Cancer Research and Treatment

Original Articles

Postoperative Radiotherapy May Improve Survival in Certain Patients with pN2 Non-Small Cell Lung Cancer Who Do Not Have Extranodal Extension: Seung Hyuck Jeon, Changhoon Song, Jae Hyun Jeon, Jin-Haeng Chung, Sukki Cho, Kwhanmien Kim, Sanghoon Jheon, Se Hyun Kim, Yu Jung Kim, Jae-Sung Kim; Received June 20, 2025 Accepted February 1, 2026 Published online February 3, 2026; DOI: https://doi.org/10.4143/crt.2025.644 [Epub ahead of print]

Abstract PDF: Purpose
The aim of this study was to identify subgroups of patients with pathologic N2 (pN2) non-small cell lung cancer (NSCLC) who may benefit from postoperative radiotherapy (PORT). Particular attention was given to evaluating whether extranodal extension (ENE) influences the therapeutic efficacy of PORT.
Materials and Methods
A total of 231 patients with pN2 NSCLC who underwent surgical resection followed by adjuvant chemotherapy at a single institution were analyzed retrospectively. Propensity score matching was performed to compare treatment outcomes according to the receipt of PORT.
Results
Propensity score matching yielded 99 matched pairs of patients with no significant differences in clinical parameters. There were no significant differences in the overall survival (OS; p=0.112) and disease-free survival (DFS; p=0.286) between the PORT and no PORT groups. However, PORT significantly improved the locoregional recurrence (LRR)–free rate (p=0.011), whereas the distant metastasis–free rate was comparable between groups (p=0.646). In subgroup analyses, PORT was associated with improved OS in patients with 1-3 positive N2 lymph nodes (p=0.013) and with significantly improved DFS among patients without ENE (p=0.046) or lymphatic invasion (p=0.032).
Conclusion
Although PORT did not improve OS or DFS in the matched overall cohort, it significantly reduced LRR. Subgroup analyses suggested potential benefits in patients with limited nodal burden and in those without ENE or lymphatic invasion. These findings, however, should be interpreted cautiously given small subgroup sizes and inherent limitations of retrospective design.

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Biomarker Testing Practices for Non–Small Cell Lung Cancer: Survey Insights from South Korean Pathology Laboratories: Sehui Kim, Dajeong Kim, Lucia Kim, Wan-Seop Kim; Received September 29, 2025 Accepted January 28, 2026 Published online January 30, 2026; DOI: https://doi.org/10.4143/crt.2025.927 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Molecular biomarker testing is essential for lung cancer management and precision medicine. This study evaluated biomarker testing practices for non–small cell lung cancer (NSCLC) across pathology laboratories in South Korea.
Materials and Methods
A nationwide survey of 30 pathology laboratories assessed testing policies, biomarker adoption, testing platforms, next-generation sequencing (NGS) implementation, reporting practices, turnaround times (TATs), and perceived challenges.
Results
All institutions routinely performed biomarker testing; 20 (66.7%) employed reflex testing at least in part. Tissue was the primary specimen type, and cytology and liquid biopsy specimens were accepted by 90.0% and 46.7% of institutions, respectively. For non-squamous NSCLC, all institutions tested epidermal growth factor receptor, anaplastic lymphoma kinase, ROS1, and programmed cell death ligand 1 (PD-L1), with additional testing for BRAF (86.7%) and KRAS (80.0%); other actionable targets were rarely tested outside NGS. In squamous NSCLC, PD-L1 was routinely assessed, whereas other drivers were tested less frequently. All institutions performed tissue-based NGS using companion diagnostic (CDx) and/or non-CDx platforms, and liquid biopsy–based NGS was available in 46.7% of institutions. Median TATs were 2-3, 5, 9, 19, and 15 days for immunohistochemistry, polymerase chain reaction, fluorescence in situ hybridization, tissue-based NGS, and liquid biopsy–based NGS, respectively. Reported barriers included limited sample availability, workforce shortages, prolonged TATs, regulatory restrictions, and lack of standardization.
Conclusion
Biomarker testing is widely implemented in South Korea, with increasing integration of NGS. Despite alignment with international recommendations, systemic and policy reforms are needed to harmonize workflows, reduce variability, and optimize precision oncology.

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Preferential Sensitivity of the EGFR L858M/L861R Mutation to Second-Generation EGFR Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer: Chaelin Lee, Sheehyun Kim, Soyeon Kim, Taekeun Park, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Jeonghwan Youk; Received March 11, 2025 Accepted August 19, 2025 Published online August 20, 2025; DOI: https://doi.org/10.4143/crt.2025.279 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub

Purpose
Non–small cell lung cancer (NSCLC) frequently harbors targetable epidermal growth factor receptor (EGFR) mutations. However, rare variants such as EGFR L858M or L861R remain poorly characterized. This study aimed to elucidate the oncogenic potential and EGFR tyrosine kinase inhibitors (TKIs) sensitivity of the EGFR L858M/L861R mutation to inform personalized treatment strategies.
Materials and Methods
Tumor samples from an NSCLC patient were analyzed using targeted panel sequencing and confirmed with the FoundationOne Liquid CDx assay. EGFR-mutant constructs, including L858M, L858R, L861R, L861Q, L858M/L861R, and L858R/L861Q, were generated and transduced into various cell lines. Cell viability, immunoblot, and soft agar colony formation assays were conducted to assess the oncogenicity and drug sensitivity, while computational protein modeling and docking simulations evaluated the drug-binding affinities of EGFR-TKIs.
Results
Ba/F3 cells expressing the EGFR L858M/L861R mutation exhibited robust interleukin-3–independent proliferation accompanied by markedly increased EGFR phosphorylation, while NIH-3T3 cells showed anchorage-independent colony formation. Compared to other mutations, cells expressing EGFR L858M/L861R mutation were less sensitive to first-generation EGFR-TKIs (gefitinib, erlotinib) and third-generation EGFR-TKIs (osimertinib, lazertinib), whereas second-generation EGFR-TKIs (afatinib, poziotinib) demonstrated potent inhibitory effects. Computational modeling revealed a narrower drug-binding efficiency of first-generation inhibitors.
Conclusion
The EGFR L858M/L861R mutation drives strong oncogenic signaling and exhibits preferential sensitivity to second-generation EGFR-TKIs. These findings underscore the importance of accurate molecular diagnosis for guiding effective, personalized therapeutic strategies in NSCLC.

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Real-World Outcomes and Subsequent Treatment Patterns in Patients with Advanced Non-Small Cell Lung Cancer and Atypical EGFR Mutations Receiving First-Line Osimertinib Monotherapy
Jorge J. Nieva, Xuejun Wang, Deborah Doroshow, Leslie Servidio, Miranda Cooper, Yan Kwan Lau, Pritesh S. Karia, Jacqulyne Robichaux
Oncology and Therapy.2026; 14(1): 225. CrossRef
Leitlinienentwicklung zur MRD-Diagnostik der AML als Blaupause für solide Tumoren
Michael Heuser, Claudia Wickenhauser, Leonie Oevel, Marcus Bauer
Die Pathologie.2026; 47(4): 273. CrossRef

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Lung and Thoracic cancer

Tracing Metastatic Evolutionary Patterns in Lung Adenocarcinoma: Prognostic Dissection Based on a Multi-state Model: Geewon Lee, Yang-Jin Kim, Insuk Sohn, Jong Hoon Kim, Ho Yun Lee; Cancer Res Treat. 2025;57(4):1019-1029. Published online January 24, 2025; DOI: https://doi.org/10.4143/crt.2024.700

Abstract PDF Supplementary Material PubReader ePub

Purpose
After surgery for lung adenocarcinoma, a patient may experience various states of recurrence, with multiple factors potentially influencing the transitions between these states. Our purpose was to investigate the effects of clinical and pathological factors on tumor recurrence, death, and prognosis across various metastasizing pathways.
Materials and Methods
Our study group included 335 patients with all demographic and pathologic data available who underwent surgical resection for lung adenocarcinoma for more than 10 years. The following states of disease were defined: initial state, operation (OP); three intermediate states of local recurrence (LR), metastasis (Meta), and concurrent LR with metastasis (LR+Meta); and a terminal state, death. We identified eight transitions representing various pathways of tumor progression. We employed a multi-state model (MSM) to separate the impacts of multiple prognostic factors on the transitions following surgery.
Results
After surgery, approximately half of patients experienced recurrence. Specifically, 142 (42.4%), 54 (16.1%), and seven (2.1%) patients developed Meta, LR+Meta, and LR, respectively. Clinical and pathological factors associated with the transitions were different. Impact of pathological lymph node remained a risk factor for both OP to Meta (λ02, p=0.001) and OP to LR+Meta (λ03, p=0.001).
Conclusion
Lung adenocarcinoma displays a broad spectrum of clinical scenarios even after curative surgery. Incidence, risk factors, and prognosis varied across different pathways of recurrence in lung adenocarcinoma patients. The greatest implication of this MSM is its ability to predict the timing and type of clinical intervention that will have the greatest impact on survival.

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A‐to‐I RNA Edited miR‐3167 Restrains Malignant Behaviors of Lung Adenocarcinoma by Influencing SSR2‐Meditated Hippo Signaling
Dawei Qian, Dongsheng Zha, Yuanyao Sang, Jiangquan Tao, Bufeng Zhuang, Youshuang Cheng
Molecular Carcinogenesis.2025; 64(9): 1552. CrossRef

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Upfront Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy in Elderly Patients with Brain Metastases from Non–Small Cell Lung Cancer: A Retrospective Analysis of a 10-Year Bi-institutional Experience: Myungsoo Kim, Jihye Cha, Hun Jung Kim, Woo Chul Kim, Jeongshim Lee; Cancer Res Treat. 2025;57(1):47-56. Published online July 3, 2024; DOI: https://doi.org/10.4143/crt.2024.223

Abstract PDF PubReader ePub

Purpose
Stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) are increasingly used as initial therapies for brain metastases (BM). We aimed to assess the outcomes of SRS/FSRT in patients aged ≥ 65 years who had 1-10 BM from non–small cell lung cancer (NSCLC).
Materials and Methods
We retrospectively reviewed 91 elderly NSCLC patients with 222 BM who were treated with SRS/FSRT at two institutions between 2010 and 2020. The primary endpoint was overall survival (OS) after SRS/FSRT. In addition, in-field local control (IFLC) within the treated field was evaluated. Statistical analysis was performed to identify the prognostic factors affecting OS and IFLC.
Results
During a median follow-up of 18 months, the median OS was 32 months. The 1- and 2-year survival rates were 69.8% and 56.1%, respectively. In multivariate analysis, the NSCLC-specific graded prognostic assessment (GPA) score (p=0.007) and administration of systemic therapy (p=0.039) were defined as prognosticators affecting OS. The median IFLC period was 31 months, and the 1- and 2-year IFLC rates were 75.9% and 57.6%, respectively. The total BM volume (p=0.042) significantly affected IFLC. No severe adverse events were reported after SRS/FSRT.
Conclusion
SRS/FSRT is an effective upfront treatment option for BM arising from NSCLC in elderly patients, with a good OS without severe side effects. Higher GPA score and active systemic treatment were associated with improved OS, indicating that elderly patients are significant candidates for SRS/FSRT.

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Prognostic factors, patterns of failure and re-irradiation in hypofractionated stereotactic radiotherapy-treated brain metastases from non-small cell lung cancer
Dayu Xu, Yechun Pang, Jinghan Qu, Jiuang Mao, Tiantian Guo, Shanshan Jiang, Yue Zhou, Li Chu, Xi Yang, Xiao Chu, Shengping Wang, Tong Tong, Zhengfei Zhu, Jianjiao Ni
Clinical and Translational Radiation Oncology.2025; 55: 101038. CrossRef
Prognostic Analysis of Lung Cancer With Brain Metastases in Elderly Patients: A Multicenter Retrospective Study
Anqi Li, Daqin Feng, Chang Liu, Chaojue Huang, Tang Li, Donggui Wei, Fangyi Wei, Muling Shen, Congzhi Qin, Shufang Deng, Hui Liang, Panlin Mo, Minhai Dong, Yongjia Yu, Lun Liang
AGING MEDICINE.2025; 8(6): 585. CrossRef

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Revolutionizing Non–Small Cell Lung Cancer Diagnosis: Ultra-High-Sensitive ctDNA Analysis for Detecting Hotspot Mutations with Long-term Stored Plasma: Ji-Young Lee, Seyeon Jeon, Ha Ra Jun, Chang Ohk Sung, Se Jin Jang, Chang-Min Choi, Sung-Min Chun; Cancer Res Treat. 2024;56(2):484-501. Published online October 23, 2023; DOI: https://doi.org/10.4143/crt.2023.712

Abstract PDF Supplementary Material PubReader ePub

Purpose
Circulating cell-free DNA (cfDNA) has great potential in clinical oncology. The prognostic and predictive values of cfDNA in non–small cell lung cancer (NSCLC) have been reported, with epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in tumor-derived cfDNAs acting as biomarkers during the early stages of tumor progression and recurrence. However, extremely low tumor-derived DNA rates hinder cfDNA application. We developed an ultra-high-sensitivity lung version 1 (ULV1) panel targeting BRAF, KRAS, and EGFR hotspot mutations using small amounts of cfDNA, allowing for semi-quantitative analysis with excellent limit-of-detection (0.05%).
Materials and Methods
Mutation analysis was performed on cfDNAs extracted from the plasma of 104 patients with NSCLC by using the ULV1 panel and targeted next-generation sequencing (CT-ULTRA), followed by comparison analysis of mutation patterns previously screened using matched tumor tissue DNA.
Results
The ULV1 panel demonstrated robust selective amplification of mutant alleles, enabling the detection of mutations with a high degree of analytical sensitivity (limit-of-detection, 0.025%-0.1%) and specificity (87.9%-100%). Applying ULV1 to NSCLC cfDNA revealed 51.1% (23/45) samples with EGFR mutations, increasing with tumor stage: 8.33% (stage I) to 78.26% (stage IV). Semi-quantitative analysis proved effective for low-mutation-fraction clinical samples. Comparative analysis with PANAMutyper EGFR exhibited substantial concordance (κ=0.84).
Conclusion
Good detection sensitivity (~80%) was observed despite the limited volume (1 mL) and long-term storage (12-50 months) of plasma used and is expected to increase with high cfDNA inputs. Thus, the ULV1 panel is a fast and cost-effective method for early diagnosis, treatment selection, and clinical follow-up of patients with NSCLC.

Citations

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Interlesional Heterogeneity of EGFR Mutations: A Systematic Review and Meta-analysis
Diana Ivonne Rodríguez Sánchez, Selin Asli Öztürk, Olga Maxouri, Stevie van der Mierden, Winnie Schats, Sajjad Rostami, Stephan Ursprung, Petur Snaebjornsson, Zuhir Bodalal, Regina Beets-Tan
Molecular Diagnosis & Therapy.2026; 30(2): 177. CrossRef
Emerging role of low-frequency somatic mutations in cancer relapse: from early detection to precision oncology
Eunsoo Kim, Gu Seob Roh, Seong Gyu Kwon
Frontiers in Oncology.2026;[Epub] CrossRef
The Role of ctDNA for Diagnosis and Histological Prediction in Early Stage Non-Small-Cell Lung Cancer: A Narrative Review
Carolina Sassorossi, Jessica Evangelista, Alessio Stefani, Marco Chiappetta, Antonella Martino, Annalisa Campanella, Elisa De Paolis, Dania Nachira, Marzia Del Re, Francesco Guerrera, Luca Boldrini, Andrea Urbani, Stefano Margaritora, Angelo Minucci, Emil
Diagnostics.2025; 15(7): 904. CrossRef
Longitudinal dynamics of circulating tumor DNA for treatment monitoring in patients with breast cancer recurrence
Tae-Kyung Robyn Yoo, Ji-Young Lee, Hwan Park, Whi-Kyung Cho, Seyeon Jeon, Ha Ra Jun, Sae Byul Lee, Il Yong Chung, Hee Jeong Kim, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei-Hyun Ahn, Jae Ho Jeong, Jeong Eun Kim, Jin-Hee Ahn, Kyung Hae Jung, Sung-Bae Kim
Scientific Reports.2024;[Epub] CrossRef

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Targeting CD73 to Overcomes Resistance to First-Generation EGFR Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer: Miso Kim, Soyeon Kim, Jeemin Yim, Bhumsuk Keam, Tae Min Kim, Yoon Kyung Jeon, Dong-Wan Kim, Dae Seog Heo; Cancer Res Treat. 2023;55(4):1134-1143. Published online May 23, 2023; DOI: https://doi.org/10.4143/crt.2023.311

Abstract PDF Supplementary Material PubReader ePub

Purpose
In patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitors (TKIs) improve response rate and survival. However, most patients eventually develop resistance. This study aimed to identify the role of CD73 in EGFR-mutant NSCLC and explore whether CD73 inhibition may serve as a therapeutic strategy in NSCLC patients with acquired resistance to EGFR-TKIs.
Materials and Methods
We evaluated the prognostic role of CD73 expression in EGFR-mutant NSCLC using tumor samples from a single institution. We silenced CD73 in EGFR-TKI–resistant cell lines using short hairpin RNA (shRNA) targeting CD73 and also transfected a vector alone as a negative control. Using these cell lines, cell proliferation and viability assays, immunoblot assays, cell cycle analysis, colony-forming assays, flow cytometry, and apoptosis analysis were performed.
Results
High expression of CD73 was associated with shorter survival in patients with metastatic EGFR-mutant NSCLC treated with first-generation EGFR-TKI. CD73 inhibition synergistically inhibited cell viability with first-generation EGFR-TKI treatment compared with the negative control. When CD73 inhibition and EGFR-TKI treatment were combined, G0/G1 cell cycle arrest was induced through the regulation of p21 and cyclin D1. In addition, the apoptosis rate was increased in CD73 shRNA-transfected cells treated with EGFR-TKI.
Conclusion
High expression of CD73 adversely affects the survival of patients with EGFR-mutant NSCLC. The study demonstrated that inhibiting CD73 in EGFR-TKI–resistant cell lines resulted in increased apoptosis and cell cycle arrest, which overcame the acquired resistance to first-generation EGFR-TKIs. Further research is needed to determine whether blocking CD73 plays a therapeutic role in EGFR-TKI–resistant patients with EGFR-mutant NSCLC.

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Profiling of Extracellular Vesicles of Non‐Small Cell Lung Cancer Reveals Proteins Associated With Osimertinib Resistance
Albano Cáceres‐Verschae, Petra Hååg, Sofia Joelsson, Per Hydbring, Bo Franzén, Ákos Végvári, Inger Johanne Z. Eide, Nupur Agarwal, Siddharth Sourabh Sahu, Fredrik Stridfeldt, Luigi De Petris, Apurba Dev, Simon Ekman, Odd Terje Brustugun, Rolf Lewensohn, K
Journal of Extracellular Vesicles.2026;[Epub] CrossRef
CD73 expression as a resistance mechanism in advanced EGFR-mutated non-small cell lung cancer
Inger Johanne Zwicky Eide, Anne Pernille Harlem Dyrbekk, Ina Bisha, Thomas Haberichter, Sotirios Lakis, Jessica Chan, Arthur Lewis, Philip Martin, Zachary A. Cooper, Odd Terje Brustugun
Frontiers in Oncology.2026;[Epub] CrossRef
Research Progress of CD73 Inhibitors in Lung Cancer Immunotherapy
菀凌张
World Journal of Cancer Research.2026; 16(03): 176. CrossRef
Simultaneous blockade of the CD73/EGFR axis inhibits tumor growth
Keivan Ardeshiri, Hadi Hassannia, Ghasem Ghalamfarsa, Hanieh Jafary, Farhad Jadidi
IUBMB Life.2025;[Epub] CrossRef
Exploring the Expression of CD73 in Lung Adenocarcinoma with EGFR Genomic Alterations
Elodie Long-Mira, Christophe Bontoux, Guylène Rignol, Véronique Hofman, Sandra Lassalle, Jonathan Benzaquen, Jacques Boutros, Salomé Lalvée-Moret, Katia Zahaf, Virginie Lespinet-Fabre, Olivier Bordone, Sophia Maistre, Christelle Bonnetaud, Charlotte Cohen
Cancers.2025; 17(6): 1034. CrossRef
Assessing the impact of CD73 inhibition on overcoming anti-EGFR resistance in glioma cells
LUIZ FERNANDO LOPES SILVA, JULIETE NATHALI SCHOLL, AUGUSTO FERREIRA WEBER, CAMILA KEHL DIAS, PAULINE RAFAELA PIZZATO, VINíCIUS PIERDONá LIMA, JEAN SÉVIGNY, ANA MARIA OLIVEIRA BATTASTINI, FABRÍCIO FIGUEIRÓ
Oncology Research.2025; 33(4): 951. CrossRef
CD39 and CD73: biological functions, diseases and therapy
Jie Shen, Bin Liao, Li Gong, Sha Li, Juan Zhao, Huiyao Yang, Yi Gong, Yongsheng Li
Molecular Biomedicine.2025;[Epub] CrossRef
Comprehensive pan-cancer analysis of CD73: Explore its association with prognosis and tumor immune microenvironment
Chen Chen, Sasa Liu, Yanfen Ma
Heliyon.2024; 10(22): e40329. CrossRef

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Sublobar Resection versus Stereotactic Body Radiation Therapy for Clinical Stage I Non–Small Cell Lung Cancer: A Study Using Data from the Korean Nationwide Lung Cancer Registry: Jeonghee Yun, Jong Ho Cho, Tae Hee Hong, Kyungmi Yang, Yong Chan Ahn, Hong Kwan Kim, Korean Association for Lung Cancer, Korea Central Cancer Registry; Cancer Res Treat. 2023;55(4):1171-1180. Published online April 17, 2023; DOI: https://doi.org/10.4143/crt.2022.1581

Abstract PDF Supplementary Material PubReader ePub

Purpose
Stereotactic body radiotherapy (SBRT) had been increasingly recognized as a favorable alternative to surgical resection in patients with high risk for surgery. This study compared survival outcomes between sublobar resection (SLR) and SBRT for clinical stage I non–small cell lung cancer (NSCLC).
Materials and Methods
Data were obtained from the Korean Association of Lung Cancer Registry, a sampled nationwide database. This study retrospectively reviewed 382 patients with clinical stage I NSCLC who underwent curative SLR or SBRT from 2014 to 2016.
Results
Of the patients, 43 and 339 underwent SBRT and SLR, respectively. Patients in the SBRT group were older and had worse pulmonary function. The 3-year overall survival (OS) rate was significantly better in the SLR group compared with the SBRT group (86.6% vs. 57%, log-rank p < 0.001). However, after adjusting for age, sex, tumor size, pulmonary function, histology, smoking history, and adjuvant therapy, treatment modality was not an independent prognostic factor for survival (hazard ratio, 0.99; 95% confidence interval, 0.43 to 2.77; p=0.974). We performed subgroup analysis in the following high-risk populations: patients who were older than 75 years; patients who were older than 70 years and had diffusing capacity of lung for carbon monoxide ≤ 80%. In each subgroup, there were no differences in OS and recurrence-free survival between patients who underwent SLR and those who received SBRT.
Conclusion
In our study, there were no significant differences in terms of survival or recurrence between SBRT and SLR in medically compromised stage I NSCLC patients. Our findings suggest that SBRT could be considered as a potential treatment option for selected patients.

Citations

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Real-world Decision-making Process for Stereotactic Body Radiotherapy Versus Minimally Invasive Surgery in Early-stage Lung Cancer Patients
Stijn Vanstraelen, Kay See Tan, Prasad S. Adusumilli, Manjit S. Bains, Matthew J. Bott, Robert J. Downey, Daniel R. Gomez, Katherine D. Gray, James Huang, James M. Isbell, Daniela Molena, Bernard J. Park, Andreas Rimner, Valerie W. Rusch, Narek Shaverdian
Annals of Surgery.2026; 283(5): 807. CrossRef
Sublobar resection, stereotactic body radiotherapy, and thermal ablation for early-stage non-small cell lung cancer: a systematic review and meta-analysis
Shahar Adar, Alexandra Ádám, Tamara Balogh, Mátyás Rédei, Karen Krisztina Fazekas, Mátyás Paczkó, Nina Galdzytska, Marie Anne Engh, András Bibok, Gábor Zoltán Duray, Péter Hegyi, Dénes Balázs Horváthy
Lung Cancer.2026; 217: 109467. CrossRef
The limits of pooled evidence in early-stage NSCLC: are we comparing treatments or patients?
Peter S.N. van Rossum, Famke L. Schneiders, Suresh Senan
Lung Cancer.2026; : 109555. CrossRef
Surgery Versus Stereotactic Body Radiotherapy for Early-Stage Non-small Cell Lung Cancer (NSCLC): A Comprehensive Review of Survival and Local Control Outcomes
Abdulrahman Bin Sumaida, Nandan M Shanbhag, Nadeem Pervez, Khalifa AlKaabi, Khalid Balaraj
Cureus.2025;[Epub] CrossRef
Surgery for all patients with T1N0 non-small cell lung cancer?
Claudia Pouypoudat, Sébastien Thureau, Nicolas Giraud, Yaniss Belaroussi, Étienne Martin
Cancer/Radiothérapie.2025; 29(5-6): 104683. CrossRef

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EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-Mutated NSCLC: A Prospective, Randomized, Exploratory Study: Weiguang Gu, Hua Zhang, Yiyu Lu, Minjing Li, Shuang Yang, Jianmiao Liang, Zhijian Ye, Zhihua Li, Minhong He, Xiaoliang Shi, Fei Wang, Dong You, Weiquan Gu, Weineng Feng; Cancer Res Treat. 2023;55(3):841-850. Published online February 13, 2023; DOI: https://doi.org/10.4143/crt.2022.1438

Abstract PDF Supplementary Material PubReader ePub

Purpose
We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)–mutated patients with or without concomitant alterations.
Materials and Methods
This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non–small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.
Results
The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.
Conclusion
EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

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Furmonertinib plus pemetrexed in the treatment of EGFR exon 19 deletion lung adenocarcinoma: two case reports
Yuan Zhang, Duofang Wang, Huaxiu Ma, Xiaojun Wang
Frontiers in Oncology.2026;[Epub] CrossRef
Tyrosine kinase inhibitor toxicity in the treatment of non-small-cell lung cancer: A bibliometric analysis (2009–2025)
Lazzat Balymbetova, Yerbolat Maratovich Iztleuov, Elnara Kereevna Ismagulova, Sarkyt Kozhantayeva, Aigerim Balapasheva
Medicine.2026; 105(9): e47860. CrossRef
Prognostic factors influencing overall survival in stage IV EGFR-mutant NSCLC patients treated with EGFR-TKIs
Linwu Kuang, Yuchen Zhang, Hao Wang, Peng Wang, Yangkai Li
BMC Pulmonary Medicine.2025;[Epub] CrossRef
Comparison of the Efficacy of Different First‐Line Therapies for EGFR L858R‐Mutated NSCLC Patients With Brain Metastases
Jing Chen, Yin Pan, Baishen Zhang, Meichen Li, Hui Yu, Mingjie Yu, Likun Chen
Cancer Science.2025; 116(11): 3125. CrossRef
SP3-induced Timeless transcription contributes to cell growth of lung adenocarcinoma cells
Ping Tian, Dajun Du, Li Yang, Nan Zhou, Ling Tao, Divijendra Natha Reddy Sirigiri
PLOS ONE.2024; 19(2): e0298295. CrossRef
PIK3CA mutation as an acquired resistance driver to EGFR-TKIs in non-small cell lung cancer: Clinical challenges and opportunities
Xiaohong Liu, Wuxuan Mei, Pengfei Zhang, Changchun Zeng
Pharmacological Research.2024; 202: 107123. CrossRef
Risk factors for interstitial lung disease in patients with non-small cell lung cancer with epidermal growth factor receptor-tyrosine kinase inhibitors: A systematic review and meta-analysis
Yosuke Fukuda, Yoshitaka Uchida, Koichi Ando, Ryo Manabe, Akihiko Tanaka, Hironori Sagara
Respiratory Investigation.2024; 62(3): 481. CrossRef
Concomitant genomic features stratify prognosis to patients with advanced EGFR mutant lung cancer
Xiao Liang, Jiali Xu, Yuqin Jiang, Yuqian Yan, Hongshuai Wu, Jiali Dai, Yanan Cui, Chen Zhang, Wei Chen, Zhihong Zhang, Renhua Guo
Molecular Carcinogenesis.2024; 63(9): 1643. CrossRef
Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review
Juan Carlos Restrepo, Darly Martínez Guevara, Andrés Pareja López, John Fernando Montenegro Palacios, Yamil Liscano
Cancers.2024; 16(13): 2338. CrossRef

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Review Article

Challenges in the Use of Targeted Therapies in Non–Small Cell Lung Cancer: Joel Rivera-Concepcion, Dipesh Uprety, Alex A. Adjei; Cancer Res Treat. 2022;54(2):315-329. Published online February 18, 2022; DOI: https://doi.org/10.4143/crt.2022.078

Abstract PDF PubReader ePub

Precision oncology has fundamentally changed how we diagnose and treat cancer. In recent years, there has been a significant change in the management of patients with oncogene-addicted advanced-stage NSCLC. Increasing amounts of identifiable oncogene drivers have led to the development of molecularly targeted drugs. Undoubtedly, the future of thoracic oncology is shifting toward increased molecular testing and the use of targeted therapies. For the most part, these novel drugs have proven to be safe and effective. As with all great innovations, targeted therapies pose unique challenges. Drug toxicities, resistance, access, and costs are some of the expected obstacles that will need to be addressed. This review highlights some of the major challenges in the use of targeted therapies in NSCLC and provides guidance for the future strategies.

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Original Articles

Lung and Thoracic cancer

Assessment of Anti-tumor Efficacy of Osimertinib in Non-Small Cell Lung Cancer Patients by Liquid Biopsy Using Bronchoalveolar Lavage Fluid, Plasma, or Pleural Effusion: Yeon Joo Kim, Won Jun Ji, Jae-Cheol Lee, Sung-Min Chun, Chang-Min Choi; Cancer Res Treat. 2022;54(4):985-995. Published online January 17, 2022; DOI: https://doi.org/10.4143/crt.2021.857

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study was to evaluate anti-tumor efficacy of osimertinib in patients positive for acquired epidermal growth factor receptor (EGFR) T790M mutation in liquid biopsy using plasma, bronchoalveolar lavage fluid (BALF) or bronchial washing fluid (BWF), and pleural effusion.
Materials and Methods
Among patients benefited from previous EGFR‒tyrosine kinase inhibitor treatment followed by treatment failure, patients in whom T790M mutations are detected in at least one of the samples including tumor tissues, BALF/BWF, plasma, and pleural effusion were enrolled. T790M mutation was detected by extracting cell free DNA from liquid biopsy samples, using PANA Mutyper. Objective response rate (ORR) and progression-free survival (PFS) with osimertinib treatment were evaluated.
Results
Between January 2018 and December 2019, 63 patients were enrolled and received osimertinib. Mean age was 63 years, and 38 (60.3%) were female. Twenty-six patients had T790M mutation in both liquid and tissue samples (group A), 19 patients had only in tissue biopsy samples (group B), and 18 patients had T790M mutation only in liquid biopsy samples (group C). ORR in overall population was 63.5%, and was 61.5% in group A, 68.4% in group B, and 61.1% in group C, respectively. Median PFS in overall patients was 15.6 months (95% confidence interval, 10.7 to 24.2). There was no significant difference in ORR or PFS between groups.
Conclusion
Osimertinib showed favorable efficacy in lung cancer patients with acquired resistance to prior EGFR-TKI therapies, who screened positive for harboring T790M mutation detected from cell free DNA extracted from plasma, BALF/BWF, and pleural effusion.

Citations

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Cardiovascular adverse events in non-small cell lung cancer patients receiving osimertinib therapy: a systematic review and meta-analysis
Wei-He Liu, Yun-Jiu Cheng, Jin Kang, Jian Chen, Zhen-Jie An, Ting-Hui Li, Ning Tan, Wen-Zhao Zhong, Yi-Long Wu, Lei Jiang
Lung Cancer.2026; 217: 109413. CrossRef
Repeated rebiopsy for detection of EGFR T790M mutation in patients with advanced-stage lung adenocarcinoma: Associated factors and treatment outcomes of Osimertinib
Taeyun Kim, Junsu Choe, Sun Hye Shin, Byeong-Ho Jeong, Kyungjong Lee, Hojoong Kim, Se-Hoon Lee, Sang-Won Um, Hamidreza Montazeri Aliabadi
PLOS ONE.2024; 19(9): e0310079. CrossRef
Can Liquid Biopsy Based on ctDNA/cfDNA Replace Tissue Biopsy for the Precision Treatment of EGFR-Mutated NSCLC?
Yi-Ze Li, Sheng-Nan Kong, Yun-Peng Liu, Yue Yang, Hong-Mei Zhang
Journal of Clinical Medicine.2023; 12(4): 1438. CrossRef
Usefulness of bronchial washing fluid for detection of EGFR mutations in non-small cell lung cancer
Woo Kyung Ryu, Seung Hyun Yong, Sang Hoon Lee, Hye Ran Gwon, Hye Ryun Kim, Min Hee Hong, Go Eun Oh, Sehee Jung, Chi Young Kim, Yoon Soo Chang, Eun Young Kim
Lung Cancer.2023; 186: 107390. CrossRef

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A Phase I/IIa Randomized Trial Evaluating the Safety and Efficacy of SNK01 Plus Pembrolizumab in Patients with Stage IV Non-Small Cell Lung Cancer: Eo Jin Kim, Yong-Hee Cho, Dong Ha Kim, Dae-Hyun Ko, Eun-Ju Do, Sang-Yeob Kim, Yong Man Kim, Jae Seob Jung, Yoonmi Kang, Wonjun Ji, Myeong Geun Choi, Jae Cheol Lee, Jin Kyung Rho, Chang-Min Choi; Cancer Res Treat. 2022;54(4):1005-1016. Published online December 3, 2021; DOI: https://doi.org/10.4143/crt.2021.986

Abstract PDF Supplementary Material PubReader ePub

Purpose
The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial.
Materials and Methods
Overall, 18 patients with advanced non–small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/– 6 weekly infusions of SNK01 at either 2×10⁹ or 4×10⁹ cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life.
Results
Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4×10⁹ cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001).
Conclusion
Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events.

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NK cell activity and methylated HOXA9 ctDNA as prognostic biomarkers in patients with non-small cell lung cancer treated with PD-1/PD-L1 inhibitors
Sara Witting Christensen Wen, Line Nederby, Rikke Fredslund Andersen, Torben Schjødt Hansen, Christa Haugaard Nyhus, Ole Hilberg, Anders Jakobsen, Torben Frøstrup Hansen
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The Value of the Illness-Death Model for Predicting Outcomes in Patients with Non–Small Cell Lung Cancer: Kum Ju Chae, Hyemi Choi, Won Gi Jeong, Jinheum Kim; Cancer Res Treat. 2022;54(4):996-1004. Published online November 19, 2021; DOI: https://doi.org/10.4143/crt.2021.902

Abstract PDF Supplementary Material PubReader ePub

Purpose
The illness-death model (IDM) is a comprehensive approach to evaluate the relationship between relapse and death. This study aimed to illustrate the value of the IDM for identifying risk factors and evaluating predictive probabilities for relapse and death in patients with non–small cell lung cancer (NSCLC) in comparison with the disease-free survival (DFS) model.
Materials and Methods
We retrospectively analyzed 612 NSCLC patients who underwent a curative operation. Using the IDM, the risk factors and predictive probabilities for relapse, death without relapse, and death after relapse were simultaneously evaluated and compared to those obtained from a DFS model.
Results
The IDM provided more detailed risk factors according to the patient’s disease course, including relapse, death without relapse, and death after relapse, in patients with resected lung cancer. In the IDM, history of malignancy (other than lung cancer) was related to relapse and smoking history was associated with death without relapse; both were indistinguishable in the DFS model. In addition, the IDM was able to evaluate the predictive probability and risk factors for death after relapse; this information could not be obtained from the DFS model.
Conclusion
Compared to the DFS model, we found that the IDM provides more comprehensive information on transitions between states and disease stages and provides deeper insights with respect to understanding the disease process among lung cancer patients.

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Variable Selection for Illness‐Death Processes Under Dual Observation Schemes
Xianwei Li, Liqun Diao, Richard J. Cook
Statistics in Medicine.2026;[Epub] CrossRef
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Andres Arguedas, David Schneck, Erjia Cui, Annette Xenopoulos-Oddsson, Ximena Arcila-Londono, Christian Lunetta, James Wymer, Nicholas Olney, Kelly Gwathmey, Senda Ajroud-Driss, Ghazala Hayat, Terry Heiman-Patterson, Federica Cerri, Christina Fournier, Jo
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.2025; 26(5-6): 550. CrossRef
Population-based epidemiological projections of rheumatoid arthritis in Germany until 2040
J Wang, S Vordenbäumen, M Schneider, R Brinks
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A population-based projection of psoriatic arthritis in Germany until 2050: analysis of national statutory health insurance data of 65 million German population
Jiancong Wang, Sabrina Tulka, Stephanie Knippschild, Matthias Schneider, Jörg H. W. Distler, Xenofon Baraliakos, Ralph Brinks, Philipp Sewerin
Rheumatology International.2023; 43(11): 2037. CrossRef
Difference of serum tumor markers in different clinical stages of elderly patients with non-small cell lung cancer and evaluation of diagnostic value
Wen Qin, Ping Wang, CuiMin Ding, Fei Peng
Journal of Medical Biochemistry.2023; 42(4): 607. CrossRef
Lung cancer mortality and associated predictors: systematic review using 32 scientific research findings
Lijalem Melie Tesfaw, Zelalem G. Dessie, Haile Mekonnen Fenta
Frontiers in Oncology.2023;[Epub] CrossRef

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Integrin αvβ3 Induces HSP90 Inhibitor Resistance via FAK Activation in KRAS-Mutant Non-Small Cell Lung Cancer: Shinkyo Yoon, Hannah Yang, Hyun-Min Ryu, Eunjin Lee, Yujin Jo, Seyoung Seo, Deokhoon Kim, Chang Hoon Lee, Wanlim Kim, Kyung Hae Jung, Sook Ryun Park, Eun Kyung Choi, Sang-We Kim, Kang-Seo Park, Dae Ho Lee; Cancer Res Treat. 2022;54(3):767-781. Published online September 30, 2021; DOI: https://doi.org/10.4143/crt.2021.651

Abstract PDF Supplementary Material PubReader ePub

Purpose
Heat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.
Materials and Methods
We established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.
Results
We identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.
Conclusion
The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.

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Hibiki Udagawa, Yuji Shibata, Monique B. Nilsson, Kazuya Nishii, Jacqulyne P. Robichaux, Ana Galan-Cobo, Junqin He, Alissa Poteete, Yu Qian, David Molkentine, Xiaoxing Yu, Qian Huang, Marcelo V. Negrao, John V. Heymach
Journal of Thoracic Oncology.2026; : 103991. CrossRef
Triiodothyronine promotes the proliferation and chemoresistance of cholangiocarcinoma cells via HIF-1α/Glut1-stimulated glycolysis
Dihua Huang, Feng Xu, Luohang Xu, Zekai Tang, Yanxin Hu, Jiandong Li, Jianhua Yu
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2025; 1871(5): 167814. CrossRef
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Yoshinobu Kariya, Michiru Nishita
International Journal of Molecular Sciences.2025; 26(7): 3143. CrossRef
Integrin αV Inhibition by GMI, a Ganoderma Microsporum Immunomodulatory Protein, Abolish Stemness and Migration in EGFR‐Mutated Lung Cancer Cells Resistant to Osimertinib
Yu‐Ting Kang, Hui‐Yi Chang, Ya‐Chu Hsieh, Chia‐Hsuan Chou, I‐Lun Hsin, Jiunn‐Liang Ko
Environmental Toxicology.2024; 39(12): 5238. CrossRef
Junctional adhesion molecular 3 (JAM3) is a novel tumor suppressor and improves the prognosis in breast cancer brain metastases via the TGF-β/Smad signal pathway
Kaitao Zhu, Shiwei Li, Hongru Yao, Jilong Hei, WenGuo Jiang, Tracey Martin, Shanyi Zhang
Journal of Neuro-Oncology.2024; 170(2): 331. CrossRef
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Bashar Alhasan, Marina Mikeladze, Irina Guzhova, Boris Margulis
Cancer and Metastasis Reviews.2023; 42(1): 217. CrossRef

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miR-4487 Enhances Gefitinib-Mediated Ubiquitination and Autophagic Degradation of EGFR in Non-Small Cell Lung Cancer Cells by Targeting USP37: Mi Seong Kim, So Hui Kim, Sei Hoon Yang, Min Seuk Kim; Cancer Res Treat. 2022;54(2):445-457. Published online August 3, 2021; DOI: https://doi.org/10.4143/crt.2021.622

Abstract PDF PubReader ePub

Purpose
With the identification of epidermal growth factor receptor (EGFR) mutations in non–small cell lung cancer (NSCLC) cells, EGFR–tyrosine kinase inhibitors (TKIs) are being used widely as the first-line of treatment in NSCLC. These inhibitors block auto-phosphorylation of activated EGFR by competing with ATP binding and mediate EGFR degradation independent of exogenous epidermal growth factor, which is associated with the mutation variants of EGFR. However, the precise mechanisms underlying the TKI-mediated EGFR degradation are still unclear.
Materials and Methods
To examine the physiological roles of miR-4487 and ubiquitin-specific peptidase 37 (USP37) in gefitinib-mediated EGFR degradation in NSCLC cells, multiple NSCLC cell lines were applied. The level of EGFR expression, apoptosis marker and autophagic flux were determined by western blot. Expression level of miR-4487 and cell cycle arrest was analyzed by TaqMan assay and flow cytometry respectively.
Results
We found that gefitinib mediates EGFR degradation under normal culture conditions, and is dependent on autophagic flux and the mutation variants of EGFR. Gefitinib reduced expression levels of USP37, which mediated EGFR degradation similar to gefitinib. Our results also showed a gefitinib-mediated increase in endogenous miR-4487 level and presented evidence for the direct targeting of USP37 by miR-4487, resulting in the sequential enhancement of ubiquitination, autophagy, and EGFR degradation. Thus, the depletion of USP37 and overexpression of miR-4487 led to an increase in gefitinib-mediated apoptotic cell death.
Conclusion
These data suggest that miR-4487 is a potential target for treating NSCLC, and miR-4487/USP37-regulated EGFR degradation is a determinant for developing gefitinib resistance.

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Identification of Raptor and GLI1 as USP37 substrates highlight its context-specific function in medulloblastoma cells
Ashutosh Singh, Donghang Cheng, Amanda R. Haltom, Yanwen Yang, Tara Dobson, Rashieda Hatcher, Veena Rajaram, Vidya Gopalakrishnan
Oncogene.2026; 45(4): 521. CrossRef
The ubiquitination–autophagy axis in cancer therapy resistance: mechanistic insights and therapeutic opportunities
Hengrui Zhang, Hanxi Yan, Yulin Liu, Anqi Zeng, Linjiang Song
Frontiers in Pharmacology.2026;[Epub] CrossRef
USP37 facilitates hepatocellular carcinoma progression by deubiquitinating RAF1 and activating ERK1/2 signaling
Yuming Wang, Ruidong Ding, Yilin Wang, Xiangheng Cai, Jijun Shan
Functional & Integrative Genomics.2026;[Epub] CrossRef
Epigenetic code underlying EGFR-TKI resistance in non-small cell lung cancer: Elucidation of mechanisms and perspectives on therapeutic strategies
XiaoYu Yao, Chundi Gao, Changgang Sun, Zhe-Sheng Chen, Jing Zhuang
Drug Discovery Today.2025; 30(3): 104321. CrossRef
Deubiquitination of epidermal growth factor receptor by ubiquitin-specific peptidase 54 enhances drug sensitivity to gefitinib in gefitinib-resistant non-small cell lung cancer cells
Mi Seong Kim, Min Seuk Kim, Chien-Feng Li
PLOS ONE.2025; 20(4): e0320668. CrossRef
MicroRNAs as Sensitizers of Tyrosine Kinase Inhibitor Resistance in Cancer: Small Molecule Partnerships
Alma D. Campos-Parra, David Sánchez-Marín, Víctor Acevedo-Sánchez
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Mechanistic Insights and Therapeutic Potentials of Ubiquitin‐Proteasome System in Non‐Small Cell Lung Cancer
Guangyao Zhou, Jiaxiong Tan, Pengpeng Zhang, Zhaokai Zhou, Lianmin Zhang, Zhenfa Zhang
Cell Proliferation.2025;[Epub] CrossRef
Exploring the potential function of high expression of ANAPC1 in regulating ubiquitination in hepatocellular carcinoma
Yu-Xing Tang, Wei-Zi Wu, Sheng-Sheng Zhou, Da-Tong Zeng, Guang-Cai Zheng, Rong-Quan He, Di-Yuan Qin, Wan-Ying Huang, Ji-Tian Chen, Yi-Wu Dang, Yu-Lu Tang, Bang-Teng Chi, Yan-Ting Zhan, Gang Chen
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Autophagy-associated ncRNAs in lung cancer: From drug resistance to therapeutic targets
Ming Yu, Hanqing Li, Yin Wu, Ping Liu, Quangang Xu, Yi Zhang
International Journal of Biological Macromolecules.2025; 319: 145477. CrossRef
Bioinformatics based exploration of the anti-liver fibrosis mechanism of Pien Tze Huang via EGFR/JAK1/STAT3 pathway
Xiaoting Hong, Yonghua Ye, Chunfeng Lin, Miaolan Zheng, Fan Lin, Qing Xiong, Wei Xu, Huang Li, Yuqin Zhang, Haiyin Zheng
Frontiers in Immunology.2025;[Epub] CrossRef
The significance of the crosstalk between ubiquitination or deubiquitination and ncRNAs in non-small cell lung cancer
Yiyang Sun, Ping He, Li Li, Xue Ding
Frontiers in Oncology.2023;[Epub] CrossRef
Lung adenocarcinoma cell-derived exosomes promote M2 macrophage polarization through transmission of miR-3153 to activate the JNK signaling pathway
L Xu, L Wang, R Yang, T Li, X Zhu
Human Molecular Genetics.2023; 32(13): 2162. CrossRef
The potential role of miRNAs in the pathogenesis of salivary gland cancer – A Focus on signaling pathways interplay
Ahmed I. Abulsoud, Shereen Saeid Elshaer, Ahmed A. El-Husseiny, Doaa Fathi, Nourhan M. Abdelmaksoud, Sherif S. Abdel Mageed, Aya Salman, Mohamed Bakr Zaki, Hesham A. El-Mahdy, Ahmed Ismail, Elsayed G.E. Elsakka, Mai A. Abd-Elmawla, Hussein M. El-Husseiny,
Pathology - Research and Practice.2023; 247: 154584. CrossRef

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Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer: Chaelin Lee, Miso Kim, Dong-Wan Kim, Tae Min Kim, Soyeon Kim, Sun-Wha Im, Yoon Kyung Jeon, Bhumsuk Keam, Ja-Lok Ku, Dae Seog Heo; Cancer Res Treat. 2022;54(1):140-149. Published online May 3, 2021; DOI: https://doi.org/10.4143/crt.2021.385

Abstract PDF Supplementary Material PubReader ePub

Purpose
Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs.
Materials and Methods
We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDD^WT), EGFR-KDD domain 1 T790M (EGFR-KDD^D1T), EGFR-KDD domain 2 T790M (EGFR-KDD^D2T), and EGFR-KDD both domain T790M (EGFR-KDD^BDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening.
Results
In cell viability assays, SNU-4784 cells and EGFR-KDD^WT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDD^T790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDD^BDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDD^T/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs.
Conclusion
Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDD^T790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

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Acquired Resistance to Afatinib Mediated by EGFR T790M in Lung Adenocarcinoma Patients Harboring EGFR-KDD: A Case Report and Literature Review
Qian Liu, Lu Lv, Guanchao Pang, Pingli Wang
Current Oncology.2026; 33(4): 214. CrossRef
Colorectal cancer harboring EGFR kinase domain duplication response to EGFR tyrosine kinase inhibitors
Tomohiro Kondo, Osamu Kikuchi, Yoshihiro Yamamoto, Tomohiko Sunami, Yafeng Wang, Keita Fukuyama, Tomoki Saito, Hideto Nakahara, Sachiko Minamiguchi, Masashi Kanai, Atsushi Sueyoshi, Manabu Muto
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Virtual Screening and Biological Evaluation of T22306 as a Potent Third-generation EGFR Inhibitor for NSCLC Treatment
Ran Wang, Wei Ruan, Dang Fan, Li Long, Han Zhang, Min Li, Shan Xu, Linxiao Wang
Anti-Cancer Agents in Medicinal Chemistry.2025; 25(15): 1128. CrossRef
Epidermal Growth Factor Receptor Kinase Domain Duplication in Lung Adenocarcinoma with Sensitive Response to Afatinib: A Case Report and Literature Review
Shuangru Chen, Liting Zhang, Jun Wang, Jiayao Lu, Ye Chen, Mingzhu Ling
Lung Cancer: Targets and Therapy.2025; Volume 16: 97. CrossRef
A Constitutive EGFR Kinase Dimer to Study Inhibitor Pharmacology
Justin J. Kim, Ilse K. Schaeffner, David E. Heppner, Ciric To, Pasi A. Jänne, Tyler S. Beyett, Michael J. Eck
Molecular Pharmacology.2024; 105(2): 97. CrossRef
Tumor-associated Macrophages Mediate Gefitinib Resistance in Lung Cancer through HGF/c-met Signaling Pathway
Xiali Tang, Yu Chen, Demin Jiao, Xiang Liu, Jun Chen, Yongyang Liu, Chunyan Jiang, Qingyong Chen
Anti-Cancer Agents in Medicinal Chemistry.2024; 24(1): 30. CrossRef
Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer
Ziyang Jiang, Zhihan Gu, Xiaomin Yu, Tao Cheng, Bofu Liu
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Molecular Targets and Mechanisms of Casein-Derived Tripeptides Ile-Pro-Pro and Val-Pro-Pro on Hepatic Glucose Metabolism
Chenyang Wang, Lin Zheng, Mouming Zhao
Journal of Agricultural and Food Chemistry.2023; 71(48): 18802. CrossRef
Erlotinib

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Lung cancer

Active Treatment Improves Overall Survival in Extremely Older Non–Small Cell Lung Cancer Patients: A Multicenter Retrospective Cohort Study: Su Yeon Lee, Yoon-Ki Hong, Wonjun Ji, Jae Cheol Lee, Chang Min Choi, Korean Association for Lung Cancer, Korea Central Cancer Registry; Cancer Res Treat. 2021;53(1):104-111. Published online October 5, 2020; DOI: https://doi.org/10.4143/crt.2020.894

Abstract PDF Supplementary Material PubReader ePub

Purpose
As the aging of society progresses, the proportion of extremely older lung cancer patients has also increased; However, studies of these patients with non–small cell lung cancer are limited. Therefore, we investigated the initial treatment modalities and survival outcomes for patients aged 80 years or over.
Materials and Methods
We included a multicenter retrospective cohort from the Korean Association for Lung Cancer Registry, which surveys 10% of the newly diagnosed lung cancer patients across 52 hospitals in Korea. We analyzed and compared the 2014–2016 data of the non–small cell lung cancer patients aged ≥ 80 years and those aged < 80 years.
Results
Of the 6,576 patients reviewed, 780 patients were aged ≥ 80 years, and 5,796 patients were aged < 80 years. In the patients aged ≥ 80 years, surgery and radiation therapy resulted in longer patient survival among those with a resectable tumor (stage I–II) than the best supportive care (median survival, not reached [surgery] vs. 32.2 months [radiation therapy] vs. 11.43 months [best supportive care]). The duration of survival in patients with advanced-stage (IV) lung cancers was higher after chemotherapy than after the best supportive care (median survival, 8.63 months vs. 2.5 months). Patients with stage IV adenocarcinoma who received targeted therapy had better survival than those who did not (median survival, 9.0 months vs. 4.3 months).
Conclusion
Even in extremely older patients, active treatments, such as surgery, radiation therapy, and chemotherapy, can result in better survival outcomes than the best supportive care.

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Changes in Cancer Care for Patients Aged 80 and Above: A Cohort Study from Samsung Comprehensive Cancer Center in South Korea
Seung Tae Kim, Danbee Kang, Seok Jin Kim, Jun Ho Lee, Hong Kwan Kim, Yong Beom Cho, Yong Han Paik, Seok Won Kim, Byong Chang Jeong, Ho Jun Seol, Man Ki Chung, Kyu Taek Lee, Kihyun Kim, Sung-wook Seo, Jeong-Won Lee, Hee Chul Park, Dong Wook Shin, Juhee Cho
Cancers.2025; 17(12): 2017. CrossRef
The delayed cancer treatment and economic inequality in Korea: results of common cancers by the time-to-surgery
Noorhee Son, Woo-Ri Lee, Dong-Woo Choi, Kyu-Tae Han
Epidemiology and Health.2025; 47: e2025056. CrossRef
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Marcelo Vinicius Pereira Silva, Elizeu Augusto de Freitas Junior, Allan Martins de Oliveira, Elaine Timm, Mariana Brito Siqueira, Mônica Stefany Martelli, Elielson Mendonça de Oliveira, Victor Cavalcante Machado, Igor Vinicius Barbino Ferrari, Pamella Hag
Revista Contemporânea.2024; 4(5): e4464. CrossRef
Association between clinical outcomes and local treatment in stage IV non‐small cell lung cancer patients with single extrathoracic metastasis
Jeong Uk Lim, Hye Seon Kang, Ah Young Shin, Chang Dong Yeo, Chan Kwon Park, Sang Haak Lee, Seung Joon Kim
Thoracic Cancer.2022; 13(9): 1349. CrossRef
Characteristics and clinical outcomes of patients with nonsmoking small cell lung cancer in Korea
Hye Seon Kang, Jung Uk Lim, Chang Dong Yeo, Chan Kwon Park, Sang Haak Lee, Seung Joon Kim, Ho Cheol Kim, Chang Min Choi, Chi Young Jung, Deog Gon Cho, Jae Hyun Jeon, Jeong Eun Lee, Jin Seok Ahn, Yeongdae Kim, Yoo-Duk Choi, Yang-Gun Suh, Jung-Eun Kim, Youn
BMC Pulmonary Medicine.2022;[Epub] CrossRef

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A Phase II Trial of Osimertinib as the First-Line Treatment of Non–Small Cell Lung Cancer Harboring Activating EGFR Mutations in Circulating Tumor DNA: LiquidLung-O-Cohort 1: Cheol-Kyu Park, Hyun-Ju Cho, Yoo-Duk Choi, In-Jae Oh, Young-Chul Kim; Cancer Res Treat. 2021;53(1):93-103. Published online September 21, 2020; DOI: https://doi.org/10.4143/crt.2020.459

Abstract PDF Supplementary Material PubReader ePub

Purpose
Osimertinib is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for both EGFR-activating and T790M resistant mutation. The treatment efficacy of osimertinib was assessed in previously untreated patients with metastatic non–small cell lung carcinoma (NSCLC) harboring activating EGFR mutations in circulating tumor DNA (ctDNA) as well as tumor DNA.
Materials and Methods
Patients with activating EGFR mutations in their tumor DNA underwent screening with ctDNA analysis using Mutyper and Cobas v2 assays. Enrolled subjects received osimertinib 80 mg, once daily. Primary endpoint was objective response rate (ORR) and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety.
Results
Among 39 screened patients, 29 were ctDNA positive for activating EGFR mutations and 19 were enrolled (ex19del, n=11; L858R/L861Q, n=7; G719A, n=1). Median age was 70 and most patients had brain metastases (15/19, 79%). ctDNA test sensitivity for activating EGFR mutations was 74% using both methods and 62% (Mutyper) or 64% (Cobas v2) for individual methods. ORR was 68% (13/19), median PFS was 11.1 months (95% confidence interval [CI], 0.0 to 26.7), and median DoR was 17.6 months (95% CI, 3.5 to 31.7). ORR and median PFS were significantly superior with ex19del (91%; 21.9 months; 95% CI, 5.5 to 38.3) than with L858R/L861Q (43%; 5.1 months; 95% CI, 2.3 to 7.9). One patient discontinued the drug because of drug-related interstitial pneumonitis.
Conclusion
Osimertinib had favorable efficacy in the first-line treatment of metastatic NSCLC harboring activating EGFR mutations in ctDNA as well as tumor DNA.

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Xiumei Tang, Yanmei Chen, Yuan Zhu, Yuan Liu, Weimin Li, Wenzhao Wang, Zhoufeng Wang
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Xiumei Tang, Yuan Zhu, Jiayi Yan, Haoying Wu, Yanmei Chen, Yuan Liu, Huairong Tang, Wenzhao Wang, Zhoufeng Wang
Journal of Translational Genetics and Genomics.2026; 10(2): 228. CrossRef
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Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non-small Cell Lung Cancer: Junghoon Shin, Jin-Haeng Chung, Se Hyun Kim, Kyu Sang Lee, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Jeong-Ok Lee, Jin-Won Kim, Yu-Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Jong-Seok Lee; Cancer Res Treat. 2019;51(3):1086-1097. Published online November 5, 2018; DOI: https://doi.org/10.4143/crt.2018.537

Abstract PDF PubReader ePub

Purpose
Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum-based chemotherapy on tumor PD-L1 expression and its clinical implications.
Materials and Methods
We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival.
Results
The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1‒negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar’s test, p < 0.001). Increase in PD-L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival.
Conclusion
Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome.

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Acquired Resistance of MET-Amplified Non-small Cell Lung Cancer Cells to the MET Inhibitor Capmatinib: Seulki Kim, Tae Min Kim, Dong-Wan Kim, Soyeon Kim, Miso Kim, Yong-Oon Ahn, Bhumsuk Keam, Dae Seog Heo; Cancer Res Treat. 2019;51(3):951-962. Published online October 10, 2018; DOI: https://doi.org/10.4143/crt.2018.052

Abstract PDF Supplementary Material PubReader ePub

Purpose
Amplified mesenchymal-epithelial transition factor, MET, is a receptor tyrosine kinase (RTK) that has been considered a druggable target in non-small cell lung cancer (NSCLC). Although multiple MET tyrosine kinase inhibitors (TKIs) are being actively developed for MET-driven NSCLC, the mechanisms of acquired resistance to MET-TKIs have not been well elucidated. To understand the mechanisms of resistance and establish therapeutic strategies, we developed an in vitro model using the MET-amplified NSCLC cell line EBC-1.
Materials and Methods
We established capmatinib-resistant NSCLC cell lines and identified alternative signaling pathways using 3′ mRNA sequencing and human phospho-RTK arrays. Copy number alterations were evaluated by quantitative polymerase chain reaction and cell proliferation assay; activation of RTKs and downstream effectors were compared between the parental cell line EBC-1 and the resistant cell lines.
Results
We found that EBC-CR1 showed an epidermal growth factor receptor (EGFR)‒dependent growth and sensitivity to afatinib, an irreversible EGFR TKI. EBC-CR2 cells that had overexpression of EGFR-MET heterodimer dramatically responded to combined capmatinib with afatinib. In addition, EBC-CR3 cells derived from EBC-CR1 cells that activated EGFR with amplified phosphoinositide-3 kinase catalytic subunit α (PIK3CA) were sensitive to combined afatinib with BYL719, a phosphoinositide 3-kinase α (PI3Kα) inhibitor.
Conclusion
Our in vitro studies suggested that activation of EGFR signaling and/or genetic alteration of downstream effectors like PIK3CA were alternative resistance mechanisms used by capmatinib-resistant NSCLC cell lines. In addition, combined treatments with MET, EGFR, and PI3Kα inhibitors may be effective therapeutic strategies in capmatinib-resistant NSCLC patients.

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Salvage Concurrent Chemo-radiation Therapy for Loco-regional Recurrence Following Curative Surgery of Non-small Cell Lung Cancer: Kyung Hwa Lee, Yong Chan Ahn, Hongryull Pyo, Jae Myoung Noh, Seung Gyu Park, Tae Gyu Kim, Eonju Lee, Heerim Nam, Hyebin Lee, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park; Cancer Res Treat. 2019;51(2):769-776. Published online September 11, 2018; DOI: https://doi.org/10.4143/crt.2018.366

Abstract PDF PubReader ePub

Purpose
This study is to report clinical outcomes of salvage concurrent chemo-radiation therapy (CCRT) in treating patients with loco-regional recurrence (LRR) following initial complete resection of non-small cell lung cancer.
Materials and Methods
Between February 2004 and December 2016, 127 patients underwent salvage CCRT for LRR. The median radiation therapy (RT) dose was 66 Gy and clinical target volume was to cover recurrent lesion with margin without elective inclusion of regional lymphatics. Majority of patients (94.5%) received weekly platinum-based doublet chemotherapy during RT course.
Results
The median follow-up time from the start of CCRT was 25 months. The median survival duration was 49 months, and overall survival (OS) rates at 2 and 5 years were 72.9% and 43.9%. The 2- and 5-year rates of in-field failure-free survival, distant metastasis free survival, and progression free survival were 82.4% and 73.8%, 50.4% and 39.9%, and 34.6% and 22.3%, respectively. Grade ≥ 3 radiation-related esophagitis and pneumonitis occurred in 14 (11.0%) and six patients (4.7%), respectively. On both univariate and multivariate analysis, higher biologically equivalent dose (BED10) (≥ 79.2 Gy10 vs. < 79.2 Gy10; hazard ratio [HR], 0.431), smaller CTV (≤ 80 cm3 vs. > 80 cm3; HR, 0.403), and longer disease-free interval (> 1 year vs. ≤ 1 year; HR, 0.489) were significantly favorable factors for OS.
Conclusion
The current study has demonstrated that high dose salvage CCRT focused to the involved lesion only was highly effective and safe. In particular, higher BED₁₀, smaller CTV, and longer disease-free interval were favorable factors for improved survival.

Citations

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International Journal of Surgery.2024; 110(1): 238. CrossRef
Prognosis of non‐small cell lung cancer with postoperative regional lymph node recurrence
Yoichi Ohtaki, Toshiteru Nagashima, Naoko Okano, Nobuteru Kubo, Takeru Ohtaka, Noriaki Sunaga, Reiko Sakurai, Yosuke Miura, Seshiru Nakazawa, Natsuko Kawatani, Tomohiro Yazawa, Ryohei Yoshikawa, Eiji Narusawa, Ken Shirabe
Thoracic Cancer.2024; 15(11): 859. CrossRef
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Kathleen Bowes, Nick Jovanoski, Audrey E. Brown, Danilo Di Maio, Rossella Belleli, Shkun Chadda, Seye Abogunrin
Medical Oncology.2022;[Epub] CrossRef
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NaiBin Chen, QiWen Li, SiYu Wang, Mai Xiong, YiFeng Luo, Bin Wang, Li Chen, MaoSheng Lin, XiaoBo Jiang, JianLan Fang, SuPing Guo, JinYu Guo, Nan Hu, XinLei Ai, DaQuan Wang, Chu Chu, FangJie Liu, Hao Long, JunYe Wang, Bo Qiu, Hui Liu
Lung Cancer.2021; 156: 82. CrossRef
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Yoon Young Jo, Su Ssan Kim, Si Yeol Song, Eun Kyung Choi
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Cole Friedes, Nicholas Mai, Wei Fu, Chen Hu, Peijin Han, Kristen A. Marrone, K. Ranh Voong, Russell K. Hales
Lung Cancer.2020; 145: 119. CrossRef

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A Phase II Trial of Osimertinib in the Second-Line Treatment of Non-small Cell Lung Cancer with the EGFR T790M Mutation, Detected from Circulating Tumor DNA: LiquidLung-O-Cohort 2: Cheol-Kyu Park, Hyun-Ju Cho, Yoo-Duk Choi, In-Jae Oh, Young-Chul Kim; Cancer Res Treat. 2019;51(2):777-787. Published online September 7, 2018; DOI: https://doi.org/10.4143/crt.2018.387

Abstract PDF Supplementary Material PubReader ePub

Purpose
Administering the best treatment after failure of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy requires knowledge of resistance status. In this trial, treatment efficacy of osimertinib was assessed in patients with non-small cell lung carcinoma (NSCLC) harboring the T790M resistance mutation, detected from circulating tumor DNA (ctDNA) with unknown tumor mutation status.
Materials and Methods
To extract ctDNA from plasma, 15 mL of peripheral blood was withdrawn and centrifuged immediately before storage. Cobas ver. 2 and PANA Mutyper were used for ctDNA genotyping. Patients with T790M, detected from ctDNA, were enrolled and they received a oncedaily administration of osimertinib 80 mg. The primary endpoint was objective response rate (ORR), and secondary endpoints were ctDNA test sensitivity, progression-free survival (PFS), duration of response (DoR), and safety.
Results
Eighty patients with acquired resistance to prior EGFR-TKI therapies were screened. ctDNA of 21 patients showed T790M positivity, and 19 patients were enrolled. In the responseevaluable population (n=15), ORR was 66.7% (10/15). Median PFS was 8.3 months (95% confidence interval [CI], 7.9 to 8.7) and median DoR was 6.8 months (95% CI, 5.3 to 8.3) in the intent-to-treat population (n=19). No subject experienced drug-related adverse event of grades ≥ 3 or required dose reduction. The sensitivity of the ctDNA tests was 56.8% using both methods and 45.9% with either method from the estimated T790M-positive cases.
Conclusion
Osimertinib has favorable efficacy in patients with NSCLC harboring T790M, detected from ctDNA with unknown tumor mutation status, in whom disease had progressed during prior EGFR-TKI therapy.

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A Randomized, Open-Label, Phase II Study Comparing Pemetrexed Plus Cisplatin Followed by Maintenance Pemetrexed versus Pemetrexed Alone in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer after Failure of First-Line EGFR Tyrosine Kinase Inhibitor: KCSG-LU12-13: Kwai Han Yoo, Su Jin Lee, Jinhyun Cho, Ki Hyeong Lee, Keon Uk Park, Ki Hwan Kim, Eun Kyung Cho, Yoon Hee Choi, Hye Ryun Kim, Hoon-Gu Kim, Heui June Ahn, Ha Yeon Lee, Hwan Jung Yun, Jin-Hyoung Kang, Jaeheon Jeong, Moon Young Choi, Sin-Ho Jung, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn; Cancer Res Treat. 2019;51(2):718-726. Published online September 3, 2018; DOI: https://doi.org/10.4143/crt.2018.324

Abstract PDF PubReader ePub

Purpose
The optimal cytotoxic regimens have not been established for patients with non-small cell lung cancer (NSCLC) who develop disease progression on first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI).
Materials and Methods
We conducted a multi-center randomized phase II trial to compare the clinical outcomes between pemetrexed plus cisplatin combination therapy followed by maintenance pemetrexed (PC) and pemetrexed monotherapy (P) after failure of first-line EGFR-TKI. The primary objective was progression-free survival (PFS), and secondary objectives included overall response rate (ORR), overall survival (OS), health-related quality of life (HRQOL), and safety and toxicity profiles.
Results
A total of 96 patientswere randomized, and 91 patientswere treated at 14 centers in Korea. The ORR was 34.8% (16/46) for the PC arm and 17.8% (8/45) for the P arm (p=0.066). With 23.4 months of follow-up, the median PFS was 5.4 months in the PC arm and 6.4 months in the P arm (p=0.114). The median OS was 17.9 months and 15.7 months in PC and P arms, respectively (p=0.787). Adverse events ≥ grade 3 were reported in 12 patients (26.1%) in the PC arm and nine patients (20.0%) in the P arm (p=0.491). The overall time trends of HRQOL were not significantly different between the two arms.
Conclusion
The outcomes of pemetrexed therapy in NSCLC patients with disease progression after firstline EGFR-TKI might not be improved by adding cisplatin.

Citations

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Acquired ROS1 Intragenic Rearrangements as a Resistance Mechanism in EGFR-Mutant Non-Small Cell Lung Cancer: A Case Series
Po-Tsen Liu, Yi-Lin Chen, Wan-Li Chen, Chung-Liang Ho, Chun-Hui Lee
Current Oncology.2026; 33(6): 311. CrossRef
The Survival and Financial Benefit of Investigator-Initiated Trials Conducted by Korean Cancer Study Group
Bum Jun Kim, Chi Hoon Maeng, Bhumsuk Keam, Young-Hyuck Im, Jungsil Ro, Kyung Hae Jung, Seock-Ah Im, Tae Won Kim, Jae Lyun Lee, Dae Seog Heo, Sang-We Kim, Keunchil Park, Myung-Ju Ahn, Byoung Chul Cho, Hoon-Kyo Kim, Yoon-Koo Kang, Jae Yong Cho, Hwan Jung Yu
Cancer Research and Treatment.2025; 57(1): 39. CrossRef
A randomised non-comparative phase II study of atezolizumab, bevacizumab and chemotherapy in EGFR-mutant NSCLC with acquired resistance – The ETOP 15-19 ABC-lung trial
R.A. Soo, K. Vervita, M. Früh, B.C. Cho, M. Majem, D. Rodriguez Abreu, K. Ribi, A. Callejo, T. Moran, M. Domine Gomez, M. Provencio, A. Addeo, J.Y. Han, A.L. Ortega Granados, M. Reck, A. Blasco, R. Garcia Campelo, M.A. Sala González, C. Britschgi, H. Rosc
Lung Cancer.2025; 202: 108454. CrossRef
Real-world treatment outcomes in South Korean patients with epidermal growth factor receptor-mutant non-small cell lung cancer
Young Saing Kim, Eun Young Lee, Hyun Woo Lee, Jin-Hyuk Choi, Tae-Hwan Kim, Yong Won Choi, Mi Sun Ahn
The Korean Journal of Internal Medicine.2025; 40(6): 1029. CrossRef
Osimertinib with Chemotherapy in EGFR -Mutated NSCLC

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Real-world outcomes on platinum-containing chemotherapy for EGFR-mutated advanced nonsquamous NSCLC with prior exposure to EGFR tyrosine kinase inhibitors
Balazs Halmos, Pragya Rai, Jae Min, Xiaohan Hu, Diana Chirovsky, Mark Shamoun, Bin Zhao
Frontiers in Oncology.2024;[Epub] CrossRef
Clinical efficacy and safety of pemetrexed with or without either Bevacizumab or Pembrolizumab in patients with metastatic nonsquamous non–small cell carcinoma
Wang Chun Kwok, Tan Fong Cheong, Ka Yan Chiang, James Chung Man Ho, David Chi Leung Lam, Mary Sau Man Ip, Terence Chi Chun Tam
Asia-Pacific Journal of Clinical Oncology.2023; 19(1): 87. CrossRef
Factors associated with outcomes of second-line treatment for EGFR-mutant non-small-cell lung cancer patients after progression on first- or second-generation EGFR-tyrosine kinase inhibitor treatment
Cheng-Yu Chang, Chung-Yu Chen, Shih-Chieh Chang, Ching-Yi Chen, Yi-Chun Lai, Chun-Fu Chang, Yu-Feng Wei
Frontiers in Oncology.2023;[Epub] CrossRef
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Joseph N. Samuel, Christopher M. Booth, Elizabeth Eisenhauer, Michael Brundage, Scott R. Berry, Bishal Gyawali
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Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)
Ruizhu Sun, Zhansheng Hou, Yankui Zhang, Bo Jiang
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Haematological toxicity of pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung with third-space fluid
Wang Chun Kwok, Tan Fong Cheong, Ka Yan Chiang, James Chung Man Ho, David Chi Leung Lam, Mary Sau Man Ip, Terence Chi Chun Tam
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PLOS ONE.2021; 16(9): e0255133. CrossRef
Risk factors of nephrotoxicity of maintenance pemetrexed in patients with metastatic non-squamous non-small cell carcinoma of lung
Wang Chun Kwok, Ka Yan Chiang, James Chung Man Ho, David Chi Leung Lam, Mary Sau Man Ip, Terence Chi Chun Tam
Lung Cancer.2021; 162: 169. CrossRef
Impact of Value Frameworks on the Magnitude of Clinical Benefit: Evaluating a Decade of Randomized Trials for Systemic Therapy in Solid Malignancies
Ellen Cusano, Chelsea Wong, Eddy Taguedong, Marcus Vaska, Tasnima Abedin, Nancy Nixon, Safiya Karim, Patricia Tang, Daniel Y. C. Heng, Doreen Ezeife
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Wang Chun Kwok, David Chi Leung Lam, Ka Yan Chiang, James Chung Man Ho, Mary Sau Man Ip, Terence Chi Chun Tam
Journal of Chemotherapy.2020; 32(8): 429. CrossRef

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Efficacy and Safety of Afatinib for EGFR-mutant Non-small Cell Lung Cancer, Compared with Gefitinib or Erlotinib: Youjin Kim, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Jong-Mu Sun; Cancer Res Treat. 2019;51(2):502-509. Published online June 13, 2018; DOI: https://doi.org/10.4143/crt.2018.117

Abstract PDF Supplementary Material PubReader ePub

Purpose
We tried to evaluate whether there are any specific features in treatment outcomes of firstline afatinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), compared with gefitinib or erlotinib.
Materials and Methods
We analyzed patients treated with first-line afatinib, gefitinib, or erlotinib for advanced EGFR-mutant NSCLC at Samsung Medical Center between 2014 and 2016.
Results
In total, 467 patients received first-line afatinib (n=165), gefitinib (n=230), or erlotinib (n=72). Afatinib was used more often in patients with tumors harboring deletion in exon 19 (Del19), whereas the gefitinib group had more elderly, females, and never smokers. The median progression-free survival (PFS) time for afatinib, gefitinib, and erlotinib was 19.1 months, 13.7 months, and 14.0 months, respectively (p=0.001). The superior PFS of afatinib was more remarkable in subgroups of Del19 or uncommon EGFR mutations. Overall toxicity profiles of the three drugs were comparable, though more grade 3 or 4 toxicities were detected in afatinib (7.3%) compared with gefitinib (2.6%) or erlotinib (1.8%). The common grade 3 or 4 toxicities of afatinib included diarrhea (3.0%), paronychia (2.4%), and skin rash (1.8%). Dose modification was more frequently required in patients treated with afatinib (112/165, 68%), compared with gefitinib (5/230, 2%) and erlotinib (4/72, 6%). Interestingly, however, dose reduction in the afatinib group did not impair its efficacy in terms of PFS (dose reduction vs. no reduction group, 23.5 months vs. 12.4 months).
Conclusion
First-line afatinib showed satisfactory efficacy data and manageable toxicity profiles.

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MicroRNA-373 Inhibits Cell Proliferation and Invasion via Targeting BRF2 in Human Non-small Cell Lung Cancer A549 Cell Line: Lei Wang, Junfeng Qu, Li Zhou, Fei Liao, Ju Wang; Cancer Res Treat. 2018;50(3):936-949. Published online October 12, 2017; DOI: https://doi.org/10.4143/crt.2017.302

Abstract PDF PubReader ePub

Purpose
The purpose of this study was to investigate the biological role and mechanism of miR-373 targeting of TFIIB-related factor 2 (BRF2) in the regulation of non-small cell lung cancer (NSCLC) cells. MaterialsandMethods miRNA microarray chip analysis of four paired NSCLC and adjacent non-tumor tissues was performed. Quantitative real-time polymerase chain reaction (qRT-PCR) andwestern blotting were used to detect the expression levels of miR-373 and BRF2 in NSCLC tissues and cell lines. The dual-luciferase reporter method was performed to determine if BRF2 is a target of miR-373. MTT, wound-healing, Transwell, and flow cytometric assays were conducted to examine the proliferation, migration, invasion, and cell cycle progression of NSCLC A549 cells, respectively; western blotting was used to detect the expression of epithelial-mesenchymal transition (EMT)–related proteins.
Results
The miRNA microarray chip analysis demonstrated that miR-373 was down-regulated in NSCLC tissues, and this result was confirmed by qRT-PCR. Additionally, miR-373 was confirmed to target BRF2. Moreover, miR-373 expression was inversely correlated with BRF2 expression in NSCLC tissues and cell lines; both miR-373 down-regulation and BRF2 up-regulation were strongly associated with the clinicopathological features and prognosis of NSCLC patients. In vitro, overexpression of miR-373 markedly inhibited cell proliferation, migration, and invasion; up-regulated the expression of E-cadherin; and down-regulated the expression of N-cadherin and Snail in A549 cell. Knockdown BRF2 by siRNA resulted in effects similar to those caused by overexpression of miR-373.
Conclusion
MiR-373 is decreased in NSCLC, and overexpression of miR-373 can suppress cell EMT, and inhibit the proliferation, migration, and invasion of NSCLC A549 cells by targeting BRF2.

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Haibo Liu, Leng Han, Zhengjia Liu, Nan Gao
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The Effect of Hospice Consultation on Aggressive Treatment of Lung Cancer: Shin Hye Yoo, Bhumsuk Keam, Miso Kim, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo; Cancer Res Treat. 2018;50(3):720-728. Published online July 14, 2017; DOI: https://doi.org/10.4143/crt.2017.169

Abstract PDF PubReader ePub

Purpose
The aims of this study were to investigate trends of aggressive treatment of non-small cell lung cancer (NSCLC) patients at the end-of-life (EOL) during the recent 5 years and examine the relationship between hospice consultation (HC) and aggressive care.
Materials and Methods
The medical records of 789 patients with stage IIIB-IV NSCLC at Seoul National University Hospital (SNUH) who received palliative chemotherapy and died from 2010 to 2014 were retrospectively reviewed. Indicators of aggressive treatment were evaluated, and the association of HC with these indicators was analyzed.
Results
During the last 5 years, the frequency of HC increased from 26.7% to 43.6%. The time interval from last chemotherapy to death increased, and the proportion of patients who received palliative chemotherapy, visited an emergency room, were admitted to intensive care unit, during the last month of life, and died in SNUH significantly decreased over time. Referral to HC was significantly associated with lower intensive care unit admission rates, lower out-of-hospital death rates, and less use of the chemotherapy within 1 month prior to death. Overall survival did not differ by HC.
Conclusion
The pattern of cancer care nearthe EOL has become less aggressivewhen HCwas provided. The positive association of HCwith better EOL care suggests that providing HC at the optimal time might help to avoid futile aggressive treatment.

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Amanda J.W. Gibson, Haocheng Li, Adrijana D’Silva, Anifat A. Elegbede, Roxana A. Tudor, Shannon Otsuka, D. Gwyn Bebb, Winson Y. Cheung
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Nauzley C Abedini, Rachel K Hechtman, Achintya D Singh, Rafina Khateeb, Jason Mann, Whitney Townsend, Vineet Chopra
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Crizotinib versus Chemotherapy in Asian Patients with ALK-Positive Advanced Non-small Cell Lung Cancer: Makoto Nishio, Dong-Wan Kim, Yi-Long Wu, Kazuhiko Nakagawa, Benjamin J. Solomon, Alice T. Shaw, Satoshi Hashigaki, Emiko Ohki, Tiziana Usari, Jolanda Paolini, Anna Polli, Keith D. Wilner, Tony Mok; Cancer Res Treat. 2018;50(3):691-700. Published online July 6, 2017; DOI: https://doi.org/10.4143/crt.2017.280

Abstract PDF Supplementary Material PubReader ePub

Purpose
Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials.
Materials and Methods
This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and “as-treated” populations for efficacy and safety endpoints, respectively.
Results
In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity.
Conclusion
These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.

Citations

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Retrospective Molecular Epidemiology Study of PD-L1 Expression in Patients with EGFR-Mutant Non-small Cell Lung Cancer: Jong Ho Cho, Wei Zhou, Yoon-La Choi, Jong-Mu Sun, Hyejoo Choi, Tae-Eun Kim, Marisa Dolled-Filhart, Kenneth Emancipator, Mary Anne Rutkowski, Jhingook Kim; Cancer Res Treat. 2018;50(1):95-102. Published online March 17, 2017; DOI: https://doi.org/10.4143/crt.2016.591

Abstract PDF PubReader ePub

Purpose
Data are limited on programmed death ligand 1 (PD-L1) expression in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC).
Materials and Methods
We retrospectively evaluated the relationship between PD-L1 expression and recurrence-free survival (RFS) and overall survival in 319 patients with EGFR-mutant NSCLC who were treated at Samsung Medical Center from 2006 to 2014. Membranous PD-L1 expression on tumor cells was measured using the PD-L1 IHC 22C3 pharmDx antibody and reported as tumor proportion score (TPS). Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis.
Results
All patients had ≥ 1 EGFR mutation—54% in exon 19 and 39% in exon 21. Overall, 51% of patients had PD-L1–positive tumors. The prevalence of PD-L1 positivity was higher among patients with stages II-IV versus stage I disease (64% vs. 44%) and among patients with other EGFR mutations (75%) than with L858R mutation (39%) or exon 19 deletion (52%). PD-L1 positivity was associated with shorter RFS, with an adjusted hazard ratio of 1.52 (95% confidence interval [CI], 0.81 to 2.84; median, 18 months) for the PD-L1 TPS ≥ 50% group, 1.51 (95% CI, 1.02 to 2.21; median, 31 months) for the PD-L1 TPS 1%-49% group, and 1.51 (95% CI, 1.05 to 2.18) for the combined PD-L1–positive groups (TPS ≥ 1%) compared with the PD-L1–negative group (median, 35 months).
Conclusion
PD-L1 expression is associated with disease stage and type of EGFR mutation. PD-L1 positivity might be associated with worse RFS among patients with surgically treated EGFR-mutant NSCLC.

Citations

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Eriko Miyawaki, Haruyasu Murakami, Keita Mori, Nobuaki Mamesaya, Takahisa Kawamura, Haruki Kobayashi, Shota Omori, Kazushige Wakuda, Akira Ono, Hirotsugu Kenmotsu, Tateaki Naito, Toshiaki Takahashi
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Yoon Ah Cho, Yoon‐La Choi, Inwoo Hwang, Kyungjong Lee, Jong Ho Cho, Joungho Han
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Impact of EGFR mutation on the clinical efficacy of PD-1 inhibitors in patients with pulmonary adenocarcinoma
Jang Ho Cho, Hyun Ae Jung, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Jong-Mu Sun
Journal of Cancer Research and Clinical Oncology.2019; 145(5): 1341. CrossRef
The canonical TGF-β/Smad signalling pathway is involved in PD-L1-induced primary resistance to EGFR-TKIs in EGFR-mutant non-small-cell lung cancer
Yang Zhang, Yuanyuan Zeng, Ting Liu, Wenwen Du, Jianjie Zhu, Zeyi Liu, Jian-an Huang
Respiratory Research.2019;[Epub] CrossRef
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Role of Adjuvant Thoracic Radiation Therapy and Full Dose Chemotherapy in pN2 Non-small Cell Lung Cancer: Elucidation Based on Single Institute Experience: Hyojung Park, Dongryul Oh, Yong Chan Ahn, Hongryull Pyo, Jae Myung Noh, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Hong Kwan Kim, Yong Soo Choi, Jhingook Kim, Jae Ill Zo, Young Mog Shim; Cancer Res Treat. 2017;49(4):880-889. Published online December 12, 2016; DOI: https://doi.org/10.4143/crt.2016.442

Abstract PDF PubReader ePub

Purpose
The optimal adjuvant therapy modality for treating pN2 non-small cell lung cancer patients has not yet been established. In this study, the authors investigated clinical outcomes following three different adjuvant therapy modalities.
Materials and Methods
From January 2006 to December 2012, 240 patients with cN0/1 disease were found to have pN2 disease following curative resection and received one of three adjuvant therapy modalities:thoracic radiation therapy (TRT) and concurrent chemotherapy (CTx) (CCRT) (group I), CCRT plus consolidation CTx (group II), and CTx alone (group III). TRT was delivered to 155 patients (groups I/II), and full dose CTxwas delivered to 172 patients either as a consolidative or a sole modality (group II/III).
Results
During 30 months of median follow-up, 44 patients died and 141 developed recurrence. The 5-year overall survival (OS), locoregional control (LRC), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates of all patients were 76.2%, 80.7%, 36.4%, and 29.6%, respectively. There was no difference in OS among groups. TRT (groups I/II) significantly improved LRC, full dose CTx (groups II/III) did DMFS, and CCRT plus consolidation CTx (group II) did DFS, respectively.
Conclusion
The current study could support that TRT could improve LRC and full dose CTx could improve DMFS and that CCRT plus consolidation CTx could improve DFS.

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Survey of the Patterns of Using Stereotactic Ablative Radiotherapy for Early-Stage Non-small Cell Lung Cancer in Korea: Sanghyuk Song, Ji Hyun Chang, Hak Jae Kim, Yeon Sil Kim, Jin Hee Kim, Yong Chan Ahn, Jae-Sung Kim, Si Yeol Song, Sung Ho Moon, Moon June Cho, Seon Min Youn; Cancer Res Treat. 2017;49(3):688-694. Published online October 31, 2016; DOI: https://doi.org/10.4143/crt.2016.219

Abstract PDF Supplementary Material PubReader ePub

Purpose
Stereotactic ablative radiotherapy (SABR) is an effective emerging technique for early-stage non-small cell lung cancer (NSCLC). We investigated the current practice of SABR for early-stage NSCLC in Korea.
Materials and Methods
We conducted a nationwide survey of SABR for NSCLC by sending e-mails to all board-certified members of the Korean Society for Radiation Oncology. The survey included 23 questions focusing on the technical aspects of SABR and 18 questions seeking the participants’ opinions on specific clinical scenarios in the use of SABR for early-stage NSCLC. Overall, 79 radiation oncologists at 61/85 specialist hospitals in Korea (71.8%) responded to the survey.
Results
SABR was used at 33 institutions (54%) to treat NSCLC. Regarding technical aspects, the most common planning methods were the rotational intensity-modulated technique (59%) and the static intensity-modulated technique (49%). Respiratory motion was managed by gating (54%) or abdominal compression (51%), and 86% of the planning scans were obtained using 4-dimensional computed tomography. In the clinical scenarios, the most commonly chosen fractionation schedule for peripherally located T1 NSCLC was 60 Gy in four fractions. For centrally located tumors and T2 NSCLC, the oncologists tended to avoid SABR for radiotherapy, and extended the fractionation schedule.
Conclusion
The results of our survey indicated that SABR is increasingly being used to treat NSCLC in Korea. However, there were wide variations in the technical protocols and fractionation schedules of SABR for early-stage NSCLC among institutions. Standardization of SABR is necessary before implementing nationwide, multicenter, randomized studies.

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