<i>EGFR</i>
            Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

Páez, J. Guillermo; Jänne, Pasi A.; Lee, Jeffrey C.; Tracy, Sean I.; Greulich, Heidi; Gabriel, Stacey; Herman, Paula; Kaye, Frederic J.; Lindeman, Neal I.; Boggon, Titus J.; Naoki, Katsuhiko; Sasaki, Hidefumini; Fujii, Yoshitaka; Eck, Michael J.; Sellers, William R.; Johnson, Bruce E.; Meyerson, Matthew

doi:10.1126/science.1099314

Cited by 8,700 publications

(6,489 citation statements)

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“…It is interesting to note that in our study population, 26% of evaluable tissue specimens were found to contain mutation, which is higher than the 10% to 15% incidence typically reported in the general North American and Western European populations. 5 It is possible that the enhanced sensitivity of the dHPLC might have contributed to our higher mutation rate. The higher rate among our cohort may also be attributable to an imbalance in the pathological type or other patient characteristics.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…The other is a point mutation in exon 21 (2573T>G) that results in substitution of leucine by arginine at codon 858 (L858R). [4][5][6][7][8][9][10] Other much less common mutations have also been described in exons 18, 20, and 21.…”

mentioning

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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“…4 In recent years, attention has been paid to the role that 'driver mutations,' such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), have in the tumorigenesis of adenocarcinomas, and their potential use as targets for therapy. [5][6][7][8][9] Recent data suggest EGFR may also serve as a prognostic factor, in addition to its role as a predictive factor, as patients-bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy. [10][11][12][13] EGFR and members of its family have an important role in carcinogenesis through their involvement in the modulation of cell proliferation, apoptosis, cell motility, and neovascularization.…”

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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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“…For example, mutated forms of the EGFR found in some NSCLCs can be inhibited by EGFR kinase inhibitors at concentrations approximately 100-fold lower than those required to inhibit wild-type EGFRs. 42 Such marked genetic variations in drug sensitivity can complicate the establishment of dose-response relationships in phase I studies.…”

Section: Measuring Target Inhibitionmentioning

confidence: 99%

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

et al. 2008

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SUMMARYTargeted drugs hold great promise for the treatment of malignant tumors; however, there are several challenges for efficient evaluation of these drugs in preclinical and clinical studies. These challenges include identifying the 'correct', biologically active concentration and dose schedule, selecting the patients likely to benefit from treatment, monitoring inhibition of the target protein or pathway, and assessing the response of the tumor to therapy. Although anatomic imaging will remain important, molecular imaging provides several new opportunities to make the process of drug development more efficient. Various techniques for molecular imaging that enable noninvasive and quantitative imaging are now available in the preclinical and clinical settings, to aid development and evaluation of new drugs for the treatment of cancer. In this Review, we discuss the integration of molecular imaging into the process of drug development and how molecular imaging can address key questions in the preclinical and clinical evaluation of new targeted drugs. Examples include imaging of the expression and inhibition of drug targets, noninvasive tissue pharmacokinetics, and early assessment of the tumor response.

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EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

Cited by 8,700 publications

References 22 publications

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

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

Technology Insight: novel imaging of molecular targets is an emerging area crucial to the development of targeted drugs

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