Cancer Research and Treatment

Original Articles

The Profile of Gut Microbiota in Carcinogenesis Driven by Mutant EGFR in Non-Small Cell Lung Cancer: Da-Som Kim, Eun Hye Kim, Ji Yong Kim, Dong Ha Kim, Yun Jung Choi, Jaeyi Jeong, Young Hoon Sung, Dong-Cheol Woo, Chong Jai Kim, Jae Cheol Lee, Miyong Yun, Jin-Yong Jeong, Jin Kyung Rho; Received December 9, 2024 Accepted March 2, 2025 Published online March 4, 2025; DOI: https://doi.org/10.4143/crt.2024.1177 [Accepted]

Abstract PDF: Purpose
Accumulating evidence has clarified that gut dysbiosis is involved in lung cancer development and progression. Although the relationship between tumors and gut microbiota has been extensively studied using clinical samples, no studies have examined the association between mutant EGFR-induced lung carcinogenesis and dysbiosis in gut microbiota. Therefore, we investigated the gut microbiota profiles in stool samples from human lung-specific conditional EGFR-mutant transgenic mice during lung tumor carcinogenesis.
Materials and Methods
Stool samples were collected before tamoxifen treatment (V1) and at each time point following mutant EGFR expression in lung tissue (V2) and lung tumor appearance (V3). Fecal 16S rRNA taxonomy was analyzed to assess microbial diversity, composition, and dynamic changes at each time point.
Results
We found that microbiota richness and diversity were significantly elevated when tumors developed and grew in the lung. Phylogenetic analysis of the microbial community revealed that Lachnospiraceae, Ruminococcaceae, Porphyromonadaceae, Rhodospirillaceae, Odoribacteraceae, and Desulfovibrionaceae showed a significant increase at the V3 stage compared to the V1 stage at the family level. In contrast, Lactobacillaceae, Bacteroidaceae, Muribaculaceae, Coriobacteriaceae, and Rikenellaceae significantly decreased at the V3 stage compared to the V1 stage. Furthermore, Lactobacillus species, also known as SCFA-producing bacteria, were relatively abundant at the V1 stage but were depleted with the occurrence of lung tumors at the V3 stage.
Conclusion
Changes in gut microbiota, such as Lactobacillus species, may be a predictive factor for the emergence and progression of tumors in an animal model of lung adenocarcinoma induced by mutant EGFR.

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Epidermal Growth Factor Receptor Aberrations Identified by Next-generation Sequencing in Patients with Metastatic Cancers: Minkyue Shin, Dae-Ho Choi, Jaeyun Jung, Deok geun Kim, Sung Hee Lim, Seung Tae Kim, Jung Yong Hong, Se Hoon Park, Joon Oh Park, Kyoung-Mee Kim, Jeeyun Lee; Received June 17, 2024 Accepted January 21, 2025 Published online February 21, 2025; DOI: https://doi.org/10.4143/crt.2024.564 [Accepted]

Abstract PDF: Purpose
The epidermal growth factor receptor (EGFR) is a therapeutic target with confirmed clinical efficacy for several cancer types. We aimed to identify EGFR aberrations and their associations with other genomic alterations in patients with metastatic diseases of various cancers.
Materials and Methods
We used real-world data from the next-generation sequencing (NGS) of 3,286 patients with metastatic cancer at the Samsung Medical Center. We analyzed the distribution of EGFR amplification, mutation, and fusion, as well as their correlations with microsatellite instability (MSI), tumor mutation burden (TMB), and other gene aberrations.
Results
A total of 3,286 patients were tested using NGS of a panel covering 523 cancer-related genes (TSO500, Illumina) as part of clinical practice between October 2019 and October 2022. Patients with lung cancer and gliomas were not included in the analysis. Of the 3,286 patients, 175 (5.3%) had EGFR amplification, 38 (1.2%) had EGFR mutations, and 8 (0.2%) had EGFR fusion. All 175 patients with EGFR amplifications had microsatellite-stable (MSS) tumors, but 102 had co-amplifications in other cancer-related genes, and 78 had mutations with clinical significance (tier I/II). Among the 38 patients with EGFR mutations, three (8%) showed MSI-high status, and eleven (29%) demonstrated high TMB (≥ 10 mutations/mb). Among eight patients with EGFR fusion, three exhibited possible functionalities of the EGFR gene.
Conclusion
EGFR aberrations, mainly amplification, followed by mutation and fusion, were present in 6.4% of patients with metastatic solid tumors.

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Single-Cell Heterogeneity of EGFR Pathway Is Linked to Unique Signatures of Drug Response and Malignancy in Patient Derived Glioblastoma Stem Cells: Michael D. Masterman-Smith, Nicholas A. Graham, Eduard H. Panosyan, Jack Mottahedeh, Eric R. Samuels, Araceli Nunez, Tiffany Phillips, Meeryo Choe, Timothy F. Cloughesy, Jorge A. Lazareff, Linda M. Liau, William H. Yong, Thomas G. Graeber, Harley I. Kornblum, Ming-Fei Lang, Yanzhao Li, Jing Sun; Received September 4, 2024 Accepted January 6, 2025 Published online January 7, 2025; DOI: https://doi.org/10.4143/crt.2024.859 [Accepted]

Abstract PDF: Purpose
In glioblastoma, the therapeutically intractable and resistant phenotypes can be derived from glioma stem cells, which often have different underlying mechanisms from non-stem glioma cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR pathways have been shown as common drivers of glioblastoma. Revealing the inter and intra-cellular heterogeneity within glioma stem cell populations in relations to signaling patterns through these pathways may be key to precision diagnostic and therapeutic targeting of these cells.
Materials and Methods
Single cell parallel proteomic heterogeneity profiling of the EGFR-PTEN-AKT-mTOR pathways was conducted in a panel of fifteen glioma stem cell models derived from patient glioblastoma biopsies.
Results
The analysis included 59,464 data points from 14,866 cells and identified forty-nine molecularly distinct signaling phenotypes. High content bioinformatics resolved two unique patient clusters diverging on EGFR expression and AKT/TORC1 activation. Phenotypic validation indicated drug responsive phenotypes to EGFR blocking in the high EGFR expressing cluster with lower tumor initiating potential in comparison to the AKT/TORC1 activated cluster. High EGFR expression trended with improved patient prognosis while AKT/TORC1 activated samples trended with poorer patient outcomes. Genetic heterogeneity was observed in both clusters with proneural, classical and mesenchymal subtypes observed.
Conclusion
Quantitative single cell heterogeneity profiling reveals divergent EGFR-PTEN-AKT-mTOR pathways of patient derived glioma stem cells, which would inform future research and personalized therapeutic strategies.

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Lung and Thoracic cancer

Comparison of Clinicopathogenomic Features and Treatment Outcomes of EGFR and HER2 Exon 20 Insertion Mutations in Non–Small Cell Lung Cancer: Single-Institution Experience: So Heun Lee, Hyehyun Jeong, Deok Hoon Kim, Se Jin Jang, Sang-We Kim, Shinkyo Yoon, Dae Ho Lee; Cancer Res Treat. 2024;56(3):774-784. Published online January 30, 2024; DOI: https://doi.org/10.4143/crt.2023.1177

Abstract PDF PubReader ePub: Purpose
Exon 20 insertion mutations (E20ins) in epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) in non–small cell lung cancer (NSCLC) patients has become more important with emergence of novel agents targeting E20ins.
Materials and Methods
Advanced/Metastatic NSCLC patients with E20ins were included. EGFR E20ins was identified by two methods, next-generation sequencing (NGS) or real-time polymerase chain reaction (PCR), while HER2 E20ins was done by NGS only.
Results
Between December 2013 and July 2021, E20ins were identified in 107 patients at Asan Medical Center; 67 EGFR E20ins and 40 HER2 E20ins. Out of 32 patients with EGFR E20ins who had tested both PCR and NGS, 17 were identified only through NGS and the other 15 through both tests, giving a discordance rate of 53.1%. There was no clinically significant difference in clinicopathologic features between EGFR and HER2 E20ins; both were observed more frequently in adenocarcinoma, female and never-smokers. Brain metastases were evident at diagnosis in 31.8% of EGFR E20ins and 27.5% of HER2 E20ins, respectively. Platinum-based doublets demonstrated objective response rates (ORR) of 13.3% with a median progression-free survival (PFS) of 4.2 months for EGFR E20ins and 35.3% with 4.7 months for HER2 E20ins, respectively. In contrast, novel EGFR E20ins-targeted agents exhibited an ORR of 46.2% with a median PFS of 5.4 months, while HER2-targeted agents showed an ORR of 50% with that of 7.0 months.
Conclusion
Identification of EGFR and HER2 E20ins is more important as their targeted therapies improved outcomes. Upfront NGS test as a comprehensive molecular approach is strongly warranted.

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Clinical Validation of the Unparalleled Sensitivity of the Novel Allele-Discriminating Priming System Technology–Based EGFR Mutation Assay in Patients with Operable Non–Small Cell Lung Cancer: Il-Hyun Park, Dae-Soon Son, Yoon-La Choi, Ji-Hyeon Choi, Ji-Eun Park, Yeong Jeong Jeon, Minseob Cho, Hong Kwan Kim, Yong Soo Choi, Young Mog Shim, Jung Hee Kang, Suzy Park, Jinseon Lee, Sung-Hyun Kim, Byung-Chul Lee, Jhingook Kim; Cancer Res Treat. 2024;56(1):81-91. Published online June 20, 2023; DOI: https://doi.org/10.4143/crt.2023.408

Abstract PDF Supplementary Material PubReader ePub

Purpose
Recently, we developed allele-discriminating priming system (ADPS) technology. This method increases the sensitivity of conventional quantitative polymerase chain reaction up to 100 folds, with limit of detection, 0.01%, with reinforced specificity. This prospective study aimed to develop and validate the accuracy of ADPS epidermal growth factor receptor (EGFR) Mutation Test Kit using clinical specimens.
Materials and Methods
In total 189 formalin-fixed paraffin-embedded tumor tissues resected from patients with non–small cell lung cancer were used to perform a comparative evaluation of the ADPS EGFR Mutation Test Kit versus the cobas EGFR Mutation Test v2, which is the current gold standard. When the two methods had inconsistent results, next-generation sequencing–based CancerSCAN was utilized as a referee.
Results
The overall agreement of the two methods was 97.4% (93.9%-99.1%); the positive percent agreement, 95.0% (88.7%-98.4%); and the negative percent agreement, 100.0% (95.9%-100.0%). EGFR mutations were detected at a frequency of 50.3% using the ADPS EGFR Mutation Test Kit and 52.9% using the cobas EGFR Mutation Test v2. There were 10 discrepant mutation calls between the two methods. CancerSCAN reproduced eight ADPS results. In two cases, mutant allele fraction was ultra-low at 0.02% and 0.06%, which are significantly below the limit of detection of the cobas assay and CancerSCAN. Based on the EGFR genotyping by ADPS, the treatment options could be switched in five patients.
Conclusion
The highly sensitive and specific ADPS EGFR Mutation Test Kit would be useful in detecting the patients who have lung cancer with EGFR mutation, and can benefit from the EGFR targeted therapy.

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Highly Sensitive 3D‐Nanoplasmonic‐Based Epidermal Growth Factor Receptor Mutation Multiplex Assay Chip for Liquid Biopsy
Ji Young Lee, Byeong‐Ho Jeong, Ho Sang Jung, Taejoon Kang, Yeonkyung Park, Jin Kyung Rho, Sung‐Gyu Park, Min‐Young Lee
Small Science.2024;[Epub] CrossRef
The Advantage of Targeted Next-Generation Sequencing over qPCR in Testing for Druggable EGFR Variants in Non-Small-Cell Lung Cancer
Adam Szpechcinski, Joanna Moes-Sosnowska, Paulina Skronska, Urszula Lechowicz, Magdalena Pelc, Malgorzata Szolkowska, Piotr Rudzinski, Emil Wojda, Krystyna Maszkowska-Kopij, Renata Langfort, Tadeusz Orlowski, Pawel Sliwinski, Mateusz Polaczek, Joanna Chor
International Journal of Molecular Sciences.2024; 25(14): 7908. CrossRef

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Case Report

Osimertinib Combined with Systemic Chemotherapy for EGFR Mutant, T790M-Negative, Non–Small Cell Lung Cancer Patients Who Develop Leptomeningeal Metastases with Extracranial Progression to Prior EGFR TKI: Hye Ryeon Kim, Hyunji Jo, Hongsik Kim, Joohyun Hong, Sehhoon Park, Hyun Ae Jung, Se-Hoon Lee, Jin-Seok Ahn, Myung-Ju Ahn; Cancer Res Treat. 2023;55(1):344-349. Published online March 26, 2022; DOI: https://doi.org/10.4143/crt.2021.1603

Abstract PDF PubReader ePub

Leptomeningeal metastasis (LM) is a rare but fatal clinical condition with a short survival time. The incidence of LM from epidermal growth factor receptor mutant (EGFRm) non–small cell lung cancer (NSCLC) has increased due to the limited efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the central nervous system (CNS). Osimertinib is a third-generation, irreversible, CNS penetrant, oral EGFR TKI that demonstrates promising efficacy in CNS metastases regardless of T790M. Herein, we report four cases of T790M-negative EGFRm NSCLC patients treated with osimertinib combined with systemic chemotherapy, who progressed on prior EGFR TKI and developed LM with extracranial lesions. The combination treatment was well tolerated, and the mean overall survival from LM diagnosis was 14.7 months (95% confidence interval, 10.4 to 19.0). These results suggest that osimertinib combined with systemic chemotherapy would be a reasonable treatment option for T790M-negative EGFRm NSCLC patients who develop LM with extracranial progression to prior EGFR TKI. A further prospective study is warranted.

Citations

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The research progress on meningeal metastasis in solid tumors
Yi Yue, Yuqing Ren, Chunya Lu, Nan Jiang, Sihui Wang, Junkai Fu, Mengrui Kong, Guojun Zhang
Discover Oncology.2025;[Epub] CrossRef
An overview of the therapeutic strategies for neoplastic meningitis due to breast cancer: when and why?
Mainak Bardhan, Debankur Dey, Vinay Suresh, Binish Javed, Vyshak Alva Venur, Neha Joe, Ritvika Kalidindi, Ahmad Ozair, Marium Khan, Reshma Mahtani, Simon Lo, Yazmin Odia, Manmeet S. Ahluwalia
Expert Review of Neurotherapeutics.2024; 24(1): 77. CrossRef
Osimertinib is associated with improved outcomes in pre-treated non-small cell lung cancer leptomeningeal metastases: A systematic review and meta-analysis
David J.H. Bian, Anna-Maria Lazaratos, Sarah M. Maritan, Andrea Quaiattini, Zhimin Zeng, Zhengfei Zhu, Ugur Sener, Rachna Malani, Yu Jung Kim, Eiki Ichihara, Victor Cohen, April A.N. Rose, Nathaniel Bouganim, Matthew Dankner
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Original Articles

Breast cancer

Clinical Significance of Major Angiogenesis-Related Effectors in Patients with Metastatic Breast Cancer Treated with Trastuzumab-Based Regimens: Helen P. Kourea, Foteinos-Ioannis Dimitrakopoulos, Georgia-Angeliki Koliou, Anna Batistatou, Kyriaki Papadopoulou, Mattheos Bobos, Anthoula Asimaki-Vlachopoulou, Sofia Chrisafi, Kitty Pavlakis, Kyriakos Chatzopoulos, Eleni Galani, George Pentheroudakis, Dimitrios Pectasides, Dimitrios Bafaloukos, Eleni Res, Pavlos Papakostas, Angelos Koutras, Vassiliki Kotoula, George Fountzilas; Cancer Res Treat. 2022;54(4):1053-1064. Published online November 17, 2021; DOI: https://doi.org/10.4143/crt.2021.748

Abstract PDF Supplementary Material PubReader ePub

Purpose
Angiogenesis is a crucial phenomenon in the development and progression of breast cancer (BC), but the clinical significance of angiogenesis-related proteins in metastatic BC remains unknown. This study investigates the prognostic value of vascular endothelial growth factor receptors 1, 2, 3 (VEGFR1, VEGFR2, VEGFR3) as well as vascular endothelial growth factors A and C (VEGFA and VEGFC) in metastatic BC patients treated with trastuzumab-based regimens.
Materials and Methods
Two hundred female patients were included. Protein and mRNA expression of the studied angiogenesis-related factors were evaluated by immunohistochemistry and quantitative polymerase chain reaction, respectively.
Results
High expression of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in the tumor cells was observed in 43.5%, 24.2%, 36%, 29.5%, and 43%, respectively. Stromal elements expressed high levels of VEGFA, VEGFC, VEGFR1, VEGFR2, and VEGFR3 in 78.9%, 93.3%, 90.7%, 90.2%, and 74.8% of tumors with available data. High tumor cell expression of VEGFR1 was a favorable prognosticator for survival among patients with human epidermal growth factor receptor 2 (HER2)–positive tumors (hazard ratio [HR], 0.55; p=0.013). A trend towards longer progression-free survival was detected univariately for patients with HER2-negative tumors and high expression of VEGFR2 (HR, 0.60; p=0.059).
Conclusion
VEGFR1 and VEGFR2 seem to have significant prognostic value in BC patients with metastatic disease treated with trastuzumab-based regimens.

Citations

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Apatinib beyond first progression is associated with prolonged overall survival in patients with advanced breast cancer: Results from an observational study
Jing Wang, Jinghao Jia, Jingjing Liu, Xuemin Yao, Zhiyong Yuan
Experimental and Therapeutic Medicine.2024;[Epub] CrossRef

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Lung and Thoracic cancer

The Impact of EGFR Tyrosine Kinase Inhibitor on the Natural Course of Concurrent Subsolid Nodules in Patients with Non–Small Cell Lung Cancer: Noeul Kang, Ki Hwan Kim, Byeong-Ho Jeong, Kyungjong Lee, Hojoong Kim, O Jung Kwon, Myung-Ju Ahn, Jeonghee Cho, Ho Yun Lee, Sang-Won Um; Cancer Res Treat. 2022;54(3):817-826. Published online November 9, 2021; DOI: https://doi.org/10.4143/crt.2021.822

Abstract PDF Supplementary Material PubReader ePub

Purpose
The role of epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) in the management of persistent subsolid nodules (SSNs) is unclear. This study aimed to investigate the impact of EGFR-TKIs on concurrent SSNs in patients with stage IV non–small cell lung cancer (NSCLC).
Materials and Methods
Patients who received an EGFR-TKI for at least 1 month for stage IV NSCLC and had concurrent SSN(s) that had existed for at least 3 months on chest computed tomography were included in this retrospective study. Size change of each nodule before and after EGFR-TKI therapies were evaluated using a cutoff value of 2 mm; increase (≥ 2 mm), decrease (≤ –2 mm), and no change (–2 mm < size change < +2 mm).
Results
A total of 77 SSNs, 51 pure ground-glass (66.2%) and 26 part-solid nodules (33.8%), were identified in 59 patients who received gefitinib (n=45) and erlotinib (n=14). Among 58 EGFR mutation analysis performed for primary lung cancer, 45 (77.6%) were EGFR mutant. The proportions of decrease group were 19.5% (15/77) on per-nodule basis and 25.4% (15/59) on per-patient basis. Four SSNs (5.2%) disappeared completely. On per-patient based multivariable analysis, EGFR exon 19 deletion positivity for primary lung cancer was associated with a decrease after initial EGFR-TKI therapy (adjusted odds ratio, 4.29; 95% confidence interval, 1.21 to 15.29; p=0.025).
Conclusion
Approximately 20% of the concurrent SSNs decreased after the initial EGFR-TKI therapy. EGFR exon 19 deletion positivity for primary lung cancer was significantly associated with the size change of concurrent SSNs.

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Genetic Polymorphisms of ACE1 Rs4646994 Associated with Lung Cancer in Patients with Pulmonary Nodules: A Case–Control Study
Rong Qiao, Siyao Sang, Jiajun Teng, Hua Zhong, Hui Li, Baohui Han
Biomedicines.2023; 11(6): 1549. CrossRef
Deep learning analysis to predict EGFR mutation status in lung adenocarcinoma manifesting as pure ground-glass opacity nodules on CT
Hyun Jung Yoon, Jieun Choi, Eunjin Kim, Sang-Won Um, Noeul Kang, Wook Kim, Geena Kim, Hyunjin Park, Ho Yun Lee
Frontiers in Oncology.2022;[Epub] CrossRef

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Case Report

EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation: Sehhoon Park, Bo Mi Ku, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Se-Hoon Lee, Keunchil Park, Myung-Ju Ahn; Cancer Res Treat. 2020;52(4):1288-1290. Published online June 22, 2020; DOI: https://doi.org/10.4143/crt.2020.278

Abstract PDF PubReader ePub

The non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutation eventually acquires resistant to either first or second-generation EGFR tyrosine kinase inhibitor (TKI). As the following option, targeting EGFR T790M with third-generation EGFR TKI is now established as a standard treatment option. In this study, we are reporting the first case of resistance mechanism to the novel third-generation EGFR TKI, lazertinib, which showed promising clinical efficacy in phase 1-2 study. The patients showed resistance to the treatment by acquiring the additional EGFR C797S mutation in cis which is also confirmed from the patient-derived cell lines.

Citations

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Research Advances of Small Molecule EGFR-TKIs in NSCLC
亚南胡
Pharmacy Information.2024; 13(01): 1. CrossRef
An assessment of EGFR and HER2 inhibitors with structure activity relationship of fused pyrimidine derivatives for breast cancer: a brief review
Prasad Sanjay Dhiwar, Gurubasavaraja Swamy Purawarga Matada, Rohit Pal, Ekta Singh, Abhishek Ghara, Lalmohan Maji, Sindhuja Sengupta, Ganesh Andhale
Journal of Biomolecular Structure and Dynamics.2024; 42(3): 1564. CrossRef
The efficacy of almonertinib and anlotinib combination therapy for advanced non‐small‐cell lung cancer patients who continued to experience cancer progression during third‐generation EGFR‐TKI treatment: a retrospective study
Yu Zhang, Chengmeng Wang, Jing Zhao, Meng Wang
Thoracic Cancer.2024; 15(23): 1757. CrossRef
Successful treatment of a patient with advanced lung adenocarcinoma (EGFR-T790M and C797S cis) with lazertinib: A case report and literature review
Yue Fang, Qiankun Zhang, Weimin Wang, Juanjuan Tong, Xialin Li
Frontiers in Oncology.2023;[Epub] CrossRef
A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure–Activity Relationship
Tanuja T. Yadav, Gulam Moin Shaikh, Maushmi S. Kumar, Meena Chintamaneni, Mayur YC
Frontiers in Chemistry.2022;[Epub] CrossRef
Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448)
David E. Heppner, Florian Wittlinger, Tyler S. Beyett, Tatiana Shaurova, Daniel A. Urul, Brian Buckley, Calvin D. Pham, Ilse K. Schaeffner, Bo Yang, Blessing C. Ogboo, Earl W. May, Erik M. Schaefer, Michael J. Eck, Stefan A. Laufer, Pamela A. Hershberger
ACS Medicinal Chemistry Letters.2022; 13(12): 1856. CrossRef
Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer
Kyu Sic You, Yong Weon Yi, Jeonghee Cho, Jeong-Soo Park, Yeon-Sun Seong
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Paired analysis of tumor mutation burden calculated by targeted deep sequencing panel and whole exome sequencing in non-small cell lung cancer
Sehhoon Park, Chung Lee, Bo Mi Ku, Minjae Kim, Woong-Yang Park, Nayoung K. D. Kim, Myung-Ju Ahn
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Original Articles

Randomized Phase II Study of Afatinib Plus Simvastatin Versus Afatinib Alone in Previously Treated Patients with Advanced Nonadenocarcinomatous Non-small Cell Lung Cancer: Youngjoo Lee, Ki Hyeong Lee, Geon Kook Lee, Soo-Hyun Lee, Kun Young Lim, Jungnam Joo, Yun Jung Go, Jin Soo Lee, Ji-Youn Han; Cancer Res Treat. 2017;49(4):1001-1011. Published online January 13, 2017; DOI: https://doi.org/10.4143/crt.2016.546

Abstract PDF PubReader ePub

Purpose
This phase II study examined whether the addition of simvastatin to afatinib provides a clinical benefit compared with afatinib monotherapy in previously treated patients with nonadenocarcinomatous non-small cell lung cancer (NA-NSCLC).
Materials and Methods
Patientswith advancedNA-NSCLCwho progressed after one ortwo chemotherapy regimens were randomly assigned to a simvastatin (40 mg/day) plus afatinib (40 mg/day) (AS) arm or to an afatinib (A) arm. The primary endpoint was response rate (RR).
Results
Sixty-eight patients were enrolled (36 in the AS arm and 32 in the A arm). The RR was 5.7% (95% confidence interval [CI], 0.7 to 19.2) for AS and 9.4% (95% CI, 2.0 to 25.0) for A (p=0.440). In arms AS and A, the median progression-free survival (PFS) was 1.0 versus 3.6 months (p=0.240) and the overall survival was 10.0 months versus 7.0 months (p=0.930), respectively. Skin rash, stomatitis, and diarrhea were the most common adverse events in both arms. More grade 3 or 4 diarrhea was observed in arm A (18.8% vs. 5.6% in arm AS). In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976). However, skin rash severity was significantly related to the risk of progression for afatinib (hazard ratio for skin rash grade ≥ 2 vs. grade < 2, 0.44; 95% CI, 0.25 to 0.78; p=0.005).
Conclusion
There were no significant differences in the efficacy between AS and A arms in patients with NA-NSCLC.

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Incorporating Erlotinib or Irinotecan Plus Cisplatin into Chemoradiotherapy for Stage III Non-small Cell Lung Cancer According to EGFR Mutation Status: Youngjoo Lee, Ji-Youn Han, Sung Ho Moon, Byung-Ho Nam, Kun Young Lim, Geon Kook Lee, Heung Tae Kim, Tak Yun, Hye Jin An, Jin Soo Lee; Cancer Res Treat. 2017;49(4):981-989. Published online January 6, 2017; DOI: https://doi.org/10.4143/crt.2016.522

Abstract PDF Supplementary Material PubReader ePub

Purpose
Concurrent chemoradiotherapy (CCRT) is the standard care for stage III non-small cell lung cancer (NSCLC) patients; however, a more effective regimen is needed to improve the outcome by better controlling occult metastases. We conducted two parallel randomized phase II studies to incorporate erlotinib or irinotecan-cisplatin (IP) into CCRT for stage III NSCLC depending on epidermal growth factor receptor (EGFR) mutation status.
Materials and Methods
Patients with EGFR-mutant tumors were randomized to receive three cycles of erlotinib first and then either CCRT with erlotinib followed by erlotinib (arm A) or CCRT with IP only (arm B). Patients with EGFR unknown or wild-type tumors were randomized to receive either three cycles of IP before (arm C) or after CCRT with IP (arm D).
Results
Seventy-three patients were screened and the study was closed early because of slow accrual after 59 patients were randomized. Overall, there were seven patients in arm A, five in arm B, 22 in arm C, and 25 in arm D. The response rate was 71.4% and 80.0% for arm A and B, and 70.0% and 73.9% for arm C and D. The median overall survival (OS) was 39.3 months versus 31.2 months for arm A and B (p=0.442), and 16.3 months versus 25.3 months for arm C and D (p=0.050). Patients with sensitive EGFR mutations had significantly longer OS than EGFR-wild patients (74.8 months vs. 25.3 months, p=0.034). There were no unexpected toxicities.
Conclusion
Combined-modality treatment by molecular diagnostics is feasible in stage III NSCLC. EGFR-mutant patients appear to be a distinct subset with longer survival.

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Lung Cancer.2024; 187: 107414. CrossRef
The ASCENT Trial: a phase 2 study of induction and consolidation afatinib and chemoradiation with or without surgery in stage III EGFR-mutant NSCLC
Allison E B Chang, Andrew J Piper-Vallillo, Raymond H Mak, Michael Lanuti, Alona Muzikansky, Julia Rotow, Pasi A Jänne, Mari Mino-Kenudson, Scott Swanson, Cameron D Wright, David Kozono, Paul Marcoux, Zofia Piotrowska, Lecia V Sequist, Henning Willers
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Management of Non-Metastatic Non-Small Cell Lung Cancer (NSCLC) with Driver Gene Alterations: An Evolving Scenario
Valeria Fuorivia, Ilaria Attili, Carla Corvaja, Riccardo Asnaghi, Ambra Carnevale Schianca, Pamela Trillo Aliaga, Ester Del Signore, Gianluca Spitaleri, Antonio Passaro, Filippo de Marinis
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Comparison of treatment regimens for unresectable stage III epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer
Xin Dai, Qian Xu, Lei Sheng, Xue Zhang, Miao Huang, Song Li, Kai Huang, Jiahui Chu, Jian Wang, Jisheng Li, Yanguo Liu, Jianyuan Zhou, Shulun Nie, Lian Liu
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Tyrosine Kinase Inhibitor Therapy in Unresectable Locally Advanced NSCLC: Keep Holding Our Breaths or Time to Take a Breather?
Aruz Mesci, Theodoros Tsakiridis, Anand Swaminath
Journal of Thoracic Oncology.2021; 16(10): 1607. CrossRef
Experiences of patients with lung cancer receiving concurrent chemo-radiotherapy
Choi Eunsook, Park Sunhee
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Recent advances and new insights in the management of early-stage epidermal growth factor receptor-mutated non-small-cell lung cancer
Miguel J Sotelo, José Luis García, Cesar Torres-Mattos, Héctor Milián, Carlos Carracedo, María Ángeles González-Ruiz, Xabier Mielgo-Rubio, Juan Carlos Trujillo-Reyes, Felipe Couñago
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PLGA nanoparticle-reinforced supramolecular peptide hydrogels for local delivery of multiple drugs with enhanced synergism
Can Wu, Chunlu Wang, Lu Sun, Keming Xu, Wenying Zhong
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Ruifeng Liu, Shihong Wei, Qiuning Zhang, Xueliang Zhang, Hongtao Luo, Jinhui Tian, Yi Li, Long Ge, Xiaohu Wang
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Sanjal Desai, Chul Kim, Irina Veytsman
Current Oncology Reports.2019;[Epub] CrossRef

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Antitumor Activity of HM781-36B, alone or in Combination with Chemotherapeutic Agents, in Colorectal Cancer Cells: Mi Hyun Kang, Sung Ung Moon, Ji Hea Sung, Jin Won Kim, Keun Wook Lee, Hye Seung Lee, Jong Seok Lee, Jee Hyun Kim; Cancer Res Treat. 2016;48(1):355-364. Published online March 5, 2015; DOI: https://doi.org/10.4143/crt.2014.260

Abstract PDF PubReader ePub

Purpose
HM781-36B is a novel and irreversible pan-human epidermal growth factor receptor (HER) inhibitor with TEC cytoplasmic kinase inhibition. The aim of this study is to evaluate the antitumor activity and mechanism of action for HM781-36B in CRC cell lines.
Materials and Methods
The CRC cell lines were exposed to HM781-36B and/or oxaliplatin (L-OHP), 5-fluorouracil (5-FU), SN-38. The cell viability was examined by Cell Titer-Glo luminescent cell viability assay kit. Change in the cell cycle and protein expression was determined by flow cytometry and immunoblot analysis, respectively. Synergism between 2 drugs was evaluated by the combination index.
Results
The addition of HM781-36B induced potent growth inhibition in both DiFi cells with EGFR overexpression and SNU-175 cells (IC50 = 0.003 and 0.005 M, respectively). Furthermore, HM781-36B induced G1 arrest of the cell cycle and apoptosis, and reduced the levels of HER family and downstream signaling molecules, pERK and pAKT, as well as nonreceptor/cytoplasmic tyrosine kinase, BMX. The combination of HM781-36B with 5-FU, L-OHP, or SN-38 showed an additive or synergistic effect in most CRC cells.
Conclusion
These findings suggest the potential roles of HM781-36B as the treatment for EGFR-overexpressing colon cancer, singly or in combination with chemotherapeutic agents. The role of BMX expression as a marker of response to HM781-36B should be further explored.

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Synthesis, cytotoxic evaluation, and in silico studies of novel benzenesulfonamide-thiazolidinone derivatives against colorectal carcinoma
Belma Zengin Kurt, Mustafa Gökçe, Halil Şenol, Dilek Öztürk Civelek, Gülnur Dandin, Isil Gazioglu
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Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations
Meng Hu, Congying Zhong, Jiabing Wang, JinQin Chen, Tao Zhou
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Piperazine-derived ionizable lipids for enhanced mRNA delivery and cancer immunotherapy
Kai Xu, Yujia Xu, Jin Sun, Xinwei Cheng, Chenxi Lu, Wenzhong Chen, Bingfang He, Tianyue Jiang
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A small-molecule pan-HER inhibitor alone or in combination with cisplatin exerts efficacy against nasopharyngeal carcinoma
Jing Yang, Yanfei Yang, Yuquan Wei, Xiawei Wei
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Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4)
Robin Cornelissen, Arsela Prelaj, Sophie Sun, Christina Baik, Mirjana Wollner, Eric B. Haura, Hirva Mamdani, Jonathan W. Riess, Federico Cappuzzo, Marina C. Garassino, John V. Heymach, Mark A. Socinski, Szu-Yun Leu, Gajanan Bhat, Francois Lebel, Xiuning L
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Poziotinib in Non–Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial
Xiuning Le, Robin Cornelissen, Marina Garassino, Jeffrey M. Clarke, Nishan Tchekmedyian, Jonathan W. Goldman, Szu-Yun Leu, Gajanan Bhat, Francois Lebel, John V. Heymach, Mark A. Socinski
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Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells
Yongchao Zhang, Zhuo-Xun Wu, Yuqi Yang, Jing-Quan Wang, Jun Li, Zoey Sun, Qiu-Xu Teng, Charles R. Ashby, Dong-Hua Yang
Cancers.2020; 12(11): 3249. CrossRef
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Hsueh-Chuan Liu, Yi-Shian Peng, Hoong-Chien Lee
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Niclosamide enhances the cytotoxic effect of cisplatin in cisplatin-resistant human lung cancer cells via suppression of lung resistance-related protein and c-myc
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FXR1 is elevated in colorectal cancer and acts as an oncogene
Xin Jin, Bo Zhai, Taishi Fang, Xiaohui Guo, Lishan Xu
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How Molecular Understanding Affects to Prescribing Patterns and Clinical Outcome of Gefitinib in Non-small Cell Lung Cancer? 10 Year Experience of Single Institution: Bhumsuk Keam, Dong-Wan Kim, Jin Hyun Park, Jeong-Ok Lee, Tae Min Kim, Se-Hoon Lee, Doo Hyun Chung, Dae Seog Heo; Cancer Res Treat. 2013;45(3):178-185. Published online September 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.3.178

Abstract PDF PubReader ePub

PURPOSE
Gefitinib was introduced in 2002 for treatment of non-small cell lung cancer (NSCLC); however, it is not clear whether its use in daily practice has changed the outcome of patients. The purpose of this study is to evaluate the question of how molecular understanding regarding gefitinib and epidermal growth factor receptor (EGFR) mutation affect the prescribing patterns and clinical outcomes of treatment with gefitinib in NSCLC, in a real practical field.
MATERIALS AND METHODS
We conducted a retrospective analysis of the consecutive database of NSCLC patients who were treated with gefitinib at Seoul National University Hospital between January 2002 and December 2011. Prescribing patterns and clinical outcomes were analyzed by year.
RESULTS
A total of 1,115 NSCLC patients, who received gefitinib at recurred or metastatic setting, were included in this study. Proportion of patients receiving gefitinib, for the first line, showed a gradual increase, from 5.2% in 2002-2003 to 30.6% in 2010-2011. Proportion of patients who underwent EGFR mutation testing showed a rapid increase, from 0.6% in 2004-2005 to 73.5% in 2010-2011. The response rate also showed a gradual increase, from 17.2% in 2002-2003 to 57.1% in 2010-2011 (p<0.001). The median progression-free survival of gefitinib was increased with statistical significance from 2.8 months in 2002-2003 to 9.1 months in 2010-2011 (p<0.001).
CONCLUSION
We demonstrated that molecular understanding and practical use of EGFR mutation testing have resulted in a change in the prescription patterns of gefitinib. Use of an enrichment strategy can lead to improvement in the efficacy of gefitinib in real practice.

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Utilisation and Determinants of Epidermal Growth Factor Receptor Mutation Testing in Patients with Non-small Cell Lung Cancer in Routine Clinical Practice: A Global Systematic Review
Aye Myat Thi, Sandar Tin Tin, Mark McKeage, J. Mark Elwood
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The Risk of Herpes Zoster in Patients with Non-small Cell Lung Cancer according to Chemotherapy Regimens: Tyrosine Kinase Inhibitors versus Cytotoxic Chemotherapy
Ji Young Choi, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo, Seong Jin Jo
Cancer Research and Treatment.2019; 51(1): 169. CrossRef
EGFR Mutation Testing of non-squamous NSCLC: Impact and Uptake during Implementation of Testing Guidelines in a Population-Based Registry Cohort from Northern New Zealand
Mark McKeage, Mark Elwood, Sandar Tin Tin, Prashannata Khwaounjoo, Phyu Aye, Angie Li, Karen Sheath, Phillip Shepherd, George Laking, Nicola Kingston, Christopher Lewis, Donald Love
Targeted Oncology.2017; 12(5): 663. CrossRef
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Baohui Han, Sergei Tjulandin, Koichi Hagiwara, Nicola Normanno, Laksmi Wulandari, Konstantin Laktionov, Achmad Hudoyo, Yong He, Yi-Ping Zhang, Meng-Zhao Wang, Chien Ying Liu, Marianne Ratcliffe, Rose McCormack, Martin Reck
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The prognostic value of CT radiomic features for patients with pulmonary adenocarcinoma treated with EGFR tyrosine kinase inhibitors
Hyungjin Kim, Chang Min Park, Bhumsuk Keam, Sang Joon Park, Miso Kim, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo, Jin Mo Goo, Fan Yang
PLOS ONE.2017; 12(11): e0187500. CrossRef
Gefitinib-Induced Interstitial Lung Disease in Korean Lung Cancer Patients
Seung-Hoon Beom, Dong-Wan Kim, Sung Hoon Sim, Bhumsuk Keam, Jin Hyun Park, Jeong-Ok Lee, Tae Min Kim, Se-Hoon Lee, Dae Seog Heo
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Total Lesion Glycolysis in Positron Emission Tomography Can Predict Gefitinib Outcomes in Non–Small-Cell Lung Cancer with Activating EGFR Mutation
Bhumsuk Keam, Soo Jin Lee, Tae Min Kim, Jin Chul Paeng, Se-Hoon Lee, Dong-Wan Kim, Yoon Kyung Jeon, Doo Hyun Chung, Keon Wook Kang, June-Key Chung, Dae Seog Heo
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The gefitinib dose reduction on survival outcomes in epidermal growth factor receptor mutant non-small cell lung cancer
Sung Hoon Sim, Bhumsuk Keam, Dong-Wan Kim, Tae Min Kim, Se-Hoon Lee, Doo Hyun Chung, Dae Seog Heo
Journal of Cancer Research and Clinical Oncology.2014; 140(12): 2135. CrossRef

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Review Article

Treatment of Non-small Cell Lung Carcinoma after Failure of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor: Jae Cheol Lee, Seung Hun Jang, Kye Young Lee, Young-Chul Kim; Cancer Res Treat. 2013;45(2):79-85. Published online June 30, 2013; DOI: https://doi.org/10.4143/crt.2013.45.2.79

Abstract PDF PubReader ePub

Since the first description of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, studies have proved EGFR tyrosine kinase inhibitors (TKIs) as a first choice of treatment. The median response duration of TKIs as a first-line treatment for EGFR mutant tumors ranges from 11 to 14 months. However, acquired resistance to EGFR-TKIs is inevitable due to various mechanisms, such as T790M, c-Met amplification, activation of alternative pathways (IGF-1, HGF, PI3CA, AXL), transformation to mesenchymal cell or small cell features, and tumor heterogeneity. Until development of a successful treatment strategy to overcome such acquired resistance, few options are currently available. Here we provide a summary of the therapeutic options after failure of first line EGFR-TKI treatment for NSCLC.

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Original Articles

Impact of KRAS Mutation Status on Outcomes in Metastatic Colon Cancer Patients without Anti-Epidermal Growth Factor Receptor Therapy: Seung Tae Kim, Kyong Hwa Park, Jun Suk Kim, Sang Won Shin, Yeul Hong Kim; Cancer Res Treat. 2013;45(1):55-62. Published online March 31, 2013; DOI: https://doi.org/10.4143/crt.2013.45.1.55

Abstract PDF PubReader ePub

PURPOSE
Activating mutation of the KRAS oncogene is an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, KRAS mutation as a prognostic factor of survival outcome remains controversial in CRC, independent of anti-EGFR therapies.
MATERIALS AND METHODS
We conducted a retrospective analysis of 103 CRC patients who were available for evaluation of KRAS mutation status. None of the patients analyzed had received anti-EGFR therapies. The role of KRAS mutation status was evaluated as a predictive factor for oxaliplatin or irinotecan and as a prognostic factor in CRC patients who did not receive anti-EGFR therapies.
RESULTS
Mutations in KRAS were observed in 48.5% of patients. The response for oxaliplatin- (p=0.664) and irinotecan-based (p=0.255) cytotoxic chemotherapy did not differ according to the KRAS mutation status. In addition, no significant difference in progression free survival (PFS; oxaliplatin, p=0.583 and irinotecan, p=0.426) and overall survival (OS; p=0.258) was observed between the wild and mutant type of the KRAS gene. In univariate and multivariate analyses, KRAS mutations did not have a major prognostic value regarding PFS (oxaliplatin: hazard ratio, 0.892; 95% confidence interval [CI], 0.590 to 1.347; p=0.586 and irinotecan: hazard ratio, 0.831; 95% CI, 0.524 to 1.319; p=0.433) or OS (hazard ratio, 0.754; 95% CI, 0.460 to 1.236; p=0.263). In addition, anti-vascular endothelial growth factor therapies did not affect PFS to oxaliplatin or irinotecan and OS.
CONCLUSION
KRAS mutation is not a prognostic marker for PFS to oxaliplatin or irinotecan and OS in CRC patients who did not receive anti-EGFR therapies.

Citations

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Prognostic Significance of Immunohistochemical Expression of EGFR and C-erbB-2 Oncoprotein in Curatively Resected Gastric Cancer: Hong Suk Song, Young Rok Do, In Ho Kim, Soo Sang Sohn, Kun Young Kwon; Cancer Res Treat. 2004;36(4):240-245. Published online August 31, 2004; DOI: https://doi.org/10.4143/crt.2004.36.4.240

Abstract PDF PubReader ePub

Purpose

The purpose of this study was to investigate the prognostic significance of the expression of EGFR and C-erbB-2 gene products by immunohistochemical analysis for curatively resected gastric adenocarcinoma.

Materials and Methods

Between January 1996 and December 2001, 739 patients with curatively resected gastric cancer patients underwent immunohistochemical staining for EGFR and C-erbB-2 proteins, and we retrospectively analyzed their correlation with the clinical outcome.

Results

The overexpressions of EGFR and C-erbB-2 were 25.4% and 26.2%, respectively. The overexpressions of EGFR was associated with the more poorly differentiated tumor (p=0.000) and with neuronal invasion (p=0.03). Overexpression of C-erbB-2 was associated with less vascular invasion (p=0.001). Tumor depth or node metastasis was not related to the overexpression of EGFR or C-erbB-2. The seven-year overall survival and relapse-free survival rates were 87.2% and 75.8%, respectively. Upon multivariate Cox regression analysis, the tumor stage, tumor size and patient age were important prognostic factors for overall survival, and tumor stage was the important factor for relapse-free survival. Overexpressions of EGFR or c-erbB-2 were not significant prognostic factors.

Conclusion

Immunohistochemical staining of EGFR and C-erbB-2 gene products were not independent prognostic factors for predicting the overall survival and the relapse-free survival in curatively resected gastric cancer.

Citations

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An independent survival prognostic role for human epidermal growth factor receptor 2 in gastric cancer: evidence from a meta-analysis
Y. Wang, L. He, Y. Cheng
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IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules
Nikolaos A. Afratis, Panagiotis Bouris, Spyros S. Skandalis, Hinke A. Multhaupt, John R. Couchman, Achilleas D. Theocharis, Nikos K. Karamanos
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The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas
Aleksandra Paliga, Horia Marginean, Basile Tessier-Cloutier, Bibianna Purgina, Derek Jonker, Esmeralda C. Marginean
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Roberto de Moraes Cordts Filho, Paulo Kassab, Laura Carolina Lopez Claro, Mabel Tatty de Medeiros Fracassi, Patrícia Colombo-Souza, Daniel Kenji Fukuhara, Fábio Rodrigues Thuler, Wilson Rodrigues de Freitas Junior, Elias Jirjoss Ilias, Carlos Alberto Malh
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K. AYDIN, S.K. OKUTUR, M. BOZKURT, I. TURKMEN, E. NAMAL, K. PILANCI, A. OZTURK, Z. AKCALI, G. DOGUSOY, O.G. DEMIR
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Akin Atmaca, Dominique Werner, Claudia Pauligk, Kristina Steinmetz, Ralph Wirtz, Hans-Michael Altmannsberger, Elke Jäger, Salah-Eddin Al-Batran
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Expression of EGF Receptor Family Genes and Proteins in Gastric Cacner ( EGFR , c-erbB-2 , c-erbB-3 , c-erbB-4 ): Hae Wan Lee, Eun Young Choi, Chang Dae Bae, Han Kwang Yang, Woo Ho Kim, Jin Pok Kim; J Korean Cancer Assoc. 1998;30(5):853-868.

Abstract PDF: PURPOSE
to evaluate the relationship between the expression of EGF receptor gene family and clinico-pathologic parameters.
MATERIALS AND METHODS
We compared adenocarcinoma tissue with normal mucosa obtained from same patients in 60 cases. The amplifications of DNA was examined by slot blot, while the expression of mRNA by ribonuclease protection assay, and that of protein by immunohistochemistry.
RESULTS
Expression of EGFR mRNA was observed in 9 of 59, that of c-erbB-2 mRNA in 8 of 57, that of c-erbB-3 mRNA in 4 of 60, and that of c-erbB-4 mRNA in 13 of 59. The expression of EGFR in expanding type showed a higher tendency than that in infiltrative type. The expression of c-erbB-2 in poorly differentiated adenocarcinoma showed a higher tendency than that in well differentiated adenocarcinoma. And expression of c-erbB-2 was correlated with presence of endolymphatic tumor emboli. No significant correlation was observed between expression of EGFR mRNA and that of its protein or amplification of its DNA. Similarly, No clear relationship between c-erbB-2 gene amplification and expression of mRNA or proteins was detected.
CONCLUSION
EGFR, c-erbB-2, c-erbB-3, and c-erbB-4 were expressed in gastric adenocarcinoma in Korea. The presence of EGF receptor gene family by various tumor cells suggested that it may play an important role in adenocarcinoma. Therefore further studies are currently being carried out to clarify the role of these oncogenes in tumor behavior and gastric carcinogenesis.

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The Prognostic Value of Epidermal Growth Factor Receptor in Primary Breast Cancer: Bong Geun Park, Sung Jae Cha, Sung Joon Park; J Korean Cancer Assoc. 1998;30(4):711-718.

Abstract PDF: PURPOSE
The objective of this study was to ascertain the relationship between epidermal growth factor receptor(EGFR) status and estrogen receptor(ER) and other prognostic factors in primary human breast cancer patients. We tried to evaluate the value of EGFR as a prognostic factor.
MATERIALS AND METHODS
EGFR and ER were measured by immunohistochemical staining. It was performed on section from paraffin blocks of 60 primary breast cancer patients who underwent mastectomy at Chung-Ang University Hospital. And we evaluate the relationship between EGFR and ER and other prognostic factors.
RESULTS
In 20 of 60 patients(33.3%), the staining was positive for the expression of EGFR. Of the 60 patients, 6 were both positive for EGFR and ER, 25 were both negative, 14 were EGFR positive and ER negative, 15 were EGFR negative and ER positive. Between EGFR and estrogen receptor(ER) status, previously known clear inverse relationship was not observed in our study. The EGFR status was not correlated with axillary lymph node involvement, histologic type, and histologic grading. But it was correlated with tumor size(p=0.049), and there was a high tendency of recurrence rate of patients with EGFR-positive tumors as compared with those with EGFR-negative tumors(p=0.078).
CONCLUSION
EGFR status may be valuable as a prognostic factor in determining the prognosis of breast cancer. However, the study of more cases will be needed for the significance of the information about the EGFR as an independent prognostic factor.

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Value of Phospholipase C gamma-1, Epidermal Growth Factor Receptor, and Her-2/neu in Human Breast Cancer: Ki Hoon Jung, Sung Han Bae, Eun Sook Lee, Jeoung Won Bae, Bum Whan Koo, In Sun Kim, Cheung Wung Whang; J Korean Cancer Assoc. 1997;29(5):724-737.

Abstract PDF: PURPOSE
Oncogen or growth factor receptor such as phospholipase C isoenzyme gamma-1 (PLC gamma-1), epidermal growth factor receptor (EGFR), and Her-2/neu which related with tyrosin kinasemay and then regulating vell proliferation may have a role as prognostic factors for breast cancer. MATERIAL AND METHODS: With assumption that expression of PLC gamma-1, EGFR and Her-2/neu oncogene has close relationship with prognosis of breast cancer, 59 breast cancer patients who were operated upon at Korea University Hospital during a period of 6 years starting June 1988 to May 1994 were selected for this study. This study was carried out by comparing between expression of PLC gamma-1, EGFR and Her-2/neu oncogene and patient's survival rate. These expression were also compared with TNM system, estrogen and progesterone receptor and at same time these expressions were compared with each other to see whether there are any relationship among these expression.
RESULTS
Expression of PLC gamma-1, EGFR and Her-2/neu were present in 42% (25/59), 46% (27/59) and 20% (12/59). The expression of PLC gamma-1 was closely related with the expression of EGFR (p<0.05) and Her-2/neu (p<0.05), but there were no relationship between the expression of PLC gamma-1 and hormonal receptors and TNM stage (p>0.05). The expression of EGFR was closely related with the expression of Her-2/neu (p<0.05) and hormone receptors (p<0.05), but there were no relationship between the expression of EGFR and pathologic TNM stage (p>0.05). The expression of Her-2/neu was not closely related with hormone receptors and TNM stage except axillary lymph node metastasis. There were close relationship between overall and disease free survival and PLC gamma-1 and Her-2/neu. But EGFR had only related with disease free survival rate.
CONCLUSION
In conclusion, the expression of PLC gamma-1, EGFR and Her-2/neu oncogene in human breast cancer may be useful prognostic factors independently and it may potentiated its individual value as a prognostic factors if use them together.

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Expression of Epidermal Growth Fasctor Receptor in Breast Cancer Detected by Immunothistochemical Stain in Breast Cancer: Yong Sung Won, Nam Il Kim, Jung Soo Kim, Hae Myung Jeon, Eung Kook Kim, Jae Kwang Kim; J Korean Cancer Assoc. 1994;26(4):567-576.

Abstract PDF: Recently, several growth factors, growth factor receptors and oncogenes have been investigated to find out their relations and potential roles in the development and progression of human cancers. Among them, epidermal growth factor receptors (EGFR) have been found in normal and malignant human breast tissues. The purpose of this study was to find out the relation between the expression of EGFR and clinical stage, tumor size, estrogen and progesterone receptor status. We used an improved immunohistochemical staining method for identification of EGFR in formalin-fixed paraffin-embedded section of 45 human breast cancer tissues, 10 normal breast tissues around the cancer masses, l2 metastatic lymph nodes, and 10 breast benign tumor tis- sues using monoclonal antibodies against EGFR. The results were as follows: 1) Immunoreactivity of EGFR was in 57.8% (28/45) of breast cancer tissues, in 10.0% (1/10) of noncancerous breast tissues, in 16.7% (2/12) of metastatic lymph nodes, and in 20.0% (2/10) of benign tmor tissues. 2) The immunoreactivity of EGFR was related to clinical stage; positivity of stage I was 60.0 % (3/5), stage II was 6L1% (l8/29), and stage III was 45.5% (5/1 1 ), respectively. 3) The positivity of EGFR was related to tumor size; positivity of tumor size 0-2 cm was 60.0 / (3/5), tumor size 2-5 cm 61.3% (19/31), tumor size > 5 cm was 44.4% (4/9), respectively. 4) The intensity of EGFR immunoreactivity was increased in stage I and II. 5) Expression of EGFR had an inverse relation between both estrogen and progesterone re- ceptor expressions. with above results, authors considered the expression of EGFR may play an important role in early stage of human breast cancer development, growth and proliferation. And according to the relationship between estrogen receptor and progesterone receptor status, EGFR may offer an additional factor in prognosis of breast cancer.

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The Expression of c-erbB-2 Oncoprotein and Epidermal Growth Factor Receptor ( EGFR ) in Breast Cancer Patients in Korea: Won Park, Nam Sun Paik, Yong Kyu Kim, Nan Mo Moon, Jong Inn Lee, Dong Wook Choi, Dae Yong Hwang, Ja June Jang; J Korean Cancer Assoc. 1994;26(6):901-912.

Abstract PDF: Samples of breast carcinoma were collected from 1l7 patients who underwent mastectomy in Korea Cancer Center Hospital from Jan. 1982 to Dec. 1984. We studied expression of the c-erbB- 2 oncoprotein and EGFR with the immunohistochemical technique. We also analyzed to clarify the relationship between expression of the c-erbB-2 oncoprotein and/or EGFR and tumor size, node metastasis, stage, histo1ogic grade, TIL, and EIC, and to evaluate the prognostic significance of c-erbB-2 oncoprotein and EGFR in breast cancer. EGFR expression rate was 37.6%(44/ ll7) and EGFR status had positive correlation with histologic grade(p<0.05), But, we did not find any other relationship with other clinicopathological prognostic factors. c-erbB-2 expression rate was 64.1%(71/1 l7). There was no relevance between c-erdB-2 expression and other prognostic factors. Higher histologic grade was poorer survival rate. EGFR positive patients had poorer prognosis than negative patients in stage I and II breast cancer(p<0.05).

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Immunohisochemical study on the Role of TGF-α / EGFR Autocrine Loop in the Cellular Proliferation and Progression of Gastric Adenocarcinoma: Seong Heum Park, Sung Ock Suh, Young Jae Mok; J Korean Cancer Assoc. 1995;27(5):746-761.

Abstract PDF: Immunoreacivities for transforming growth factor-alpha(TGF-a) and epidermal grouwth factor receptor(RGFR) were assessed retrospectively in 81 cases of gastric adenocarcinomas to clarify the role of the autocrine mechanism in the cellular proliferation and progression of gas- tric cancer and to evaluate their value as the prognosticators of patients with gastric cancers. In addition to TGF-a and EGFR, also assessed in this study were such clinicopathologic features as differentiation, tumor size, gross apperance, serosal invasion, nodal status, distant metastasis and AJC(American loint Committee on Cancer) stage. Proliferative potential of the tumor was measured by calculating proliferating cell nuclear antigen labeling index(PCNA L. I.), the mean of which was 42.l +-l9.4(range, 6 to 85). The results were: 1) TGF-a and EGFR were overexpressed in 37(45.7%) and 35(43.2%) cases, respectively. 2) Concurrent overexpression of TGF-a and EGFR was found in 16(19.8%) cases. 3) There was no significant relationship between TGF-a, EGFR immunoreactivities and clinicopathologic feature. 4) Tumors belonging to high PCNA L.I. group(greater than or equal to 42.1) were significantly more for cases with synchronous overexpression of TGF-a and EGFR than cases with either TGF-a or EGFR overexpression and with normal expression of both.(p<0.05) 5) Neither TGF-a nor EGFR immunoreactivity was associated with 5 year survival rate. The above results show that the gastric cancer cells gain some advantage in proliferation via an autocrine loop between the TGF-a and EGFR. But, the potential role of autocrine mechanism in the progression of gastric cancer was not demonstrated in this study. TGFG-and EGFR were inadequate as prognosticators of patients with gastric cancers. Prospective randomized study is required to confirm these results.

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Expression of Proliferating Cell Nuclear Antigen and Epidermal Growth Factor Receptor in Colorectal carcinomas : Relation of Clinical and Patho: Young Chae Chu, Joon Mee Kim, Young Sik Kim, Young Bae Kim, Tae Sook Hwang; J Korean Cancer Assoc. 1996;28(3):432-443.

Abstract PDF: To evaluate the prognostic significance of PCNA and EGFR in colorectal carcinoma, the author analysed 66 colorectal carcinomas in paraffin sections immunohistochemically, using the monoclonal antibody PCNA and EGFR and compared with clinicopathological data. The mean PCNA index of colorectal carcinomas was 49.0¡¾10.8%. PCNA index had positive correlation with lymph node metastasis(p<0.001), distant metastasis(p<0.001), modified Dukes' stage(p<0.001), Jass new prognostic classification grouping(p<0.00l), TNM classification(p<0.001) and tumor size over 10.0cm(p<0.05), degree of histologic differentiation(p< 0.01), fibrosis(p<0.05), perineural invasion(p<0.05), lymphatic and vascular invasion(p<0.05). PCNA expression was more pronounced at the infiltrative margins of the tumor and tumor cells within the lymphatic or vascular channels. But there was no relationship between PCNA index and patients age, sex and tumor location, growth pattern, degree of peritumoral lymphocytic infiltration. The positivity of EGFR in colorectal carcinomas was 93.9% and there was an association between staining intensity and the extent of EGFR expression(rs=0.684, p<0.001) and PCNA index(rs=0.451 & 0.432, p<0.001). There was an association between staining intensity and the extent of EGFR expression and modified Duke's stage(p<0.001), Jass grouping(p<0.001), TNM classification(p<0.001), lymph node metastasis(p<0.001), fibrosis(<0.05), lymphocytic infiltration(p<0.05), lymphatics and vascular invasion(p< 0.01). These results suggest PCNA index and EGFR expression may be a useful prognostic factors in colorectal carcinomas. Knowledge af the percentage of PCNA-positive cells could be especially helpful in deciding to treat patients with adjuvant chemotherapy.

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Expression of Epidermal Growht Factor Receptor mRNA by In Situ Hybridization in Breast Cancer: Won Jong Lee, Soo Jung Lee, Dong Sug Kim, Koing Bo Kwun, Min Chul Chim; J Korean Cancer Assoc. 1996;28(6):996-1010.

Abstract PDF: Epidermal growth factor(EGF) and epidermal growth factor receptor(EGFR) have been identified as one of the prognostic factor for breast cancer. EGFR status has been determined by several methods including competitive binding assay(BA), immunohistochemical stain(IHC), enzyme immunoassay(EIA). But EGFR could be masked by endogenous ligands in some proportion of tumors. So many different methods have been developed to detect EGFR mRNA. Among these methods, in situ hybridization with biotinylated probe found to be simple and rapid. In addition, it can determine intratumoral heterogenicity in gene expression and identify specific cells that contain a particular mRNA transcript. The author investigated the expression of EGFR mRNA in 81 human breast cancers by in situ hybridization(ISH) and compared the result with EGFR detected by IHC. The author also examined the relationship between EGFR mRNA expression and clinical parameters and other prognostic markers(estrogen receptor, progesterone receptor, p53, c-erbB-2). The author also studied the relationship between EGFR mRNA and recurrence and mortality rate. According to the degree of cytoplasmic staining in ISH assay, negative were 13 cases(16.1%), + were 41 cases(50.6%), ++ were 26 cases(32.1%) and +++ was 1 case(1.2%). The overall expression of EGFR mRNA was 84%. The positive staining of EGFR by IHC was observed either on the cell membrane alone or on both cell membrane and cytoplasm. EGFR by IHC were detected in 69.l%. The 19 cases(23.5%) of EGFR negative cases by IHC were demonstrated as + or more EGFR mRNA by ISH study. On the contrary, 7 cases(8.6%) of EGFR positive by IHC were not detected by ISH. The findings in the majority of the cases were same in two methods. EGFR mRNA had shown a significant positive correlation with c-erbB-2(p<0.009). But an inverse correlation with both estrogen receptor(p<0.027) and progesterone receptor(p<0.02) status, when ++ or more were regarded as positive staining in ISH. There were no correlation was found between positive EGFR by IHC and clinical parameters and other prognostic markers except c-erbB-2(p<0.05). Among the 11 cases of tumor containing both invasive ductal carcinoma and ductal carcinoma in situ(DCIS), there were 5 cases of + and 4 cases of ++ in invasive ductal carcinoma, but negative in these cases of DCIS by ISH. Although the cases with overexpression of EGFR mRNA showed a tendency of more recurrent rate and mortality rate, but there were no statistic significance during the short follow up period (24 months). In summery, EGFR mRNA thought to be a useful prognostic factor especially when over expression is more than ++ by ISH. In situ mRNA hybridization technique is more sensitive and more accurate than immunohistochemistry.

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