Cancer Research and Treatment

Original Articles

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; Received July 25, 2024 Accepted January 22, 2025 Published online January 24, 2025; DOI: https://doi.org/10.4143/crt.2024.700 [Accepted]

Abstract PDF: 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 8 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 7 (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-value=0.001) and OP to LR+Meta (λ₀₃, p-value = 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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Lung and Thoracic cancer

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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Analytical and Clinical Validation of a Highly Sensitive NGS-Based ctDNA Assay with Real-World Concordance in Non–Small Cell Lung Cancer: Hanbaek Yi, Jeonghwan Youk, Yoojoo Lim, Hanseong Roh, Dongsoo Kyung, Hwang-Phill Kim, Duhee Bang, Bhumsuk Keam, Tae-Min Kim, Miso Kim, Dong-Wan Kim, Tae-You Kim; Cancer Res Treat. 2024;56(3):765-773. Published online January 8, 2024; DOI: https://doi.org/10.4143/crt.2023.1294

Abstract PDF Supplementary Material PubReader ePub

Purpose
There have been needs to improve the sensitivity of liquid biopsy. This report aims to report the analytical and clinical validation of a next-generation sequencing (NGS)–based circulating tumor DNA (ctDNA) assay.
Materials and Methods
Analytical validation was conducted in vitro by evaluating the limit of detection (LOD), precision, and specificity for various genomic aberrations. The real-world performance in non–small cell lung cancer (NSCLC) was assessed by comparing the results of AlphaLiquid100 to the tissue-based results.
Results
The LODs with 30 ng input DNA were 0.11%, 0.11%, 0.06%, 0.21%, and 2.13 copies for detecting single nucleotide variants, insertions, deletions, fusions, and copy number alterations (CNA), respectively. Quantitatively, single nucleotide variants/insertions and deletions, fusions, and CNAs showed a good correlation (R²=0.91, 0.40, and 0.65; y=0.95, 1.06, and 1.19) to the manufacturer’s values, and per-base specificities for all types of variants were near 100%. In real-world NSCLC (n=122), key actionable mutations in NSCLC were detected in 60.7% (74/122) with the ctDNA assay. Comparative analysis against the NGS-based tissue results for all key mutations showed positive percent agreement (PPA) of 85.3%. For individual genes, the PPA was as high as 95.7% for epidermal growth factor receptor (EGFR) mutations and 83.3% for ALK translocations. AlphaLiquid100 detected drug-sensitive EGFR mutation at a variant allele frequency as low as 0.02% and also identified an EGFR mutation in a case where tissue sample missed. Blood samples collected post-targeted therapies revealed additional acquired mutations.
Conclusion
The AlphaLiquid100 ctDNA assay demonstrates robust analytical validity, offering clinically important information for NSCLC patients.

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Next-generation sequencing impact on cancer care: applications, challenges, and future directions
Mariano Zalis, Gilson Gabriel Viana Veloso, Pedro Nazareth Aguiar Jr., Nathalia Gimenes, Marina Xavier Reis, Silvio Matsas, Carlos Gil Ferreira
Frontiers in Genetics.2024;[Epub] CrossRef
Profiling Cell-Free DNA from Malignant Pleural Effusion for Oncogenic Driver Mutations in Patients with Treatment-Naive Stage IV Adenocarcinoma: A Multicenter Prospective Study
Shih-Chieh Chang, Yu-Feng Wei, Chung-Yu Chen, Yi-Chun Lai, Po-Wei Hu, Jui-Chi Hung, Cheng-Yu Chang
Molecular Diagnosis & Therapy.2024; 28(6): 803. CrossRef
Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer
Sohyun Hwang, Seonjeong Woo, Beodeul Kang, Haeyoun Kang, Jung Sun Kim, Sung Hwan Lee, Chang Il Kwon, Dong Soo Kyung, Hwang-Phill Kim, Gwangil Kim, Chan Kim, Hong Jae Chon
Journal of Hepatology.2024;[Epub] CrossRef

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Clinical Effect of Endosonography on Overall Survival in Patients with Radiological N1 Non–Small Cell Lung Cancer: Bo-Guen Kim, Byeong-Ho Jeong, Goeun Park, Hong Kwan Kim, Young Mog Shim, Sun Hye Shin, Kyungjong Lee, Sang-Won Um, Hojoong Kim, Jong Ho Cho; Cancer Res Treat. 2024;56(2):502-512. Published online December 4, 2023; DOI: https://doi.org/10.4143/crt.2023.840

Abstract PDF Supplementary Material PubReader ePub: Purpose
It is unclear whether performing endosonography first in non–small cell lung cancer (NSCLC) patients with radiological N1 (rN1) has any advantages over surgery without nodal staging. We aimed to compare surgery without endosonography to performing endosonography first in rN1 on the overall survival (OS) of patients with NSCLC.
Materials and Methods
This is a retrospective analysis of patients with rN1 NSCLC between 2013 and 2019. Patients were divided into ‘no endosonography’ and ‘endosonography first’ groups. We investigated the effect of nodal staging through endosonography on OS using propensity score matching (PSM) and multivariable Cox proportional hazard regression analysis.
Results
In the no endosonography group, pathologic N2 occurred in 23.0% of patients. In the endosonography first group, endosonographic N2 and N3 occurred in 8.6% and 1.6% of patients, respectively. Additionally, 51 patients were pathologic N2 among 249 patients who underwent surgery and mediastinal lymph node dissection (MLND) in endosonography first group. After PSM, the 5-year OSs were 68.1% and 70.6% in the no endosonography and endosonography first groups, respectively. However, the 5-year OS was 80.2% in the subgroup who underwent surgery and MLND of the endosonography first group. Moreover, in patients receiving surgical resection with MLND, the endosonography first group tended to have a better OS than the no endosonography group in adjusted analysis using various models.
Conclusion
In rN1 NSCLC, preoperative endosonography shows better OS than surgery without endosonography. For patients with rN1 NSCLC who are candidates for surgery, preoperative endosonography may help improve survival through patient selection.

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Tissue and Plasma-Based Highly Sensitive Blocker Displacement Amplicon Nanopore Sequencing for EGFR Mutations in Lung Cancer: Patinya Akkhasutthikun, Pornchai Kaewsapsak, Pattaraporn Nimsamer, Pavit Klomkliew, Suthida Visedthorn, Pragwalai Chanchaem, Chinachote Teerapakpinyo, Sunchai Payungporn, Sutima Luangdilok; Cancer Res Treat. 2024;56(2):455-463. Published online November 20, 2023; DOI: https://doi.org/10.4143/crt.2023.1108

Abstract PDF Supplementary Material PubReader ePub

Purpose
The epidermal growth factor receptor (EGFR) mutation is a widely prevalent oncogene driver in non–small cell lung cancer (NSCLC) in East Asia. The detection of EGFR mutations is a standard biomarker test performed routinely in patients with NSCLC for the selection of targeted therapy. Here, our objective was to develop a portable new technique for detecting EGFR (19Del, T790M, and L858R) mutations based on Nanopore sequencing.
Materials and Methods
The assay employed a blocker displacement amplification (BDA)–based polymerase chain reaction (PCR) technique combined with Nanopore sequencing to detect EGFR mutations. Mutant and wild-type EGFR clones were generated from DNA from H1650 (19Del heterozygous) and H1975 (T790M and L858R heterozygous) lung cancer cell lines. Then, they were mixed to assess the performance of this technique for detecting low variant allele frequencies (VAFs). Subsequently, formalin-fixed, paraffin-embedded (FFPE) tissue and cell-free DNA (cfDNA) from patients with NSCLC were used for clinical validation.
Results
The assay can detect low VAF at 0.5% mutant mixed in wild-type EGFR. Using FFPE DNA, the concordance rates of EGFR 19Del, T790M, and L858R mutations between our method and Cobas real-time PCR were 98.46%, 100%, and 100%, respectively. For cfDNA, the concordance rates of EGFR 19Del, T790M, and L858R mutations between our method and droplet digital PCR were 94.74%, 100%, and 100%, respectively.
Conclusion
The BDA amplicon Nanopore sequencing is a highly accurate and sensitive method for the detection of EGFR mutations in clinical specimens.

Citations

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Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications
Hua-Qi Si, Peng Wang, Fei Long, Wei Zhong, Yuan-Dong Meng, Yuan Rong, Xiang-Yu Meng, Fu-Bing Wang
Molecular Cancer.2024;[Epub] CrossRef

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The Real-World Outcome of First Line Atezolizumab in Extensive-Stage Small Cell Lung Cancer: A Multicenter Prospective Cohort Study: Myeong Geun Choi, Yeon Joo Kim, Jae Cheol Lee, Wonjun Ji, In-Jae Oh, Sung Yong Lee, Seong Hoon Yoon, Shin Yup Lee, Jeong Eun Lee, Eun Young Kim, Chang-Min Choi; Cancer Res Treat. 2024;56(2):422-429. Published online October 23, 2023; DOI: https://doi.org/10.4143/crt.2023.913

Abstract PDF Supplementary Material PubReader ePub: Purpose
The addition of immune checkpoint inhibitors to chemotherapy has improved survival outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC). However, their real-world effectiveness remains unknown. Therefore, we investigated the effectiveness of atezolizumab plus chemotherapy in ES-SCLC in actual clinical settings.
Materials and Methods
In this multicenter prospective cohort study, patients with ES-SCLC receiving or scheduled to receive atezolizumab in combination with etoposide and carboplatin were enrolled between June 2021 and August 2022. The primary outcomes were progression-free survival (PFS) and the 1-year overall survival (OS) rate.
Results
A total of 100 patients with ES-SCLC were enrolled from seven centers. Median age was 69 years, and 6% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2. The median PFS was 6.0 months, the 1-year OS rate was 62.2%, and the median OS was 13.5 months. An ECOG PS of 2-3 and progressive disease as the best response were poor prognostic factors for PFS, while an ECOG PS of 2-3 and brain metastasis were associated with poor prognosis for OS. In addition, consolidative thoracic radiotherapy was found to be an independent favorable prognostic factor for OS (hazard ratio, 0.336; p=0.021). Grade ≥ 3 treatment-related adverse events were observed in 7% of patients, with treatment-related deaths occurring in 2% of patients.
Conclusion
We provided evidence of the favorable real-world effectiveness and safety of atezolizumab plus chemotherapy in ES-SCLC patients, including in the elderly and those with poor ECOG PS. Additional consolidative thoracic radiotherapy may also benefit ES-SCLC patients.

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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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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.

Citations

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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
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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Expanded Access Program Pralsetinib in Advanced Non–Small Cell Lung Cancer with Rearranged during Transfection (RET) Gene Rearrangement: Youngkyung Jeon, Hyun Ae Jung, Sehhoon Park, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Se-Hoon Lee; Cancer Res Treat. 2023;55(4):1144-1151. Published online May 22, 2023; DOI: https://doi.org/10.4143/crt.2023.403

Abstract PDF PubReader ePub

Purpose
Rearranged during transfection (RET) gene rearrangement is a well-known driver event in non–small cell lung cancer (NSCLC). Pralsetinib is a selective inhibitor of RET kinase and has shown efficacy in oncogenic RET-altered tumors. This study evaluated the efficacy and safety of expanded access program (EAP) use of pralsetinib in pretreated, advanced NSCLC patients with RET rearrangement.
Materials and Methods
Patients who received pralsetinib as part of the EAP at Samsung Medical Center were evaluated through a retrospective chart review. The primary endpoint was overall response rate (ORR) per the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1 guidelines. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS), and safety profiles.
Results
Between April 2020 and September 2021, 23 of 27 patients were enrolled in the EAP study. Two patients who were not analyzed due to brain metastasis and two patients whose expected survival was within 1 month were excluded from the analysis. After a median follow-up period of 15.6 months (95% confidence interval [CI], 10.0 to 21.2), ORR was 56.5%, the median PFS was 12.1 months (95% CI, 3.3 to 20.9), and the 12-month OS rate was 69.6%. The most frequent treatment-related adverse events (TRAEs) were edema (43.5%) and pneumonitis (39.1%). A total of 8.7% of patients experienced extra-pulmonary tuberculosis. TRAEs with a common grade of three or worse were neutropenia (43.5%) and anemia (34.8%). Dose reduction was required in nine patients (39.1%).
Conclusion
Pralsetinib presents a clinical benefit when used in patients with RET-rearranged NSCLC, consistent with a pivotal study.

Citations

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Real-World Outcomes of Pralsetinib in RET Fusion-Positive NSCLC
Francesca Lucibello, Valérie Gounant, Mihaela Aldea, Michaël Duruisseaux, Maurice Perol, Christos Chouaid, Jaafar Bennouna, Vincent Fallet, Aldo Renault, Florian Guisier, Etienne Giroux-Leprieur, Marie Wislez, Anne-Claire Toffart, Julien Mazieres, Clémenc
JTO Clinical and Research Reports.2025; 6(1): 100743. CrossRef
Clinical evidence and adverse event management update of patients with RET- rearranged advanced non-small-cell lung cancer (NSCLC) treated with pralsetinib
Giuseppe Lo Russo, Paolo Bironzo, Chiara Bennati, Laura Bonanno, Annamaria Catino, Giulio Metro, Iacopo Petrini, Marco Russano, Antonio Passaro
Critical Reviews in Oncology/Hematology.2024; 194: 104243. CrossRef
RET Fusion Testing in Patients With NSCLC: The RETING Study
Esther Conde, Susana Hernandez, Jose Luis Rodriguez Carrillo, Rebeca Martinez, Marta Alonso, Daniel Curto, Beatriz Jimenez, Alejandra Caminoa, Amparo Benito, Pilar Garrido, Sergi Clave, Edurne Arriola, Isabel Esteban-Rodriguez, Javier De Castro, Irene San
JTO Clinical and Research Reports.2024; 5(4): 100653. CrossRef
Efficacy and safety of pralsetinib in patients with RET fusion positive non–small cell lung cancer: An observational real world study
Dehua Liao, Minghui Long, Jiwen Zhang, Xingyu Wei, Fei Li, Ting Yan, Desong Yang
Lung Cancer.2024; 196: 107936. 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.

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A Randomized Phase II Study of Irinotecan Plus Cisplatin with or without Simvastatin in Ever-Smokers with Extended Disease Small Cell Lung Cancer: Youngjoo Lee, Soo-Hyun Lee, Geon Kook Lee, Eun Jin Lim, Ji-Youn Han; Cancer Res Treat. 2023;55(3):885-893. Published online March 20, 2023; DOI: https://doi.org/10.4143/crt.2023.283

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)–small cell lung cancer (SCLC).
Materials and Methods
This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥ 100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate.
Results
Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9% in the control group. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046).
Conclusion
Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

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Cardiovascular/anti‐inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta‐analysis of randomized trials
David J. Benjamin, Alyson Haslam, Vinay Prasad
Cancer Medicine.2024;[Epub] CrossRef
Repurposing simvastatin in cancer treatment: an updated review on pharmacological and nanotechnological aspects
Nargis Ara, Abdul Hafeez, Shom Prakash Kushwaha
Naunyn-Schmiedeberg's Archives of Pharmacology.2024; 397(10): 7377. CrossRef
Strategies to Target Chemoradiotherapy Resistance in Small Cell Lung Cancer
Tony Yu, Benjamin H. Lok
Cancers.2024; 16(20): 3438. CrossRef
β-blockers and statins: exploring the potential off-label applications in breast, colorectal, prostate, and lung cancers
Pedro Gabriel Senger Braga, Janaína da Silva Vieira, Aline Rachel Bezerra Gurgel, Patricia Chakur Brum
Frontiers in Pharmacology.2024;[Epub] CrossRef
Statins—From Fungi to Pharmacy
Anna Sadowska, Patryk Osiński, Alicja Roztocka, Karolina Kaczmarz-Chojnacka, Ewa Zapora, Diana Sawicka, Halina Car
International Journal of Molecular Sciences.2023; 25(1): 466. CrossRef

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Efficacy of Prophylactic Cranial Irradiation According to the Risk of Extracranial Recurrence in Limited-Stage Small Cell Lung Cancer: Tae Hoon Lee, Joo-Hyun Chung, Hong-Gyun Wu, Suzy Kim, Joo Ho Lee, Bhumsuk Keam, Jin-Soo Kim, Ki Hwan Kim, Byoung Hyuck Kim, Hak Jae Kim; Cancer Res Treat. 2023;55(3):875-884. Published online February 24, 2023; DOI: https://doi.org/10.4143/crt.2022.1583

Abstract PDF Supplementary Material PubReader ePub

Purpose
We aimed to evaluate the effectiveness of prophylactic cranial irradiation (PCI) for “early brain metastasis”, which occurs before extracranial recurrence (ECR), and “late brain metastasis”, which occurs after ECR, in limited-stage small cell lung cancer (LS-SCLC).
Materials and Methods
We retrospectively analyzed 271 LS-SCLC patients who underwent definitive chemoradiation. All patients were initially staged with brain magnetic resonance imaging and positron emission tomography. Intracranial recurrence (ICR), ECR, progression-free rate (PFR), and overall survival (OS) were analyzed as clinical endpoints. The competing risk of the first recurrence with ICR (ICRfirst) was evaluated. Significantly associated variables in multivariate analysis of ECR were considered as ECR risk factors. Patients were stratified according to the number of ECR risk factors.
Results
The application of PCI was associated with higher PFR (p=0.008) and OS (p=0.045). However, PCI was not associated with any of the clinical endpoints in multivariate analysis. The competing risk of ICRfirst was significantly decreased with the application of PCI (hazard ratio, 0.476; 95% confidence interval, 0.243 to 0.931; p=0.030). Stage III disease, sequential, and stable disease after thoracic radiation were selected as ECR risk factors. For patients without these risk factors, the application of PCI was significantly associated with increased OS (p=0.048) and a decreased risk of ICRfirst (p=0.026).
Conclusion
PCI may play a role in preventing early brain metastasis rather than late brain metastasis after ECR, suggesting that only patients with a low risk of ECR may currently benefit from PCI.

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Efficacy evaluation of prophylactic cranial irradiation for limited stage small‑cell lung cancer in the magnetic resonance imaging era: A meta‑analysis
Lihua Shao, Yumei Dong, Meiqiao Jiang, Haixia Song, Yuexiao Qi, Liyun Guo, Jinhui Tian, Shihong Wei
Oncology Letters.2025;[Epub] 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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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
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
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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

4,738 View
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Optimal Definition of Oligometastasis Showing Survival Benefits of Local Therapies during Tyrosine Kinase Inhibitor Treatment: Yoon Jung Jang, Dong-gon Hyun, Wonjun Ji, Chang-Min Choi, Shinkyo Yoon, Dae Ho Lee, Sang-We Kim, Jae Cheol Lee; Cancer Res Treat. 2023;55(2):468-478. Published online November 28, 2022; DOI: https://doi.org/10.4143/crt.2022.1342

Abstract PDF Supplementary Material PubReader ePub: Purpose
We aimed to investigate the feasibility of four criteria on oligometastasis (OM) concerning clear survival benefits of local therapy (LT) during tyrosine kinase inhibitor (TKI) treatment in non–small cell lung cancer (NSCLC).
Materials and Methods
This single-center, retrospective study included patients with advanced NSCLC who received LT because of OM during TKI treatment at Asan Medical Center from January 2011 to December 2020. At the application of LT OM was classified according to four criteria: TNM, European Organization for Research and Treatment of Cancer Lung Cancer Group (EORTC-LCG), National Comprehensive Network (NCCN), and ORGAN. We compared survival outcomes between patients with and without OM.
Results
The median overall survival of the 117 patients included in the analysis was 70.8 months (95% confidence interval [CI], 56.6 to 85.1). The patients with OM meeting all four criteria (hazard ratio [HR] with 95% CI of TNM criteria 0.24 with 0.10-0.57; p=0.001, EORTC-LCG criteria 0.34 with 0.17-0.67; p=0.002, NCCN criteria 0.41 with 0.20-0.86; p=0.018 and ORGAN criteria 0.33 with 0.18-0.60; p < 0.001) had significantly longer survival compared with patients who did not after adjusting for confounding factors. Furthermore, increasing the number of extra-thoracic metastatic organs to two or more were independent predictive factors for worse survival outcomes (2 organs: HR, 3.51; 95% CI, 1.01 to 12.14; p=0.048; 3 organs: HR, 4.31; 95% CI, 0.94 to 19.73; p=0.060; 4 organs: HR, 24.47; 95% CI, 5.08 to 117.80; p < 0.001).
Conclusion
Patients with OM defined by all four criteria showed prognostic benefits from LT during TKI therapy.

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The Role of Adjuvant Therapy Following Surgical Resection of Small Cell Lung Cancer: A Multi-Center Study: Seong Yong Park, Samina Park, Geun Dong Lee, Hong Kwan Kim, Sehoon Choi, Hyeong Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park, Tae Hee Hong, Yong Soo Choi, Jhingook Kim, Jong Ho Cho, Young Mog Shim, Jae Ill Zo, Kwon Joong Na, In Kyu Park, Chang Hyun Kang, Young-Tae Kim, Byung Jo Park, Chang Young Lee, Jin Gu Lee, Dae Joon Kim, Hyo Chae Paik; Cancer Res Treat. 2023;55(1):94-102. Published online June 9, 2022; DOI: https://doi.org/10.4143/crt.2022.290

Abstract PDF Supplementary Material PubReader ePub

Purpose
This multi-center, retrospective study was conducted to evaluate the long-term survival in patients who underwent surgical resection for small cell lung cancer (SCLC) and to identify the benefit of adjuvant therapy following surgery.
Materials and Methods
The data of 213 patients who underwent surgical resection for SCLC at four institutions were retrospectively reviewed. Patients who received neoadjuvant therapy or an incomplete resection were excluded.
Results
The mean patient age was 65.29±8.93 years, and 184 patients (86.4%) were male. Lobectomies and pneumonectomies were performed in 173 patients (81.2%), and 198 (93%) underwent systematic mediastinal lymph node dissections. Overall, 170 patients (79.8%) underwent adjuvant chemotherapy, 42 (19.7%) underwent radiotherapy to the mediastinum, and 23 (10.8%) underwent prophylactic cranial irradiation. The median follow-up period was 31.08 months (interquartile range, 13.79 to 64.52 months). The 5-year overall survival (OS) and disease-free survival were 53.4% and 46.9%, respectively. The 5-year OS significantly improved after adjuvant chemotherapy in all patients (57.4% vs. 40.3%, p=0.007), and the survival benefit of adjuvant chemotherapy was significant in patients with negative node pathology (70.8% vs. 39.7%, p=0.004). Adjuvant radiotherapy did not affect the 5-year OS (54.6% vs. 48.5%, p=0.458). Age (hazard ratio [HR], 1.032; p=0.017), node metastasis (HR, 2.190; p < 0.001), and adjuvant chemotherapy (HR, 0.558; p=0.019) were associated with OS.
Conclusion
Adjuvant chemotherapy after surgical resection in patients with SCLC improved the OS, though adjuvant radiotherapy to the mediastinum did not improve the survival or decrease the locoregional recurrence rate.

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Application of postoperative adjuvant radiotherapy in limited-stage small cell lung cancer: A systematic review and meta-analysis
Chuanhao Zhang, Genghao Zhao, Huajian Wu, Jianing Jiang, Wenyue Duan, Zhijun Fan, Zhe Wang, Ruoyu Wang
Radiotherapy and Oncology.2024; 193: 110123. CrossRef
A 15-Gene-Based Risk Signature for Predicting Overall Survival in SCLC Patients Who Have Undergone Surgical Resection
Sevcan Atay
Cancers.2023; 15(21): 5219. 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.

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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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Clemente Humberto Zúñiga, Blanca Isaura Acosta, Rufino Menchaca, Cesar A. Amescua, Sean Hong, Lucia Hui, Minchan Gil, Yong-hee Rhee, Sangwook Yoon, Minji Kim, Paul Y. Chang, Yong Man Kim, Paul Y. Song, Katia Betito
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Myeong Geun Choi, Gun Woo Son, Mi Young Choi, Jae Seob Jung, Jin Kyung Rho, Wonjun Ji, Byeong Gon Yoon, Jong-Min Jo, Yong Man Kim, Dae-Hyun Ko, Jae Cheol Lee, Chang-Min Choi
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Spencer M. Erickson, Benjamin M. Manning, Akhilesh Kumar, Manish R. Patel
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Martina Imbimbo, Laureline Wetterwald, Alex Friedlaender, Kaushal Parikh, Alfredo Addeo
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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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Shoubao Ma, Michael A. Caligiuri, Jianhua Yu
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Xin Chen, Lei Jiang, Xuesong Liu
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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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Population-based epidemiological projections of rheumatoid arthritis in Germany until 2040
J Wang, S Vordenbäumen, M Schneider, R Brinks
Scandinavian Journal of Rheumatology.2024; 53(3): 161. CrossRef
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
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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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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
Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence
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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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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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
The Oncologist.2025;[Epub] 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
Frontiers in Oncology.2024;[Epub] CrossRef
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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ADENOCARCINOMA PULMONAR - ASPECTOS EPIDEMIOLÓGICOS, FISIOPATOLÓGICOS E TERAPÊUTICOS
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

6,940 View
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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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Non-small cell lung cancer: an update on emerging EGFR-targeted therapies
Valentina Favorito, Ilaria Ricciotti, Andrea De Giglio, Laura Fabbri, Renata Seminerio, Alessandro Di Federico, Eleonora Gariazzo, Silvia Costabile, Giulio Metro
Expert Opinion on Emerging Drugs.2024; 29(2): 139. CrossRef
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Juan Carlos Restrepo, Darly Martínez Guevara, Andrés Pareja López, John Fernando Montenegro Palacios, Yamil Liscano
Cancers.2024; 16(13): 2338. CrossRef
ctDNA SNORD3F Hypermethylation is a Prognostic Indicator in EGFR-TKI-Treated Advanced Non-Small Cell Lung Cancer
Bin Liu, Bingtian Zhao, Yan Yin, Yan Jiang, Xue Feng, Lei Wang, Liang Zhai, Guangxin Liu, Dongsheng Shi, Jianwen Qin
Cancer Management and Research.2024; Volume 16: 1405. 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
Effect of Osimertinib on CTCs and ctDNA in EGFR Mutant Non-Small Cell Lung Cancer Patients: The Prognostic Relevance of Liquid Biopsy
Galatea Kallergi, Emmanouil Kontopodis, Aliki Ntzifa, Núria Jordana-Ariza, Niki Karachaliou, Evangelia Pantazaka, Haris A. Charalambous, Amanda Psyrri, Emily Tsaroucha, Ioannis Boukovinas, Anna Koumarianou, Dora Hatzidaki, Evi Lianidou, Vassilis Georgouli
Cancers.2022; 14(6): 1574. CrossRef

8,478 View
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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.

Citations

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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.

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Yoon Young Jo, Su Ssan Kim, Si Yeol Song, Eun Kyung Choi
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Propensity score adjusted analysis of patients with isolated locoregional recurrence versus de novo locally advanced NSCLC treated with definitive therapy
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.

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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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Cam Phuong Pham, Thi Thai Hoa Nguyen, Anh Tu Do, Tuan Khoi Nguyen, Thi Anh Thu Hoang, Tuan Anh Le, Dinh Thy Hao Vuong, Dac Nhan Tam Nguyen, Van Khiem Dang, Thi Oanh Nguyen, Van Luan Pham, Minh Hai Nguyen, Thi Huyen Trang Vo, Hung Kien Do, Ha Thanh Vu, Thi
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Journal of Thoracic Oncology.2024; 19(7): 973. CrossRef
Real-world analysis of afatinib as a first-line treatment for patients with advanced stage non-small-cell lung cancer with uncommon EGFR mutations: a multicenter study in Vietnam
Van Luan Pham, Tuan Anh Le, Cam Phuong Pham, Thi Thai Hoa Nguyen, Anh Tu Do, Tuan Khoi Nguyen, Minh Hai Nguyen, Thi Anh Thu Hoang, Dinh Thy Hao Vuong, Dac Nhan Tam Nguyen, Van Khiem Dang, Thi Oanh Nguyen, Thi Huyen Trang Vo, Hung Kien Do, Ha Thanh Vu, Thi
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Noha Ryad, Ayman Abo Elmaaty, Ibrahim M Ibrahim, Ali Hassan Ahmed Maghrabi, Maryam Abdulrahman Yahya Alahdal, Rasha Mohammed Saleem, Islam Zaki, Lina M A Abdel Ghany
Future Medicinal Chemistry.2024; 16(11): 1087. CrossRef
Lung cancer and pregnancy
A. L. Chernyshova, A. A. Chernyakov, Ju. M. Trushjuk, O. S. Dil, A. E. Chernyshova
PULMONOLOGIYA.2024; 34(4): 544. CrossRef
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Current Research in Toxicology.2024; 7: 100194. CrossRef
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Noha Ryad, Ayman Abo Elmaaty, Samy Selim, Mohammed S. Almuhayawi, Soad K. Al Jaouni, Mohamed S. Abdel-Aziz, Arwa Sultan Alqahtani, Islam Zaki, Lina M. A. Abdel Ghany
RSC Advances.2024; 14(46): 34005. CrossRef
Treatment Patterns, Clinical Outcomes and Health Care Resource Utilisation in Patients with EGFR-mutated Metastatic Non-Small Cell Lung Cancer: A Real-World Study in South Korea
Cliff Molife, Jae Min Cho, Jennifer Lapthorn, Min Ju Kang, Yulia D’yachkova, Sangmi Kim, Sam Colman, Saerom Kim, Agota Szende, Ji Hyun Park, Hee Kyung Ahn, Min Hee Hong, Kaisa-Leena Taipale, Hye Ryun Kim
Drugs - Real World Outcomes.2023; 10(1): 131. CrossRef
Case report: Osimertinib administration during pregnancy in a woman with advanced EGFR-mutant non-small cell lung cancer
Pamela Soberanis Pina, Luis Lara-Mejía, Venecia Matias-Cruz, Feliciano Barrón, Andrés F. Cardona, Luis E. Raez, Eduardo Rios-Garcia, Oscar Arrieta
Frontiers in Oncology.2023;[Epub] CrossRef
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Gian Marco Leone, Saverio Candido, Alessandro Lavoro, Silvia Vivarelli, Giuseppe Gattuso, Daniela Calina, Massimo Libra, Luca Falzone
Pharmaceutics.2023; 15(4): 1252. CrossRef
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Vineeth Tatineni, Patrick J. O’Shea, Shreya Saxena, Atulya A. Khosla, Ahmad Ozair, Rupesh R. Kotecha, Xuefei Jia, Yasmeen Rauf, Erin S. Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom, Manmeet S. Ahluwalia
Cancers.2023; 15(11): 3015. CrossRef
Management of diarrhea induced by EGFR-TKIs in advanced lung adenocarcinoma
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Therapeutic Advances in Medical Oncology.2023;[Epub] CrossRef
Design and Synthesis of Novel Pyrazolopyrimidine Candidates As Promising EGFR-T790M Inhibitors and Apoptosis Inducers
Ahmed A Gaber, Marwa Sharaky, Ayman Abo Elmaaty, Mohamed M Hammouda, Ahmed AE Mourad, Samy Y Elkhawaga, Mahmoud Mohamed Mokhtar, Amr S Abouzied, Mai AE Mourad, Ahmed A Al-Karmalawy
Future Medicinal Chemistry.2023; 15(19): 1773. CrossRef
Do patient characteristics affect EGFR tyrosine kinase inhibitor treatment outcomes? A network meta‐analysis of real‐world survival outcomes of East Asian patients with advanced non‐small cell lung cancer treated with first‐line EGFR‐TKIs
Huang‐Chih Chang, Chin‐Chou Wang, Chia‐Cheng Tseng, Kuo‐Tung Huang, Yu‐Mu Chen, Yu‐Ping Chang, Chien‐Hao Lai, Wen‐Feng Fang, Meng‐Chih Lin, Hung‐Yi Chuang
Thoracic Cancer.2023; 14(32): 3208. CrossRef
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Thoracic Cancer.2023; 14(32): 3217. CrossRef
Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy
Sarbjit Singh, Divya Utreja, Vimal Kumar
Medicinal Chemistry Research.2022; 31(1): 1. CrossRef
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Cancer Research and Treatment.2022; 54(2): 434. CrossRef
Comparison of Different Tyrosine Kinase Inhibitors for Treatment of Poor Performance Status Patients with EGFR-Mutated Lung Adenocarcinoma
Chiao-En Wu, Ching-Fu Chang, Chen-Yang Huang, Cheng-Ta Yang, Chih-Hsi Kuo, Ping-Chih Hsu, John Chang
Cancers.2022; 14(3): 674. CrossRef
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John Wen-Cheng Chang, Chen-Yang Huang, Yueh-Fu Fang, Ching-Fu Chang, Cheng-Ta Yang, Chih-Hsi Scott Kuo, Ping-Chih Hsu, Chiao-En Wu
Cancers.2022; 14(4): 977. CrossRef
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Cureus.2022;[Epub] CrossRef
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Journal of Medicinal Chemistry.2022; 65(6): 4709. CrossRef
Cost-Effectiveness Analysis of Afatinib versus Gefitinib in Non-small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) Mutation in Indonesia: Observational studies with Retrospectives
Seftika Sari, Tri Murti Andayani, Dwi Endarti, Kartika Widayati
Research Journal of Pharmacy and Technology.2022; : 1598. CrossRef
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Clinical Medicine Insights: Oncology.2022;[Epub] CrossRef
Pharmacokinetic and Safety Comparison of 2 Afatinib Dimaleate Tablets in Healthy Chinese Volunteers Under Fasted Conditions: A Randomized, Open‐Label, 2‐Period, Single‐Dose Crossover Study
Ping Shi, Xin Jiang, Ye Tao, Ting Li, Xin Li, Chenjing Wang, Yanping Liu, Yaping Ma, Xiaomeng Gao, Yu Cao
Clinical Pharmacology in Drug Development.2022; 11(10): 1177. CrossRef
Grb2 interacts with necrosome components and is involved in rasfonin-induced necroptosis
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Cell Death Discovery.2022;[Epub] CrossRef
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Hong-Yi Zhao, Xiao-Xiao Xi, Minhang Xin, San-Qi Zhang
Bioorganic Chemistry.2022; 128: 106057. CrossRef
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Scientific Reports.2022;[Epub] CrossRef
Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations
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The Oncologist.2021; 26(4): 281. CrossRef
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Thoracic Cancer.2021; 12(4): 444. CrossRef
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Cancer Research and Treatment.2021; 53(2): 457. CrossRef
Treatment Options of First-Line Tyrosine Kinase Inhibitors and Subsequent Systemic Chemotherapy Agents for Advanced EGFR Mutant Lung Adenocarcinoma Patients: Implications From Taiwan Cancer Registry Cohort
Sheng-Kai Liang, Li-Ta Keng, Chia-Hao Chang, Yueh-Feng Wen, Meng-Rui Lee, Ching-Yao Yang, Jann-Yuan Wang, Jen-Chung Ko, Jin-Yuan Shih, Chong-Jen Yu
Frontiers in Oncology.2021;[Epub] CrossRef
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Sojung Park, Sung Yong Lee, Dojin Kim, Yun Su Sim, Jeong-Seon Ryu, Juwhan Choi, Su Hwan Lee, Yon Ju Ryu, Jin Hwa Lee, Jung Hyun Chang
BMC Cancer.2021;[Epub] CrossRef
Real-life comparison of the afatinib and first-generation tyrosine kinase inhibitors in nonsmall cell lung cancer harboring EGFR exon 19 deletion: a Turk Oncology Group (TOG) study
Burak Bilgin, Mehmet Ali Nahit Sendur, Sebnem Yucel, Emir Celik, Deniz Tataroglu Ozyukseler, Murat Ayhan, Tugba Basoglu, Aysegul Ilhan, Nadiye Akdeniz, Ahmet Gulmez, Izzet Dogan, Burak Yasin Aktas, Mustafa Gurbuz, Sinan Koca, Semra Paydas, Ali Murat Tatli
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Gefitinib reduces oocyte quality by disturbing meiotic progression
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Toxicology.2021; 452: 152705. CrossRef
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PD-L1 Expression and Outcome in Patients with Metastatic Non-Small Cell Lung Cancer and EGFR Mutations Receiving EGFR-TKI as Frontline Treatment
Cheng-Yu Chang, Yi-Chun Lai, Yu-Feng Wei, Chung-Yu Chen, Shih-Chieh Chang
OncoTargets and Therapy.2021; Volume 14: 2301. CrossRef
Egfr Tyrosine Kinase Inhibitors for EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Outcomes in Asian Populations
Edward S Kim, Barbara Melosky, Keunchil Park, Nobuyuki Yamamoto, James C - H Yang
Future Oncology.2021; 17(18): 2395. CrossRef
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Scientific Reports.2021;[Epub] CrossRef
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Frontiers in Oncology.2021;[Epub] CrossRef
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BMC Cancer.2021;[Epub] CrossRef
Sequential treatment of afatinib and osimertinib or other regimens in patients with advanced non‐small‐cell lung cancer harboring EGFR mutations: Results from a real‐world study in South Korea
Taeyun Kim, Tae Won Jang, Chang Min Choi, Mi‐Hyun Kim, Sung Yong Lee, Cheol‐Kyu Park, Yoon Soo Chang, Kye Young Lee, Seung Joon Kim, Sei Hoon Yang, Jeong Seon Ryu, Jeong Eun Lee, Shin Yup Lee, Chan Kwon Park, Sang Hoon Lee, Seung Hun Jang, Seong Hoon Yoon
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BMC Cancer.2021;[Epub] CrossRef
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Frontiers in Pharmacology.2021;[Epub] CrossRef
Hype or hope – Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC?
Filippo Papini, Janani Sundaresan, Alessandro Leonetti, Marcello Tiseo, Christian Rolfo, Godefridus J. Peters, Elisa Giovannetti
Critical Reviews in Oncology/Hematology.2021; 166: 103454. CrossRef
Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer
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Cost-Effectiveness Analysis of Gefitinib Plus Chemotherapy versus Gefitinib Alone for Advanced Non-Small-Cell Lung Cancer with EGFR Mutations in China
Yamin Shu, Qilin Zhang, Xucheng He, Li Chen
Cancer Management and Research.2021; Volume 13: 8297. CrossRef
Impact of Dose Reduction of Afatinib Used in Patients With Non–Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
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Frontiers in Pharmacology.2021;[Epub] CrossRef
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Generics: Journal of Research in Pharmacy.2021;[Epub] CrossRef
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Yao‐Yu Hsieh, Wei‐Tse Fang, Yu‐Wen Lo, Yi‐Han Chen, Li‐Nien Chien
International Journal of Cancer.2020; 147(4): 1107. CrossRef
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Journal of Thoracic Oncology.2020; 15(5): 803. CrossRef
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Medicinal Chemistry Research.2020; 29(5): 910. CrossRef
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Acta Pharmacologica Sinica.2020; 41(10): 1366. CrossRef
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Expert Review of Anticancer Therapy.2020; 20(7): 531. CrossRef
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Ye Jiang, Wenli Chen, Weiguang Yu, Ning Shi, Guowei Han, Shuai Mao, Xinlei Zhang, Meiji Chen
Journal of International Medical Research.2020;[Epub] CrossRef
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Thoracic Cancer.2020; 11(11): 3346. CrossRef
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Thoracic Cancer.2019; 10(6): 1461. CrossRef
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International Journal of Molecular Sciences.2019; 20(22): 5701. CrossRef
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Future Oncology.2019; 15(13): 1493. CrossRef
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Future Oncology.2018; 14(27): 2861. CrossRef

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