology of lung cancer: key to personalized medicine

Analysis of EGFR mutation status in tissue and plasma for predicting response to EGFR-TKIs in advanced non-small-cell lung cancer

Association of mutant EGFR L858R and exon 19 concentration in circulating cell-free DNA using droplet digital PCR with response to EGFR-TKIs in NSCLC

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