NTRK1 gene fusions as a novel oncogene target in lung cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8023-8023 ◽  
Author(s):  
Robert Charles Doebele ◽  
Aria Vaishnavi ◽  
Marzia Capelletti ◽  
Anh T. Le ◽  
Severine Kako ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Kinase Domain ◽  
Cloning And Expression ◽  
Egfr Mutations ◽  
Fish Analysis ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Investigation Methods ◽  
Trk Inhibitors

8023 Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIP-NTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.

scholarly journals Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

2020 ◽  
Author(s):  
Xu Zhang ◽  
Tapan K. Maity ◽  
Karen E. Ross ◽  
Yue Qi ◽  
Constance M. Cultraro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Egfr Mutations ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Resistant Cells

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance both in vitro and in vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rd generation EGFR TKI sensitive and resistant cells.

Implementation of molecular testing for EGFR mutations and ALK rearrangement in lung adenocarcinoma in Brazil.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18002-e18002
Author(s):  
Sofia Palacio ◽  
Gilberto Lopes ◽  
Edna Prado
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Practice Patterns ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Limited Data ◽  
Alk Rearrangement ◽  
First Semester ◽  
Changing Practice ◽  
Current Guidelines

e18002 Background: Lung cancer is the leading cause of cancer death worldwide. In Brazil, cancer is the second most common cause of death and there were an estimated 27,330 new cases of lung cancer in 2014. Targeted therapies have changed disease prognosis and current clinical guidelines advocate for EGFR/ALK molecular testing for all patients with advanced-stage lung adenocarcinoma. Access to this testing is often limited in the developing world. In the case of Brazil, there is limited data regarding the frequency of testing and the changes in patterns of testing overtime. Methods: De-identified data was obtained from a commercial database that surveys approximately 2,000 cancer physicians in Brazil regarding practice patterns. On average 300 physicians responded to the survey, which is conducted every 6 months, and provided information on about 18,000 patients. Subsequently, we identified patients with lung cancer and calculated the frequency of testing for EGFR mutations and ALK rearrangement from 2011 to 2016. Results: 11,684 patients with lung adenocarcinoma were analyzed from 2011 to 2016. The frequency of testing for EGFR mutations increased significantly: 12.8% (287/2,228) in 2011, 34.4% (738/2,142) in 2012, 39.2% in 2013 (822/2,092), 43.9% in 2014 (866/1,972), 53.3% (1165/2,184) in 2015, and 58% (626/1,066) for the first semester of 2016. Testing for ALK rearrangement also increased noticeably over the same period: 0% in 2011 (0/2,228) and 2012 (0/2,142), 0.9% (19/2,092) in 2013, 2.99% (59/1,972) in 2014, 5.5% (121/2,184) in 2015, and 4.8% (52/1,066) for the first semester of 2016. Conclusions: To our knowledge this is the largest data analysis regarding changing practice patterns of molecular testing for lung adenocarcinoma over time in Brazil and Latin America. The frequency of testing for EGFR mutations and ALK rearrangement has increased over the last 5 years but is still below the current guidelines recommending that all patients with advanced disease be tested. Further understanding of the barriers to testing, will hopefully lead to national strategies for universal implementation of molecular testing.

scholarly journals TERT Mutation was Associated with the Risk of Recurrence in Lung Adenocarcinoma with A Micropapillary Pattern

2020 ◽  
Author(s):  
Fenfang Wang ◽  
Lu Xu ◽  
Qing Hao ◽  
Chenghui Li ◽  
Qihuan Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
High Risk ◽  
Lung Adenocarcinoma ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Molecular Characteristics ◽  
Risk Of Recurrence ◽  
Tert Mutation ◽  
Micropapillary Pattern

Abstract Background: Lung adenocarcinoma with a micropapillary pattern (MPPAC) is the histological subtype of lung cancer. It has attracted increasing attention, especially regarding its association with poor prognosis, including the predisposition towards recurrence and metastasis. Although MPPAC has been described in early-stage cases, only a few studies have reported the correlation between disease-specific prognosis and gene mutation of MPPAC. This study aimed to clarify the common genetic mutations and the prognostic characteristics in MPPAC patients.Methods: A total of 17 patients whose surgical pathology was defined as MPPAC were followed up, the molecular characteristics were elucidated by next-generation sequencing, and the prognostic characteristics were analyzed. Results: Epidermal growth factor receptor (EGFR) mutations were identified in 11/17 (65%) of patients. TP53 alterations were identified in 10/17 (59%). Other common mutations include ATM (18%), KRAS (18%), SDHA (18%), and TERT (18%). MPPAC patients harboring EGFR and TERT mutations were at a high risk of tumor recurrence, while TP53 might be associated with a low risk of recurrence. Conclusions: TERT mutation was more frequently harbored in MPPAC patients than in the other histological type of lung cancer, and such patients were at a high risk of recurrence. So TERT mutation might be associated with adverse prognosis in MPPAC patients.

scholarly journals OR28-04 Identification of Novel and Rare Receptor Tyrosine Kinase Fusions in Thyroid Fine Needle Aspirates

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lori J Wirth ◽  
Elizabeth G Grubbs ◽  
Masha J Livhits ◽  
Steven I Sherman ◽  
Steven P Weitzman ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Chromosomal Rearrangements ◽  
Kinase Domain ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Rna Seq ◽  
Fine Needle Aspirates ◽  
Genomic Markers ◽  
Treatment Naïve

Abstract Introduction: Receptor tyrosine kinases (RTKs) initiate signaling cascades, including growth and differentiation. Activation can occur through chromosomal rearrangements that lead to gene fusions. RTK fusions are potential targets for small molecule inhibitors to treat advanced cancers. The original Afirma Xpression Atlas (XA) reported 761 selected variants and 130 fusion pairs in Bethesda III/IV Afirma Genomic Sequencing Classifier (GSC) suspicious or Bethesda V/VI nodules. The landscape of additional potentially actionable gene fusions has not been explored in treatment-naïve patients. Methods: Anonymized RNA-seq data from >37,000 Bethesda III-VI samples were examined with STAR-fusion to determine gene/gene fusions. All samples were examined for NTRK1, NTRK3, RET, ALK, and BRAF fusions, regardless of fusion partner. Fusions were evaluated for being in-frame, with an intact kinase domain at the 3’ end of the fusion pair. Fusion pairs not currently reported by XA and not reported in thyroid TCGA fusion data are denoted “additional”. All fusion pairs were searched for in the literature and public fusion databases. Results: Examining the Veracyte clinical database revealed 7 additional NTRK1/3 fusions, with 3 NTRK fusions observed more than once - SQSTM1/NTRK3, VIM/NTRK3, and EML4/NTRK3. One of the 7 NTRK fusions had not been previously reported. Eight additional ALK fusions were identified, with 4 observed more than once- ITSN2/ALK, PPP1R21/ALK, PDE8B/ALK, NPAT/ALK. Five of these 8 ALK fusions had not been previously described. Seventeen additional RET fusions were identified, with 5 observed recurrently - KIAA1217/RET, AFAP1L2/RET, ACBD5/RET, SQSTM1/RET, and TFG/RET. Six of the 17 RET fusions had not been previously reported. Seventy-two additional BRAF fusions were identified, and 58 of them have not been previously reported. Eight of the 72 BRAF fusions were observed more than once. Examining >50,000 Afirma samples, NTRK1, NTRK3, RET, ALK, or BRAF fusions were not identified among the Afirma GSC Benign, and were present in 3.2% of 16,594 Bethesda III/IV Afirma GSC Suspicious samples, and 8.0% of 1,692 Bethesda V/VI samples. Correlation with surgical histology is unknown. Conclusions: By examining a large cohort of patients with an unbiased, whole-transcriptome RNA-seq assay, we identified potentially actionable kinase fusions in thyroid nodules beyond those described in TCGA. All fusions described here are either novel and not previously reported, rarely reported in one or two case studies, or not described in thyroid cancers. Additional NTRK, ALK, RET and BRAF fusions were found, all of which may be targeted with specific kinase inhibitors currently available. Future studies may determine genotype-phenotype correlations regarding the natural history of these neoplasms. Because of the potential clinical implications of these genomic markers for patient management, all 104 fusions described here are now included among the 235 gene pairs reported by the expanded Afirma XA.

scholarly journals Clinical Characteristics of Patients With Lung Adenocarcinomas Harboring BRAF Mutations

2011 ◽  
Vol 29 (15) ◽  
pp. 2046-2051 ◽  
Author(s):  
Paul K. Paik ◽  
Maria E. Arcila ◽  
Michael Fara ◽  
Camelia S. Sima ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Lung Adenocarcinoma ◽  
Clinical Characteristics ◽  
Median Overall Survival ◽  
Smoking History ◽  
Egfr Mutations ◽  
Braf Mutations ◽  
Former Smokers ◽  
Lung Adenocarcinomas

Purpose BRAF mutations occur in non–small-cell lung cancer. Therapies targeting BRAF mutant tumors have recently been identified. We undertook this study to determine the clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. Patients and Methods We reviewed data from consecutive patients with lung adenocarcinoma whose tumors underwent BRAF, EGFR, and KRAS mutation testing as well as fluorescence in situ hybridization for ALK rearrangements. Patient characteristics including age, sex, race, performance status, smoking history, stage, treatment history, and overall survival were collected. Results Among 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%; 95% CI, 2% to 4%). The BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%). Mutations in EGFR were present in 24%, KRAS in 25%, and ALK translocations in 6%. In contrast to patients with EGFR mutations and ALK rearrangements who were mostly never smokers, all patients with BRAF mutations were current or former smokers (P < .001). The median overall survival of advanced-stage patients with BRAF mutations was not reached. In comparison, the median overall survival of patients with EGFR mutations was 37 months (P = .73), with KRAS mutations was 18 months (P = .12), and with ALK rearrangements was not reached (P = .64). Conclusion BRAF mutations occur in 3% of patients with lung adenocarcinoma and occur more commonly in current and former smokers. The incidence of BRAF mutations other than V600E is significantly higher in lung cancer than in melanoma.

scholarly journals Effect of WW Domain-Containing Oxidoreductase Gene Polymorphism on Clinicopathological Characteristics of Patients with EGFR Mutant Lung Adenocarcinoma in Taiwan

2021 ◽  
Vol 18 (24) ◽  
pp. 13136
Author(s):  
Ju-Pi Li ◽  
Jinghua Tsai Chang ◽  
Po-Chung Ju ◽  
Ming-Hong Hsieh ◽  
Yu-Hua Chao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Genotype Distribution ◽  
Nucleotide Polymorphisms ◽  
Primary Tumors ◽  
Ww Domain ◽  
Significant Difference ◽  
Egfr Mutant

Lung adenocarcinoma is the most common histological type of non-small cell lung cancer, which accounts for the majority of lung cancers. Previous studies have showed that dysregulation of WW domain-containing oxidoreductase (WWOX) participates in the generation of several cancer types, including lung cancer. However, whether these WWOX polymorphisms are related to the clinical risk of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma is worthy of investigation. The present study examined the relationship between the WWOX single-nucleotide polymorphisms (SNPs; rs11545028, rs12918952, rs3764340, rs73569323, and rs383362) and the clinicopathological factors in lung adenocarcinoma patients with or without EGFR mutations. We found that there was no significant difference in the genotype distribution of WWOX polymorphism between EGFR wild-type and EGFR mutant in patients with lung adenocarcinoma. Our results demonstrated that the presence of at least one G genotype (CG and GG) allele on WWOX rs3764340 was associated with a significantly higher risk of nearby lymph node involvement in those patients harboring EGFR mutations (odds ratio (OR) = 3.881, p = 0.010) compared with the CC genotype. Furthermore, in the subgroup of lung adenocarcinoma patients with the EGFR-L858R mutation, both WWOX rs3764340 C/G (OR = 5.209, p = 0.023) and rs73569323 C/T polymorphisms (OR = 3.886, p = 0.039) exhibited significant associations with the size of primary tumors and the invasion of adjacent tissues. In conclusion, these data indicate that WWOX SNPs may help predict tumor growth and invasion in patients with EGFR mutant lung adenocarcinoma, especially those with the EGFR-L858R mutant in Taiwan.

scholarly journals Primary Erlotinib Resistance in a Patient with Non-Small Cell Lung Cancer Carrying Simultaneous Compound EGFR L718A, Q849H, and L858R Mutations

2021 ◽  
Vol 12 (1) ◽  
pp. 164-174
Author(s):  
Hanifeh Mirtavoos-mahyari ◽  
Elham Rismani ◽  
Alireza Sarkar Lotfabadi ◽  
Azizollah Abbasi Dezfouli ◽  
Kambiz Sheikhy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Domain ◽  
Small Cell ◽  
Dynamics Simulation ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase

Abstract Nowadays, mutations in the epidermal growth factor receptor (EGFR) kinase domain are studied in targeted therapy of non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors including gefitinib and erlotinib. The present study reports a rare case of a patient harboring three simultaneous EGFR mutations (L718A, Q849H, and L858R). The development of erlotinib resistance was detected in the subsequent treatment. Using a computational approach, the current study investigated the conformational changes of wild-type and mutant EGFR's kinase domains in the interaction with erlotinib. Their binding modes with erlotinib were elucidated during molecular dynamics simulation, where higher fluctuations were detected in the mutated forms of the EGFR tyrosine kinase domain. Prediction of stability and functional effect of mutations revealed that amino acidic substitutions have decreased the protein stability as well as the binding affinity to erlotinib. These results may be useful for a recommendation of EGFR mutational analysis for patients with NSCLC carcinoma.

scholarly journals Constitutively active TrkB kinase signalling reduces actin filopodia dynamics and cell migration

2020 ◽  
Author(s):  
Rohini Gupta ◽  
Melanie Bauer ◽  
Gisela Wohlleben ◽  
Vanessa Luzak ◽  
Vanessa Wegat ◽  
...  
Keyword(s):  
Cell Migration ◽  
Biological Function ◽  
Kinase Domain ◽  
Signalling Pathways ◽  
Precision Oncology ◽  
Gene Fusions ◽  
Trk Receptors ◽  
Constitutive Activation ◽  
Trk Inhibitors ◽  
Constitutively Active

AbstractTrk receptors and gene fusions of NTRK are targets in precision oncology. Classical Trk signalling concepts fail to explain ligand-independent signalling of intracellular TrkB or NTRK fusion proteins. Here, we show that abundance of the intracellular domain of TrkB is sufficient for ligand-independent autophosphorylation. This constitutive TrkB signalling reduced actin filopodia dynamics, could phosphorylate FAK, and changed cell morphology. Mutating Y705 in the kinase domain of TrkB alone specifically blocked these pathways. Engineered intracellular kinase domain proteins and a cancer-related intracellular NTRK2-fusion protein (SQSTM1-NTRK2) also underwent constitutive activation. In migrating glioblastoma-like U87MG cells, self-active TrkB kinase reduced cell migration. Moreover, we found evidences for constitutively active, intracellular TrkB in tissue of human grade IV glioblastoma. Structural modelling of the kinase domain let us postulate that ‘release from cis-autoinhibition by abundance’ is sufficient for TrkB/FAK/Actin signalling via Y705. These constitutive signalling pathways could be fully blocked within minutes by clinically approved, anti-tumorigenic Trk inhibitors. In conclusion, our data provide an explanation and biological function for TrkB kinase domain signalling in the absence of a ligand.

NTRK fusion analysis reveals enrichment in Middle Eastern BRAF wild-type PTC

2021 ◽  
Author(s):  
Yan Kong ◽  
Rong Bu ◽  
Sandeep Kumar Parvathareddy ◽  
Abdul K Siraj ◽  
Nabil Siraj ◽  
...  
Keyword(s):  
Gene Fusion ◽  
Middle Eastern ◽  
Fish Analysis ◽  
Gene Fusions ◽  
Wild Type ◽  
Pediatric Age Group ◽  
Middle Eastern Population ◽  
Fusion Analysis ◽  
Trk Inhibitors ◽  
Tumor Types

Objective: Fusions involving neurotrophic tyrosine receptor kinase (NTRK) are known oncogenic drivers in a broad range of tumor types. It recently gained attention as predictor of targeted therapy since selective NTRK inhibitors are now approved in US and Europe for patients with solid tumors harboring gene fusions. However, estimation of NTRK gene fusion/alteration frequency and its clinico-pathological characteristics in papillary thyroid cancer (PTC) is limited, especially in a population with high incidence for PTC like Middle Eastern population. This study aims to characterize the NTRK gene fusion frequency and investigate the utility of pan-Trk immunohistochemistry (IHC) as predictor of NTRK fusion in a large cohort of Middle Eastern PTC. Methods: FISH analysis for NTRK gene fusions and pan-Trk IHC was performed on 315 Middle Eastern PTCs. Correlation of NTRK gene fusion and protein expression with clinico-pathological markers and patient outcome were determined. Results: In our cohort, 6.0% (19/315) patients showed NTRK gene fusions and were significantly associated with pediatric PTC (p = 0.0143), lymph node metastasis (p = 0.0428) and BRAF wild-type tumors (p < 0.0001). Pan-Trk IHC was positive in 9.2% (29/315) of cases and significantly associated with NTRK fusions, with a sensitivity of 73.7% and specificity of 94.9% in this cohort. Conclusions: This study confirms the presence of NTRK fusions in Middle Eastern PTC which is significantly enriched in BRAF wild-type as well as pediatric age group and proposes the usefulness of IHC to screen for PTC patients with NTRK fusion that might benefit from TRK inhibitors.

Induction gefitinib followed by concurrent chemoradiotherapy in patients with unresectable stage IIIA/b lung adenocarcinoma harboring mutations of epidermal growth factor receptor: Three case reports.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17510-e17510
Author(s):  
Yoshitsugu Horio ◽  
Chiaki Kondo ◽  
Jangchul Park ◽  
Junichi Shimizu ◽  
Kimihide Yoshida ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Lung Adenocarcinoma ◽  
Concurrent Chemoradiotherapy ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Epidermal Growth

e17510 Background: Gefitinib has shown good activity in lung cancer harboring mutations in the epidermal growth factor receptor (EGFR) gene. However, how to integrate gefitinib into concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC) with EGFR mutations is uncertain. Methods: We present three cases of locally advanced lung adenocarcinoma with EGFR mutation, which were treated with gefitinib followed by weekly paclitaxel and carboplatin concurrent with radiation. Three female patients (median age, 73 years; range, 61–77 years) received induction gefitinib 150 mg daily for 1-2 months followed by weekly paclitaxel 40 mg/m2 weekly over 1 hour; carboplatin at AUC (area under the curve) of 2 weekly over 1 hour; and radiation therapy of 60 Gy in 30 fractions. Results: Gefitinib induced very rapid response within the first month without pulmonary toxicity. Subsequent concurrent chemoradiotherapy was performed with safety. One patient recurred as hematogenous lung metastases at 5 months after treatment. The remaining two patients are well doing without adverse events. Conclusions: The very quick response to induction gefitinib and sequential chemoradiotherapy may be an effective treatment with good tolerance. We believe that this treatment strategy deserves further evaluation in unresectable locally advanced NSCLC with EGFR mutations.

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