Specific <i>EGFR</i> Mutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non–Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy

Yang, Chih-Hsin; Yu, Chong‐Jen; Shih, Jin‐Yuan; Chang, Yeun‐Chung; Hu, Fu‐Chang; Tsai, Meng-Chin; Chen, Kuan‐Yu; Lin, Zhong‐Zhe; Huang, Chien-Che; Shun, Chia‐Tung; Huang, Chun‐Yao; Bean, James; Cheng, Ann‐Lii; Pao, William; Yang, Pan‐Chyr

doi:10.1200/jco.2007.15.6695

Cited by 234 publications

(161 citation statements)

References 41 publications

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“…58 MET amplification has been observed in about 10-20% of NSCLC cases and is associated with shorter survival. 59,60 Moreover, high MET copy number seems to correlate with shorter time to treatment failure in patients with gefitinib-sensitive activating EGFR mutations, 61 although these results have not been confirmed in other studies. 62 An increase in MET gene copy number is also reported to be a mechanism of acquired EGFR-TKI resistance, by driving ERBB3-dependent activation of PI3K, allowing tumor cells to bypass the activated mutant EGFR pathway.…”

Section: Metcontrasting

confidence: 37%

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Ulivi

Calistri

Zoli

et al. 2010

J Nucleic Acids Invest

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In recent years, a number of novel agents have been investigated that target specific molecular pathways in non-small cell lung cancer (NSCLC). A great deal of effort has been focused on identifying specific markers that predict treatment response, given that a tailored approach would maximize both the therapeutic index and the cost-effectiveness. The epidermal growth factor receptor (EGFR) pathway has emerged as a key regulator of cancer cell proliferation and invasion, and several specific EGFR inhibitors have been examined. Gefitinib and erlotinib are selective EGFR tyrosine kinase inhibitors (EGFR-TKIs), demonstrating good results in selected cases both in terms of objective response rate and of overall survival. At present, EGFR gene mutations are the best positive predictive factors for TKI therapy, and a number of other potential biomarkers are being investigated as additional positive or negative predictors of response. The correct selection of patients that could benefit from these innovative therapies, based on an accurate molecular characterization, is mandatory to provide the best clinical management. Currently, the main factor limiting the characterization of metastatic NSCLC patients is the small quantity of tumor cells available for molecular analysis. In this paper we provide an overview of the most important molecular predictive markers for EGFR-TKIs therapy in NSCLC patients, and focus attention on biological samples suitable for analysis and alternative sampling approaches such as plasma-or serum-derived DNA.

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Section: Metcontrasting

confidence: 37%

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Ulivi

Calistri

Zoli

et al. 2010

J Nucleic Acids Invest

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“…34 The distribution of EGFR mutation types identified in our cohort was consistent with other series, with most mutations being in-frame exon 19 deletions and the L858R point mutations in exon 21. 20,25,26,35 These 2 most frequent EGFR mutations have been consistently associated with EGFR-TKI responsiveness. 36,37 Among the individual genotype subgroups in our patient population, the frequency of a PR or SD was significantly higher among patients with an exon 19 deletion mutation compared with those with exon 21 point mutations or no detectable mutation.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

Cohen

Agulnik

Ang

et al. 2010

Cancer

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BACKGROUND:Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR‐tyrosine kinase inhibitors (EGFR‐TKI) in patients with nonsmall cell lung cancer (NSCLC).METHODS:The authors tested the possibility that nucleotide sequencing may be poorly suited for detection of mutations in tumor samples and found that denaturing high‐performance liquid chromatography (dHPLC) was an efficient and more sensitive method for screening.RESULTS:These results suggested that some reports based on standard DNA sequencing techniques may have underestimated mutation rates. In the present report, the authors examined the relationship between the presence and type of EGFR mutations detected by dHPLC and various clinicopathologic features of NSCLC, including response to therapy with EGFR‐TKI. Among 251 patients with advanced disease, 100 individuals received EGFR‐TKI. Those whose tumors harbored a detectable EGFR kinase mutation were much more likely to have a partial response (PR) or stable disease (SD) with EGFR‐TKI therapy than patients whose tumor contained no mutation (80% vs 35%; P = .001). Among the individual genotype subgroups, the frequency of a PR or SD was significantly different between patients with an exon 19 deletion compared with those with no detectable mutation (86% vs 35%; P < .001). Furthermore, patients whose tumors expressed an exon 19 mutant EGFR isoform exhibited a trend toward better EGFR‐TKI response (86% vs 67%; P = .171) and improved survival compared with patients whose tumors expressed an exon 21 mutation.CONCLUSIONS:Our findings warrant confirmation in large prospective trials and exploration of the biological mechanisms of the differences between mutation types. Cancer 2010. © 2010 American Cancer Society.

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“…28,39,41,241,242 There are two well-established mechanisms of acquired resistance: additional mutations in the EGFR gene, acquired during the course of treatment, which change the protein coding sequence; and amplification of other oncogene signaling pathways, such as those involving the RAS and MET oncogenes. 84,[221][222][223] Kobayashi et al 182 reported a gefitinib-resistant advanced adenocarcinoma patient who had a relapse after 2 years of complete remission with gefitinib.…”

Section: Acquired Resistance To Egfr Tkimentioning

confidence: 99%

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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Specific EGFR Mutations Predict Treatment Outcome of Stage IIIB/IV Patients With Chemotherapy-Naive Non–Small-Cell Lung Cancer Receiving First-Line Gefitinib Monotherapy

Abstract: In this prospective study, EGFR exon 19 deletion or L858R mutations in adenocarcinoma were the best predictors for longer TTF in stage IIIB/IV chemotherapy-naive NSCLC patients receiving first-line gefitinib monotherapy.

Cited by 234 publications

References 41 publications

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Predictive molecular markers for EGFR-TKI in non-small cell lung cancer patients: new insights and critical aspects

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

Molecular pathology of lung cancer: key to personalized medicine

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