• Tuberculosis and Respiratory Diseases
• /
• v.70 no.1
• /
• pp.21-27
• /
• 2011

Background: Although the gold standard method for research trials on epidermal growth factor receptor (EGFR) mutations has been direct sequencing, this approach has the limitations of low sensitivity and of being time-consuming. Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping is known to be a more sensitive detection tool. The aim of this study was to compare the detection rate of $EGFR$ mutation and EGFR-tyrosine kinase inhibitor (TKI) responsiveness according to $EGFR$ mutation status using both methodologies. Methods: Clinical specimens from 112 NSCLC patients were analyzed for $EGFR$ mutations in exons 18, 19, 20, and 21. All clinical data and tumor specimens were obtained from 3 university hospitals in Korea. After genomic DNA was extracted from paraffin-embedded tissue specimens, both PNA-mediated PCR clamping and direct-sequencing were performed. The results and clinical response to $EGFR$-TKIs were compared. Results: Sequencing revealed a total of 35 (22.9%) mutations: 8 missense mutations in exon 21 and 26 deletion mutations in exon 19. PNA-mediated PCR clamping showed the presence of genomic alterations in 45 (28.3%) samples, including the 32 identified by sequencing plus 13 additional samples (6 in exon 19 and 7 in exon 21). Conclusion: PNA-mediated PCR clamping is simple and rapid, as well as a more sensitive method for screening of genomic alterations in $EGFR$ gene compared to direct sequencing. This data suggests that PNA-mediated PCR clamping should be implemented as a useful screening tool for detection of $EGFR$ mutations in clinical setting.

• Tuberculosis and Respiratory Diseases
• /
• v.75 no.3
• /
• pp.95-103
• /
• 2013

Background: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms. Methods: We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment. Results: Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib. Conclusion: NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.

• Radiation Oncology Journal
• /
• v.22 no.2
• /
• pp.77-90
• /
• 2004

Purpose: The purpose of this review Is to provide an update on novel radiation treatments for head and neck cancer Recent Findings: Despite the remarkable advances In chemotherapy and radiotherapy techniques, the management of advanced head and neck cancer remains challenging. Epidermal growth factor receptor (EGFR) Is an appealing target for novel therapies In head and neck cancer because not only EGFR activation stimulates many important signaling pathways associated with cancer development and progression, and importantly, resistance to radiation. Furthermore, EGFR overexpression Is known to be portended for a worse outcome in patients with advanced head and neck cancer. Two categories of compounds designed to abrogate EGFR signaling, such as monoclonal antibodies (Cetuxlmab) and tyrosine kinase inhibitors (ZD1839 and 051-774) have been assessed and have been most extensively studied In preclinical models and clinical trials. Additional TKIs In clinical trials include a reversible agent, Cl-1033, which blocks activation of all erbB receptors. Encouraging preclinical data for head and neck cancers resulted In rapid translation Into the clinic. Results from Initial clinical trials show rather surprisingly that only minority of patients benefited from EGFR inhibition as monotherapy or In combination with chemotherapy. In this review, we begin with a brief summary of erbB- mediated signal transduction. Subsequently, we present data on prognostic-predictive value of erbB receptor expression in HNC followed by preclinlcal and clinical data on the role of EGFR antagonists alone or in combination with radiation In the treatment of HNC. Finally, we discuss the emerging thoughts on resistance to EGFR biockade and efforts In the development of multiple-targeted therapy for combination with chemotherapy or radiation. Current challenges for investigators are to determine (1 ) who will benefit from targeted agents and which agents are most appropriate to combine with radiation and/or chemotherapy, (2) how to sequence these agents with radiation and/or cytotoxlc compounds, (3) reliable markers for patient selection and verification of effective blockade of signaling in vivo, and (4) mechanisms behind intrinsic or acquired resistance to targeted agents to facilitate rational development of multi-targeted therapy, Other molecuiar-targeted approaches In head and neck cancer were briefly described, Including angloenesis Inhibitors, farnesyl transferase inhibitors, cell cycle regulators, and gene therapy Summary: Novel targeted theraples are highly appealing in advanced head and neck cancer, and the most premising strategy to use them Is a matter of intense Investigation.

• Tuberculosis and Respiratory Diseases
• /
• v.66 no.4
• /
• pp.280-287
• /
• 2009

Background: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), became an attractive therapeutic option for advanced non-small-cell lung cancer (NSCLC). Several studies suggested that there might be some different efficacy or response predictors between gefitinib and erlotinib. We compared the efficacy and toxicity of gefitinib and erlotinib in Korean patients with advanced NSCLC and evaluated specific predictors of response for both gefitinib and erlotinib. Methods: We collected the clinical information on patients with advanced NSCLC, who were treated with gefitinib or erlotinib at the Ewha Womans University Hospital, between July 2003 and February 2009. Median survival times were calculated using the Kaplan-Meier method. Results: Eighty-six patients (52 gefitinib vs. 34 erlotinib) were enrolled. Patient median age was 64 years; 53 (62%) subjects were male. Out of the 86 patients treated, 83 received response evaluation. Of the 83 patients, 35 achieved a response and 12 experienced stable disease while 36 experienced progressive disease, resulting in a response rate of 42% and a disease control rate of 57%. After a median follow-up of 502 days, the median progression-free and overall survival time was 129 and 259 days, respectively. Comparing patients by treatment (gefitinib vs erlotinib), there were no significant differences in the overall response rate (44% vs. 39%, p=0.678), median survival time (301 days vs. 202 days, p=0.151), or time to progression (136 days vs. 92 days, p=0.672). Both EGFR-TKIs showed similar toxicity. In a multivariate analysis using Cox regression model, adenocarcinoma was an independent predictor of survival (p=0.006; hazard ratio [HR], 0.487; 95% confidence interval [CI], 0.292-0.811). Analyses of subgroups did not show any difference in response predictors between gefitinib and erlotinib. Conclusion: Comparing gefitinib to erlotinib, there were no differences in the response rate, overall survival, progression-free survival, or toxicity. No specific predictor of response to each EGFR-TKI was identified.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.3
• /
• pp.1787-1790
• /
• 2013

This study evaluated the effects of ZD1839, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, on nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Influence of ZD1839 alone or combined with cisplatin on the NPC cell line CNE2 was detected by MTT assay with flow cytometry assessment of cell cycle distribution and apoptosis rates. Nude mice NPC xenografts were also used to evaluate the effects of ZD1839 alone or combined with cisplatin. The Student's t test evaluated statistical significance. ZD1839 alone or combined with cisplatin inhibited CNE2 cell line proliferation. ZD1839 induced CNE2 cell cycle arrest in the G1 phase, and higher concentrations induced apoptosis. Xenograft tumors were significantly smaller when treated with 200 mg/kg ZD1839, cisplatin, or cisplatin combined with 100 mg/kg ZD1839 than untreated controls. ZD1839 (200 mg/kg) alone showed good tumor inhibition effects, reduction of tumor weights, and smaller tumor volume without loss of body weight. ZD1839 (200 mg/kg) might provide a good and effective therapeutic reagent for NPC.

• Proceedings of the PSK Conference
• /
• 2002.10a
• /
• pp.227.2-228
• /
• 2002

ZD1839 is a new anticancer agent which selectively inhibits EGFR tyrosine kinase. Oxaliplatin (LOHP), 5-FU (FU), and paclitaxel (PTX) have shown to be highly active against the gastric carcinomas. and ZD1839 is considered as a good candidate for the treatment of gastric cancers when combined with cytotoxic agents. In this study, we evaluated the antitumor effects of these agents in SNU-l human gastric cancer cells either alone or when given as a doublet. (omitted)

• Journal of the Korean Chemical Society
• /
• v.63 no.1
• /
• pp.7-11
• /
• 2019

Olmutinib, N-[3-({2-[4-(4-methylpiperazine-1-yl)aniline]thieno[3,2-d]Pyrimidin-4-yl}oxy)phenyl]prop-2-enamide dihydrochloride monohydrate, $Olita^{TM}$ is an oral, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that was developed by Boehringer Ingelheim and Hanmi Pharmaceutical Co. Ltd for the treatment of non-small cell lung cancer (NSCLC). The aim of this work was to investigate the existence of polymorphs and pseudopolymorphs of olmutinib. Three crystal forms of olmutinib have been isolated by recrystallization and characterized by differential scanning calorimetry (DSC), thermogravimetric (TG) analysis and powder X-ray diffractometry (PXRD). From the DSC and TG data it was confirmed that Form 1 is monohydrate, Form 2 is dihydrate, Form 3 is 1.5 hydrate. The PXRD patterns of three crystal forms were different respectively. After storage of 1 month at $2^{\circ}C$, 24% RH (Relative Humidity), Form 1, Form 2, and Form 3 were not transformed.

• Journal of Yeungnam Medical Science
• /
• v.28 no.1
• /
• pp.31-44
• /
• 2011

Background: The optimal timing of treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKI) in NSCLC patients has not yet been determined. Methods: We separated 228 patients with advanced /metastatic NSCLC treated with gefitinib into an early gefitinib group (patients who received gefitinib as first- or second-line treatment) and a delayed gefitinib group (patients who received gefitinib as third or fourth-line treatment) and attempted to determine whether the timing of gefitinib treatment affected clinical outcomes. Results: Median overall survival (OS), progression free survival (PFS), and median OS from first-line treatment of advanced/metastatic disease (OSt) for 111 patients in the early gefitinib group were 6.2 months, 3.3 months, and 11.6 months. However, median OS, PFS, and OSt for 84 patients in the delayed gefitinib group were 7.8 months, 2.3 months, and 22.7 months. No differences in OS and PFS were observed between the 2 groups. However, OSt was significantly longer in the delayed gefitnib group. Timing of gefitinib therapy was one of the independent predictors of OSt. Hb ${\geq}$ 10 g/dl, and having never smoked, and ECOG performance status ${\leq}1$ were independent predictors of better PFS. Conclusion：Deferral of gefitinib therapy in patientswith advanced ormetastatic NSCLC may be preferable if they are able to tolerate chemotherapy.

• Korean Journal of Clinical Laboratory Science
• /
• v.55 no.1
• /
• pp.16-28
• /
• 2023

Lung adenocarcinoma accounts for about 40% of all lung cancers. With the recent development of gene profiling technology, studies on mutations in oncogenes and tumor suppressor genes, which are important for the development and growth of tumors, have been actively conducted. Companion diagnosis using next-generation sequencing helps improve survival with targeted therapy. In this study, formalin-fixed paraffin-embedded tissues of non-small cell lung cancer patients were subjected to hematoxylin and eosin staining for detecting genetic mutations that induce lung adenocarcinoma in Koreans. Immunohistochemical staining was also performed to accurately classify lung adenocarcinoma tissues. Based on the results, next-generation sequencing was applied to analyze the types and patterns of genetic mutations, and the association with smoking was established as the most representative cause of lung cancer. Results of next-generation sequencing analysis confirmed the single nucleotide variations, copy number variations, and gene rearrangements. In order to validate the reliability of next-generation sequencing, we additionally performed the existing genetic testing methods (polymerase chain reaction-epidermal growth factor receptor, immunohistochemistry-anaplastic lymphoma kinase (D5F3), and fluorescence in situ hybridiation-receptor tyrosine kinase 1 tests) to confirm the concordance rates with the next-generation sequencing test results. This study demonstrates that next-generation sequencing of lung adenocarcinoma patients simultaneously identifies mutation.

• Tuberculosis and Respiratory Diseases
• /
• v.74 no.1
• /
• pp.37-40
• /
• 2013

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for non-small-cell lung cancer patients. Its untoward cutaneous effects are largely well known and developed in many patients treated with EGFR TKIs. However trichomegaly of eyelash is rarely reported. Although trichomegaly is not a drug-limiting side effect, it could be troublesome of continuing the treatment because of cosmetic issue or eyeball irritation by long eyelashes. Therefore clinicians are needed to pay attention to this uncommon effect. We herein describe erlotinib induced trichomegaly of eyelashes in a woman with adenocarcinoma of the lung.