Data from A Prospective Evaluation of Circulating Tumor Cells and Cell-Free DNA in <i>EGFR</i>-Mutant Non–Small Cell Lung Cancer Patients Treated with Erlotinib on a Phase II Trial
Masahiko YanagitaAmanda J. RedigCloud P. PaweletzSuzanne E. DahlbergAllison O’ConnellNora FeeneyMyriam TaibiDavid BoucherGeoffrey R. OxnardBruce E. JohnsonDaniel B. CostaDavid M. JackmanPasi A. Jänne
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<div>Abstract<p><b>Purpose:</b> Genotype-directed therapy is the standard of care for advanced non–small cell lung cancer (NSCLC), but obtaining tumor tissue for genotyping remains a challenge. Circulating tumor cell (CTC) or cell-free DNA (cfDNA) analysis may allow for noninvasive evaluation. This prospective trial evaluated CTCs and cfDNA in <i>EGFR</i>-mutant NSCLC patients treated with erlotinib until progression.</p><p><b>Experimental Design:</b> <i>EGFR</i>-mutant NSCLC patients were enrolled in a phase II trial of erlotinib. Blood was collected at baseline, every 2 months on study, and at disease progression. Plasma genotyping was performed by droplet digital PCR for <i>EGFR</i>19del, L858R, and T790M. CTCs were isolated by CellSave, enumerated, and analyzed by immunofluorescence for CD45 and pan-cytokeratin and <i>EGFR</i> and <i>MET</i> FISH were also performed. Rebiopsy was performed at disease progression.</p><p><b>Results:</b> Sixty patients were enrolled; 44 patients discontinued therapy for disease progression. Rebiopsy occurred in 35 of 44 patients (80%), with paired CTC/cfDNA analysis in 41 of 44 samples at baseline and 36 of 44 samples at progression. T790M was identified in 23 of 35 (66%) tissue biopsies and 9 of 39 (23%) cfDNA samples. CTC analysis at progression identified <i>MET</i> amplification in 3 samples in which tissue analysis could not be performed. cfDNA analysis identified T790M in 2 samples in which rebiopsy was not possible. At diagnosis, high levels of cfDNA but not high levels of CTCs correlated with progression-free survival.</p><p><b>Conclusions:</b> cfDNA and CTCs are complementary, noninvasive assays for evaluation of acquired resistance to first-line EGFR TKIs and may expand the number of patients in whom actionable genetic information can be obtained at acquired resistance. Serial cfDNA monitoring may offer greater clinical utility than serial monitoring of CTCs. <i>Clin Cancer Res; 22(24); 6010–20. ©2016 AACR</i>.</p></div>Keywords:
T790M
Circulating tumor cell
The efficacy of erlotinib in advanced non-small-cell lung cancer has been demonstrated in several trials, but only two cases of complete and prolonged response in wild-type epidermal growth factor receptor locally advanced lung cancer have been published.We discuss a case of a 67-year-old Caucasian man, a former heavy cigarette smoker, with a diagnosis of wild-type epidermal growth factor receptor locally advanced adenocarcinoma. After platinum-based doublet chemotherapy, when a progression of disease had occurred, a second-line therapy with erlotinib was started. We observed a progressive reduction of his lung lesion during erlotinib treatment until there was a complete clinical response.This case is interesting for the choice of second-line treatment in non-small-cell lung cancer and, moreover, for the possibility of a complete and prolonged response to erlotinib even in patients without the activating mutation of epidermal growth factor receptor.
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Objective To study the effect of Erlotinib, an EGFR-selectivetyrosine kinase inhibitor, on cell proliferance of nasopharyngeal cancer (NPC) by blocking epidermal growth factor receptor (EGFR) signal pathway. Methods NPC cell line, CNE-2, was used to be incubated by Erlotinib at different concentrations. Cell growth, cell cycle progression, apoptosis of CNE-2 and target protein expression were detected by cell growth assay, flow cytometric analysis assay and Western blotting assay, respectively. Results (1)Erlotinib could inhibit the growth of CNE-2 in does-dependent manner. (2) The levels of G1 arrest and apoptosis of CNE-2 in Erlotinib group were obvious higher than those in control group(P 0.05). (3)The p-EGFR level was reduced in Erlotinib group compared with the control group. Conclusion Erlotinib can inhibit cell growth of CNE-2 by blocking EGFR signal pathway and increasing G1 arrest.
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Abstract Background The purpose of this study was to determine if there are differences in biomarker modulation and epidermal growth factor receptor (EGFR) degradation between the tumor and the normal mucosa after treatment with an EGFR inhibitor, erlotinib, in head and neck cancer. Methods Patients with primary oral cavity squamous cell cancers received a course of erlotinib, 150 mg every day for 7 days before surgical resection. Tumor and normal mucosa biopsies were obtained both pre‐erlotinib and post‐erlotinib. Changes in known markers of EGFR activity (phospho, AKT, STAT3) were measured by immunoblotting, whereas changes in tissue distribution were analyzed by immunohistochemical analysis. Results Twelve patients were enrolled; 7 had evaluable paired tumors and normal mucosa biopsies pretreatment and posttreatment. Expression of EGFR was higher in tumors compared to the normal mucosa ( p = .005). Erlotinib administration was associated with marked inhibition of phosphorylated epidermal growth factor receptor (pEGFR) and reduction in total EGFR protein ( p = .004, p = .007) in tumors, whereas there was heterogeneity in EGFR inhibition in the normal mucosa ( p = .10 [pEGFR], and p = .07 [EGFR]). Reduced levels of pSrc and pSTAT3 and enhanced p27 levels were noted in tumors after erlotinib. Cell culture studies confirmed that EGFR is degraded in tumor cells after prolonged treatment with erlotinib. Conclusion Our results show that EGFR inhibition by erlotinib led to a marked reduction in EGFR protein levels in patients. Differential effects of erlotinib on tumors compared to the normal mucosa suggest there may be individual patient heterogeneity. These preliminary data suggest EGFR degradation should be further analyzed as a potential biomarker in selecting patients likely to benefit from EGFR inhibitors. © 2012 Wiley Periodicals, Inc. Head Neck, 2013
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No AccessJournal of UrologyInvestigative urology1 Oct 2007Epidermal Growth Factor Receptor Status and the Response of Bladder Carcinoma Cells to Erlotinibis companion ofSurvival Following the Diagnosis of Noninvasive Bladder Cancer: WHO/International Society of Urological Pathology Versus WHO Classification Systems Micah A. Jacobs, Chad Wotkowicz, Egbert D. Baumgart, Brasil Silva Neto, Kimberly M. Rieger-Christ, Trisha Bernier, Michael S. Cohen, John A. Libertino, and Ian C. Summerhayes Micah A. JacobsMicah A. Jacobs Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts Equal study contribution. More articles by this author , Chad WotkowiczChad Wotkowicz Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts Equal study contribution. More articles by this author , Egbert D. BaumgartEgbert D. Baumgart Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author , Brasil Silva NetoBrasil Silva Neto Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author , Kimberly M. Rieger-ChristKimberly M. Rieger-Christ Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author , Trisha BernierTrisha Bernier Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author , Michael S. CohenMichael S. Cohen Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author , John A. LibertinoJohn A. Libertino Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author , and Ian C. SummerhayesIan C. Summerhayes Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2007.05.113AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We established the frequency of mutation of the epidermal growth factor receptor in bladder cancer and determined whether the activation status of epidermal growth factor receptor confers sensitivity to erlotinib. Materials and Methods: The identification of mutations in the kinase domain (exons 18–21) of epidermal growth factor receptor was performed using single strand conformation polymorphism. The action of erlotinib was established within a bladder carcinoma cell panel using clonogenic assays and Western blot analysis. Results: In 112 invasive bladder tumors a total of 6 mutations in 4 patients (3.6%) were identified in exon 21. Erlotinib demonstrated concentration dependent inhibition of growth where three cell lines showed high and 2 showed low sensitivity to the drug. Erlotinib inhibited activation of epidermal growth factor receptor, mitogen activated protein kinase, Akt and STAT3. However, the activation status of Akt was maintained in cell lines that were insensitive to the inhibitory action of erlotinib and were characterized as having undergone epithelial-to-mesenchymal transition. Conclusions: Although mutations in the coding region of epidermal growth factor receptor are rare in invasive bladder tumors, differential sensitivity to erlotinib was recorded within a panel of cell lines. Maintenance of the phosphorylation status of Akt in the presence of erlotinib along with epithelial-to-mesenchymal transition correlates with insensitivity to growth inhibition in bladder carcinoma cell lines. Even in the absence of epidermal growth factor receptor mutations erlotinib shows potential as a therapeutic agent for the treatment of bladder cancer. References 1 : Cancer statistics. CA Cancer J Clin2006; 56: 106. Google Scholar 2 : Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer2005; 5: 713. Google Scholar 3 : Expression of transforming growth factor alpha and epidermal growth factor receptor in human bladder cancer. Scand J Clin Lab Invest1999; 59: 267. Google Scholar 4 : Prognostic value of EGF receptor and tumor cell proliferation in bladder cancer: therapeutic implications. Urol Oncol2004; 22: 93. Google Scholar 5 : Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Res2002; 62: 4157. Google Scholar 6 : Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med2004; 350: 2129. Google Scholar 7 : Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small lung cancer. Clin Cancer Res2005; 11: 2106. Google Scholar 8 : EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol2005; 23: 857. Google Scholar 9 : Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in the gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res2005; 11: 5878. Google Scholar 10 : Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res2000; 60: 1383. Google Scholar 11 : Somatic mutations of epidermal growth factor receptor in colorectal carcinoma. Clin Cancer Res2005; 11: 1368. Google Scholar 12 : Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clin Cancer Res2005; 11: 2879. Google Scholar 13 : Gefitinib (‘Iressa’, ZD1839) inhibits the growth response of bladder tumor cell lines to epidermal growth factor and induces TIMP2. Br J Cancer2004; 90: 1679. Google Scholar 14 : Differential radiosensitisation by ZD1839 (Iressa), a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines. Br J Cancer2005; 92: 125. Google Scholar 15 : Balance between activated-STAT and MAP kinase regulates the growth of human bladder cell lines after treatment with epidermal growth factor. Int J Oncol1999; 15: 661. Google Scholar 16 : Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: Implications for therapy. Clin Cancer Res2006; 12: 4671. Google Scholar 17 : Gefitinib inhibits the growth and invasion of urothelial carcinoma cell lines in which Akt and MAPK activation is dependent on constitutive epidermal growth factor receptor activation. Clin Cancer Res2006; 12: 2937. Google Scholar 18 : Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibitions. Cancer Res2005; 65: 9455. Google Scholar 19 : Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors. Clin Cancer Res2007; 13: 1685. Google Scholar 20 : Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of gefitinib. Cancer Res2005; 65: 10524. Google Scholar © 2007 by American Urological AssociationFiguresReferencesRelatedDetailsCited byGould J, Kenney P, Rieger-Christ K, Neto B, Wszolek M, LaVoie A, Holway A, Spurrier B, Austin J, Cammarata B, Canes D, Libertino J and Summerhayes I (2010) Identification of Tumor and Invasion Suppressor Gene Modulators in Bladder Cancer by Different Classes of Histone Deacetylase Inhibitors Using Reverse Phase Protein ArraysJournal of Urology, VOL. 183, NO. 6, (2395-2402), Online publication date: 1-Jun-2010.Related articlesJournal of Urology15 Aug 2007Survival Following the Diagnosis of Noninvasive Bladder Cancer: WHO/International Society of Urological Pathology Versus WHO Classification Systems Volume 178Issue 4October 2007Page: 1510-1514 Advertisement Copyright & Permissions© 2007 by American Urological AssociationKeywordsmutationerlotinibbladderbladder neoplasmsreceptorepidermal growth factorAcknowledgmentsDNA was sequenced at the Sequencing Core Facility, Tufts University. Erlotinib was provided by OSI Pharmaceuticals, Melville, New York.Metrics Author Information Micah A. Jacobs Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts Equal study contribution. More articles by this author Chad Wotkowicz Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts Equal study contribution. More articles by this author Egbert D. Baumgart Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author Brasil Silva Neto Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author Kimberly M. Rieger-Christ Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author Trisha Bernier Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author Michael S. Cohen Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author John A. Libertino Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author Ian C. Summerhayes Cell and Molecular Biology Laboratory, R. E. Wise M. D. Research and Education Institute, Lahey Clinic Medical Center, Burlington, Massachusetts Department of Urology, Lahey Clinic Medical Center, Burlington, Massachusetts More articles by this author Expand All Advertisement PDF downloadLoading ...
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Cancer is one of the major health challenges in modern times. Considering its high mortality rate, many proteins that are linked to cancer have been targeted for therapy, with one of them being the epidermal growth factor receptor (EGFR). A drug that is currently in the market for the treatment of non-small cell lung cancer and targets EGFR is erlotinib. In a quest for improved efficacy of erlotinib, herein we report molecular docking studies of thirteen erlotinib analogues by modification of the alkyne and anilino groups, all of which displayed better binding affinity than erlotinib. We identified aziridinyl analogue (S)- 13B: with the best binding energy of all the analogues studied.
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