Cancer Research and Treatment

Original Articles

Gastrointestinal cancer

Neoadjuvant Nivolumab Therapy for Esophageal Squamous Cell Carcinoma: A Single-Arm, Phase II Study: Sehhoon Park, Yurimi Lee, Jiyun Lee, Yang Won Min, Hong Kwan Kim, Joon Young Choi, Hyun Ae Jung, Yong Soo Choi, Yoon-La Choi, Young Mog Shim, Jong-Mu Sun; Cancer Res Treat. 2024;56(2):567-579. Published online October 16, 2023; DOI: https://doi.org/10.4143/crt.2023.897

Abstract PDF Supplementary Material PubReader ePub: Purpose
Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC.
Materials and Methods
Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (≤ 10% of residual viable tumor [RVT]).
Results
Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; ≤ 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (≥ 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS ≥ 10 (3/8) and 0% in CPS < 10 (0/9).
Conclusion
Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC.

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General

Trends and Clinical Characteristics of Next-Generation Sequencing–Based Genetic Panel Tests: An Analysis of Korean Nationwide Claims Data: Mi Jang, Hae Yong Pak, Ja Yoon Heo, Hyunsun Lim, Yoon-La Choi, Hyo Sup Shim, Eun Kyung Kim; Cancer Res Treat. 2024;56(1):27-36. Published online September 7, 2023; DOI: https://doi.org/10.4143/crt.2023.844

Abstract PDF Supplementary Material PubReader ePub: Purpose
In the modern era of precision medicine, next-generation sequencing (NGS) is employed for a variety of clinical purposes. The aim of this study was to investigate the trends and clinical characteristics of NGS testing in South Korea.
Materials and Methods
This nationwide, population-based, retrospective cohort study examined National Health Insurance Service claims data from 2017 to 2021 for NGS and from 2008 to 2021 for gene-targeted anticancer drugs.
Results
Among the total 98,748 claims, there were 51,407 (52.1%) solid cancer panels, 30,173 (30.5%) hereditary disease panels, and 17,168 (17.4%) hematolymphoid cancer panels. The number of annual claims showed a persistent upward trend, exhibiting a 5.4-fold increase, from 5,436 in 2017 to 29,557 in 2021. In the solid cancer panel, colorectal cancer was the most common (19.2%), followed by lung cancer (18.8%). The annual claims for targeted cancer drugs have increased 25.7-fold, from 3,932 in 2008 to 101,211 in 2020. Drugs for the treatment of lung cancer accounted for 488,819 (71.9%) claims. The number of patients who received non-hereditary NGS testing has substantially increased, and among them, the count of patients prescribed targeted anticancer drugs consistently rose from 508 (13.9%) in 2017 to 2,245 (12.3%) in 2020.
Conclusion
This study highlights the rising nationwide demand for comprehensive genetic testing for disease diagnosis and treatment following NGS reimbursement by the National Health Insurance in South Korea, in addition to the need for greater utilization of targeted anticancer drugs.

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Lung and Thoracic cancer

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

Abstract PDF Supplementary Material PubReader ePub

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

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

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Cancer-Specific Sequences in the Diagnosis and Treatment of NUT Carcinoma: Mi-Sook Lee, Sungbin An, Ji-Young Song, Minjung Sung, Kyungsoo Jung, Eun Sol Chang, Juyoung Choi, Doo-Yi Oh, Yoon Kyung Jeon, Hobin Yang, Chaithanya Lakshmi, Sehhoon Park, Joungho Han, Se-Hoon Lee, Yoon-La Choi; Cancer Res Treat. 2023;55(2):452-467. Published online October 14, 2022; DOI: https://doi.org/10.4143/crt.2022.910

Abstract PDF Supplementary Material PubReader ePub

Purpose
NUT carcinoma (NC) is a solid tumor caused by the rearrangement of NUTM1 that usually develops in midline structures, such as the thorax. No standard treatment has been established despite high lethality. Thus, we investigated whether targeting the junction region of NUTM1 fusion breakpoints could serve as a potential treatment option for NC.
Materials and Methods
We designed and evaluated a series of small interfering RNAs (siRNAs) targeting the junction region of BRD4-NUTM1 fusion (B4N), the most common form of NUTM1 fusion. Droplet digital polymerase chain reaction using the blood of patients was also tested to evaluate the treatment responses by the junction sequence of the B4N fusion transcripts.
Results
As expected, the majority of NC fusion types were B4N (12 of 18, 67%). B4N fusion-specific siRNA treatment on NC cells showed specific inhibitory effects on the B4N fusion transcript and fusion protein without affecting the endogenous expression of the parent genes, resulting in decreased relative cell growth and attenuation of tumor size. In addition, the fusion transcript levels in platelet-rich-plasma samples of the NC patients with systemic metastasis showed a negative correlation with therapeutic effect, suggesting its potential as a measure of treatment responsiveness.
Conclusion
This study suggests that tumor-specific sequences could be used to treat patients with fusion genes as part of precision medicine for a rare but deadly disease.

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Indirect targeting of MYC and direct targeting in combination with chemotherapies are more effective than direct mono-targeting in triple negative breast cancer
Negesse Mekonnen, Hobin Yang, Nirmal Rajasekaran, Kyoung Song, Yoon-La Choi, Young Kee Shin
Translational Oncology.2025; 51: 102204. CrossRef
NUT-midline carcinoma of the lung with rare BRD3-NUTM1 fusion
Prerana Jha, Vaishakhi Trivedi, Nandini Menon, Minit Shah, Irene A George, Rohit Mishra, Trupti Pai, Fuzail Ahmad, Venkataramanan Ramachandran, Vanita Noronha, Kumar Prabhash, Prashant Kumar
Cancer Research, Statistics, and Treatment.2024; 7(1): 110. CrossRef

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Sarcoma

Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response: Jung Yong Hong, Hee Jin Cho, Kum-Hee Yun, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Sang Kyum Kim, Yurimi Lee, Yoon-La Choi, Minsuk Kwon, Hyo Song Kim, Jeeyun Lee; Cancer Res Treat. 2023;55(2):671-683. Published online September 27, 2022; DOI: https://doi.org/10.4143/crt.2022.251

Abstract PDF Supplementary Material PubReader ePub

Purpose
Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy.
Materials and Methods
We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA.
Results
Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10–4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker.
Conclusion
Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Citations

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Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial
Hee Jin Cho, Kum-Hee Yun, Su-Jin Shin, Young Han Lee, Seung Hyun Kim, Wooyeol Baek, Yoon Dae Han, Sang Kyum Kim, Hyang Joo Ryu, Joohee Lee, Iksung Cho, Heounjeong Go, Jiwon Ko, Inkyung Jung, Min Kyung Jeon, Sun Young Rha, Hyo Song Kim
Nature Communications.2024;[Epub] CrossRef
The high-density lipoprotein binding protein HDLBP is an unusual RNA-binding protein with multiple roles in cancer and disease
Jonathan Feicht, Ralf-Peter Jansen
RNA Biology.2024; 21(1): 1. CrossRef
Intracranial Relapse in Pediatric Sarcoma
Danielle E. Smith, Tyler Hamby, Kenneth Heym, Ashraf Mohamed, Kelly L. Vallance, Anish Ray
Journal of Pediatric Hematology/Oncology.2023; 45(7): e810. CrossRef

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Breast cancer

Analysis of PIK3CA Mutation Concordance and Frequency in Primary and Different Distant Metastatic Sites in Breast Cancer: Jieun Park, Soo Youn Cho, Eun Sol Chang, Minjung Sung, Ji-Young Song, Kyungsoo Jung, Sung-Su Kim, Young Kee Shin, Yoon-La Choi; Cancer Res Treat. 2023;55(1):145-154. Published online April 20, 2022; DOI: https://doi.org/10.4143/crt.2022.001

Abstract PDF Supplementary Material PubReader ePub

Purpose
The purpose of this study was to investigate the concordance rate of PIK3CA mutations between primary and matched distant metastatic sites in patients with breast cancer and to verify whether there are differences in the frequency of PIK3CA hotspot mutations depending on the metastatic sites involved.
Materials and Methods
Archived formalin-fixed paraffin-embedded (FFPE) specimens of primary breast and matched distant metastatic tumors were retrospectively obtained for 49 patients. Additionally, 40 archived FFPE specimens were independently collected from different breast cancer metastatic sites, which were limited to three common sites: the liver, brain, and lung. PIK3CA mutations were analyzed using droplet digital PCR, including hotspots involving exons 9 and 20.
Results
After analysis of 49 breast tumors with matched metastasis sites, 87.8% showed concordance in PIK3CA mutation status. According to PIK3CA hotspot mutation testing in 89 cases of breast cancer metastatic sites, the proportion of PIK3CA mutations at sites of metastasis involving the liver, brain, and lung was 37.5%, 28.6%, and 42.9%, respectively, which did not result in statistical significance.
Conclusion
The high concordance of PIK3CA mutation status between primary and matched metastasis sites suggests that metastatic sites, regardless of the metastatic organ, could be considered sample sources for PIK3CA mutation testing for improved therapeutic strategies in patients with metastatic breast cancer.

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Analysis of PIK3CA mutations in the primary and recurrent tumors of hormone receptor positive/human epidermal growth factor receptor 2 negative breast cancer
Yue Wang, Xin Li, Shuang Zhang, Li Liang, Ling Xu, Yinhua Liu, Ting Li
Japanese Journal of Clinical Oncology.2024; 54(9): 1024. CrossRef
Discordance of PIK3CA mutational status between primary and metastatic breast cancer: a systematic review and meta-analysis
Justus Rosin, Ella Svegrup, Antonios Valachis, Ioannis Zerdes
Breast Cancer Research and Treatment.2023; 201(2): 161. CrossRef
Analytical Performance of Next-Generation Sequencing and RT-PCR on Formalin-Fixed Paraffin-Embedded Tumor Tissues for PIK3CA Testing in HR+/HER2− Breast Cancer
Konstantinos Venetis, Francesco Pepe, Elisabetta Munzone, Elham Sajjadi, Gianluca Russo, Pasquale Pisapia, Mariia Ivanova, Giuseppina Bonizzi, Davide Vacirca, Alessandra Rappa, Alberto Ranghiero, Sergio Vincenzo Taormina, Giuseppe Viale, Giancarlo Troncon
Cells.2022; 11(22): 3545. CrossRef

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General

Interlaboratory Comparison Study (Ring Test) of Next-Generation Sequencing–Based NTRK Fusion Detection in South Korea: Seung Eun Lee, Mi-Sook Lee, Yoon Kyung Jeon, Hyo Sup Shim, Jun Kang, Jihun Kim, Yoon-La Choi; Cancer Res Treat. 2023;55(1):28-40. Published online February 10, 2022; DOI: https://doi.org/10.4143/crt.2021.1572

Abstract PDF Supplementary Material PubReader ePub

Purpose
Tropomyosin receptor kinase (TRK) inhibitors are approved for the treatment of neurotrophic receptor tyrosine kinase (NTRK) fusion-positive tumors. The detection of NTRK fusion using a validated method is required before therapeutic application. An interlaboratory comparison study of next-generation sequencing (NGS)–based NTRK gene fusion detection with validated clinical samples was conducted at six major hospitals in South Korea.
Materials and Methods
A total of 18 samples, including a positive standard reference and eight positive and nine negative clinical samples, were validated using the VENTANA pan-TRK (EPR17341) and TruSight Oncology 500 assays. These samples were then tested using four different NGS panels currently being used at the six participating institutions.
Results
NTRK fusions were not detected in any of the nine negative clinical samples, demonstrating 100% specificity in all six participating institutions. All assays showed 100% analytical sensitivity to identify the NTRK fusion status in formalin-fixed paraffin-embedded (FFPE) samples, although with variable clinical sensitivity. False-negative results were due to low tumor purity, poor RNA quality, and DNA-based sequencing panel. The RNA-based targeted NGS assay showed an overall high success rate of identifying NTRK fusion status in FFPE samples.
Conclusion
This study is the first to test the proficiency of NGS-based NTRK detection in South Korea with the largest participating institutions. RNA-based NGS assays to detect NTRK fusions can accurately characterize fusion transcripts if sufficient RNA of adequate quality is available. The comparative performance data will support the implementation of targeted NGS-based sequencing assays for NTRK fusion detection in routine diagnostics.

Citations

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Efficient Identification of Patients With NTRK Fusions Using a Supervised Tumor-Agnostic Approach
Susana Hernandez, Esther Conde, Aida Molero, Ana Suarez-Gauthier, Rebeca Martinez, Marta Alonso, Carlos Plaza, Carmen Camacho, Debora Chantada, Laura Juaneda-Magdalena, Enrique Garcia-Toro, Patricia Saiz-Lopez, Federico Rojo, Mar Abad, Valentina Boni, Sof
Archives of Pathology & Laboratory Medicine.2024; 148(3): 318. CrossRef
Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part III. Management of Advanced Differentiated Thyroid Cancers - Chapter 4. Systemic Therapy for Progressive Radioiodine-Refractory Differentiated Thyroid Cancer 2
Dong Yeob Shin, Ho-Cheol Kang, Sun Wook Kim, Dong Gyu Na, Young Joo Park, Young Shin Song, Eun Kyung Lee, Dong-Jun Lim, Yun Jae Chung, Won Gu Kim
International Journal of Thyroidology.2024; 17(1): 168. CrossRef
CANTRK
Tracy L. Stockley, Bryan Lo, Adrian Box, Andrea Gomez Corredor, John DeCoteau, Patrice Desmeules, Harriet Feilotter, Daria Grafodatskaya, Wenda Greer, Cynthia Hawkins, Weei Yuarn Huang, Iyare Izevbaye, Guylaine Lépine, Sebastiao N. Martins Filho, Andreas
The Journal of Molecular Diagnostics.2023; 25(3): 168. CrossRef
NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas
Seung Eun Lee, Mi-Sook Lee, Heejin Bang, Mi Young Kim, Yoon-La Choi, Young Lyun Oh
Modern Pathology.2023; 36(8): 100180. CrossRef
Validation and Clinical Application of ONCOaccuPanel for Targeted Next-Generation Sequencing of Solid Tumors
Moonsik Kim, Changseon Lee, Juyeon Hong, Juhee Kim, Ji Yun Jeong, Nora Jee-Young Park, Ji-Eun Kim, Ji Young Park
Cancer Research and Treatment.2023; 55(2): 429. CrossRef

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Lung and Thoracic cancer

Selection Strategies and Practical Application of BRAF V600E-Mutated Non–Small Cell Lung Carcinoma: Inwoo Hwang, Yoon-La Choi, Hyunwoo Lee, Soohyun Hwang, Boram Lee, Hobin Yang, Chaithanya Chelakkot, Joungho Han; Cancer Res Treat. 2022;54(3):782-792. Published online November 23, 2021; DOI: https://doi.org/10.4143/crt.2021.843

Abstract PDF Supplementary Material PubReader ePub

Purpose
The incidence of BRAF V600E mutation in non-small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to BRAF V600E and the effectiveness of the VE1 antibody as a screening method for patient selection.
Materials and Methods
The study was designed into two steps. In a first group, BRAF-mutated NSCLCs were identified from sequencing data to determine the features of BRAF V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without EGFR or ALK alterations as a second group so that the frequency of BRAF V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with BRAF V600E status.
Results
Among 39 BRAF-mutated NSCLCs in the first group, 20 (51%) were V600E. BRAF V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without EGFR and ALK alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3-1.8%).
Conclusion
BRAF V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.

Citations

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The rapidly changing field of predictive biomarkers of non-small cell lung cancer
László József Tóth, Attila Mokánszki, Gábor Méhes
Pathology and Oncology Research.2024;[Epub] CrossRef
BRAF V600E Mutation of Non-Small Cell Lung Cancer in Korean Patients
Hyo Yeong Ahn, Chang Hun Lee, Min Ki Lee, Jung Seop Eom, Yeon Joo Jeong, Yeong Dae Kim, Jeong Su Cho, Jonggeun Lee, So Jeong Lee, Dong Hoon Shin, Ahrong Kim
Medicina.2023; 59(6): 1085. CrossRef
The Impact of Liquid Biopsies Positive for EGFR Mutations on Overall Survival in Non-Small Cell Lung Cancer Patients
Jonnathan Roldan Ruiz, Marta Fuentes Gago, Luis Chinchilla Tabora, Idalia Gonzalez Morais, José Sayagués, Mar Abad Hernández, Maria Cordovilla Pérez, Maria Ludeña de la Cruz, Edel del Barco Morillo, Marta Rodriguez Gonzalez
Diagnostics.2023; 13(14): 2347. CrossRef
Usefulness of BRAF VE1 immunohistochemistry in non–small cell lung cancers: a multi-institutional study by 15 pathologists in Korea
Sunhee Chang, Yoon-La Choi, Hyo Sup Shim, Geon Kook Lee, Seung Yeon Ha
Journal of Pathology and Translational Medicine.2022; 56(6): 334. CrossRef

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Basic

TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis: Kyungsoo Jung, Joon-Seok Choi, Beom-Mo Koo, Yu Jin Kim, Ji-Young Song, Minjung Sung, Eun Sol Chang, Ka-Won Noh, Sungbin An, Mi-Sook Lee, Kyoung Song, Hannah Lee, Ryong Nam Kim, Young Kee Shin, Doo-Yi Oh, Yoon-La Choi; Cancer Res Treat. 2021;53(1):9-24. Published online September 16, 2020; DOI: https://doi.org/10.4143/crt.2020.434

Abstract PDF Supplementary Material PubReader ePub

Purpose
To find biomarkers for disease, there have been constant attempts to investigate the genes that differ from those in the disease groups. However, the values that lie outside the overall pattern of a distribution, the outliers, are frequently excluded in traditional analytical methods as they are considered to be ‘some sort of problem.’ Such outliers may have a biologic role in the disease group. Thus, this study explored new biomarker using outlier analysis, and verified the suitability of therapeutic potential of two genes (TM4SF4 and LRRK2).
Materials and Methods
Modified Tukey’s fences outlier analysis was carried out to identify new biomarkers using the public gene expression datasets. And we verified the presence of the selected biomarkers in other clinical samples via customized gene expression panels and tissue microarrays. Moreover, a siRNA-based knockdown test was performed to evaluate the impact of the biomarkers on oncogenic phenotypes.
Results
TM4SF4 in lung cancer and LRRK2 in breast cancer were chosen as candidates among the genes derived from the analysis. TM4SF4 and LRRK2 were overexpressed in the small number of samples with lung cancer (4.20%) and breast cancer (2.42%), respectively. Knockdown of TM4SF4 and LRRK2 suppressed the growth of lung and breast cancer cell lines. The LRRK2 overexpressing cell lines were more sensitive to LRRK2-IN-1 than the LRRK2 under-expressing cell lines
Conclusion
Our modified outlier-based analysis method has proved to rescue biomarkers previously missed or unnoticed by traditional analysis showing TM4SF4 and LRRK2 are novel target candidates for lung and breast cancer, respectively.

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TM4SF19—A New Biomarker for Diagnosis and Prognosis of Bladder Urothelial Carcinoma
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Advances in Clinical Medicine.2024; 14(02): 3616. CrossRef
Validating linalool as a potential drug for breast cancer treatment based on machine learning and molecular docking
Qian Zhang, Dengfeng Chen
Drug Development Research.2024;[Epub] CrossRef
DeepDRA: Drug repurposing using multi-omics data integration with autoencoders
Taha Mohammadzadeh-Vardin, Amin Ghareyazi, Ali Gharizadeh, Karim Abbasi, Hamid R. Rabiee, Amgad Muneer
PLOS ONE.2024; 19(7): e0307649. CrossRef
TM4SF4 is a diagnostic biomarker accelerating progression of papillary thyroid cancer via AKT pathway
Lizhi Lin, Jialiang Wen, Tiansheng Xu, Yuhao Si
Cancer Biology & Therapy.2024;[Epub] CrossRef
Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance
Nur Syafiqah Rahim, Yuan Seng Wu, Maw Shin Sim, Appalaraju Velaga, Srinivasa Reddy Bonam, Subash C. B. Gopinath, Vetriselvan Subramaniyan, Ker Woon Choy, Sin-Yeang Teow, Ismail M. Fareez, Chandramathi Samudi, Shamala Devi Sekaran, Mahendran Sekar, Rhanye
Pharmaceuticals.2023; 16(1): 110. CrossRef
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Yeting Hu, Xiaoqin Lv, Wenwu Wei, Xiang Li, Kaixuan Zhang, Linlin Zhu, Tao Gan, Hongjuan Zeng, Jinlin Yang, Nini Rao
Advanced Biology.2023;[Epub] CrossRef
Study on Potential Differentially Expressed Genes in Idiopathic Pulmonary Fibrosis by Bioinformatics and Next-Generation Sequencing Data Analysis
Muttanagouda Giriyappagoudar, Basavaraj Vastrad, Rajeshwari Horakeri, Chanabasayya Vastrad
Biomedicines.2023; 11(12): 3109. CrossRef
Parkinson’s disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender
Joon Yan Selene Lee, Jing Han Ng, Seyed Ehsan Saffari, Eng-King Tan
Aging.2022; 14(5): 2148. CrossRef
Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
Zhisong Yang, Li Zhou, Haiyan Ge, Weimin Shen, Lin Shan
Open Medicine.2022; 17(1): 1148. CrossRef
LncRNA ST8SIA6-AS1 facilitates hepatocellular carcinoma progression by governing miR-651-5p/TM4SF4 axis
Yanjie Mou, Xiaoming Ding
Anti-Cancer Drugs.2022; 33(8): 741. CrossRef
Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation
Mingfeng Yu, Yi Long, Yuchao Yang, Manjun Li, Theodosia Teo, Benjamin Noll, Stephen Philip, Shudong Wang
European Journal of Medicinal Chemistry.2021; 218: 113391. CrossRef
Shifting Gears in Precision Oncology—Challenges and Opportunities of Integrative Data Analysis
Ka-Won Noh, Reinhard Buettner, Sebastian Klein
Biomolecules.2021; 11(9): 1310. CrossRef

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Clinical Outcomes of EGFR Exon 20 Insertion Mutations in Advanced Non-small Cell Lung Cancer in Korea: Seonggyu Byeon, Youjin Kim, Sung Won Lim, Jang Ho Cho, Sehoon Park, Jiyun Lee, Jong-Mu Sun, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn; Cancer Res Treat. 2019;51(2):623-631. Published online July 23, 2018; DOI: https://doi.org/10.4143/crt.2018.151

Abstract PDF Supplementary Material PubReader ePub

Purpose
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established.
Materials and Methods
Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy.
Results
Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progressionfree survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response.
Conclusion
The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to firstor second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.

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Advances in the Diagnosis and Treatment of Advanced Non–Small-Cell Lung Cancer With EGFR Exon 20 Insertion Mutation
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EGFR Mutation Is Associated with Short Progression-Free Survival in Patients with Stage III Non-squamous Cell Lung Cancer Treated with Concurrent Chemoradiotherapy: Song Ee Park, Jae Myoung Noh, You Jin Kim, Han Sang Lee, Jang Ho Cho, Sung Won Lim, Yong Chan Ahn, Hongryull Pyo, Yoon-La Choi, Joungho Han, Jong-Mu Sun, Se Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn; Cancer Res Treat. 2019;51(2):493-501. Published online June 18, 2018; DOI: https://doi.org/10.4143/crt.2018.125

Abstract PDF PubReader ePub

Purpose
This study was conducted to evaluate the relationship between epidermal growth factor receptor (EGFR) mutation and clinical outcomes in patients with stage III non-squamous cell lung cancer treated with definitive concurrent chemoradiotherapy (CCRT).
Materials and Methods
From January 2008 to December 2013, the medical records of 197 patients with stage III non- squamous non-small cell lung cancer treated with definitive CCRT were analyzed to determine progression-free survival (PFS) and overall survival (OS) according to EGFR mutation status.
Results
Among 197 eligible patients, 81 patients were EGFR wild type, 36 patients had an EGFR mutation (exon 19 Del, n=18; L858R, n=9, uncommon [G719X, L868, T790M], n=9), and 80 patients had unknown EGFR status. The median age was 59 years (range, 28 to 80 years) and 136 patients (69.0%) were male. The median follow-up duration was 66.5 months (range, 1.9 to 114.5 months). One hundred sixty-four patients (83.2%) experienced disease progression. Median PFS was 8.9 months for the EGFR mutation group, 11.8 months for EGFR wild type, and 10.5 months for the unknown EGFR group (p=0.013 and p=0.042, respectively). The most common site of metastasis in the EGFR mutant group was the brain. However, there was no significant difference in OS among the three groups (34.6 months for EGFR mutant group vs. 31.9 months for EGFR wild type vs. 22.6 months for EGFR unknown group; p=0.792 and p=0.284). A total of 29 patients (80.6%) with EGFR mutation were treated with EGFR tyrosine kinase inhibitor (gefitinib, n=24; erlotinib, n=3; afatinib, n=2) upon progression.
Conclusion
EGFR mutation is associatedwith short PFS and the brain is the most common site of distant metastasis in patients with stage III non- squamous cell lung cancer treated with CCRT.

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

Abstract PDF PubReader ePub

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

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Yi Dong, Liaqat Khan, Yi Yao
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Prevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients: Mi-Sook Lee, Eun Ah Jung, Sung Bin An, Yu Jin Kim, Doo-Yi Oh, Ji-Young Song, Sang-Won Um, Joungho Han, Yoon-La Choi; Cancer Res Treat. 2017;49(4):1065-1076. Published online January 25, 2017; DOI: https://doi.org/10.4143/crt.2016.347

Abstract PDF Supplementary Material PubReader ePub

Purpose
The discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer.
Materials and Methods
We selected 100 samples through a preliminary genetic screen, including specimens from biopsies and surgical resection, and confirmed SCC by histologic examination. DDR2 mutations on exons 6, 15, 16, and 18 were analyzed by Sanger sequencing of formalin-fixed, paraffin-embedded tissue samples. The functional effects of novel DDR2 mutants were confirmed by in vitro assays.
Results
We identified novel somatic mutations of DDR2 in two of the 100 SCC samples studied. One mutation was c.1745T>A (p.V582E) and the other was c.1784T>C (p.L595P), and both were on exon 15. Both patients were smokers and EGFR/KRAS/ALK-triple negative. The expression of the mutant DDR2 induced activation of DDR2 by the collagen ligand and caused enhanced cell growth and tumor progression. Moreover, dasatinib, a DDR2 inhibitor, showed potential efficacy against DDR2 L595P mutant–bearing cells.
Conclusion
Our results suggest that a mutation in DDR2 occurs naturally with a frequency of about 2% in Korean lung SCC patients. In addition, we showed that each of the novel DDR2 mutations were located in a kinase domain and induced an increase in cell proliferation rate.

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Potentially functional variants of PARK7 and DDR2 in ferroptosis‐related genes predict survival of non‐small cell lung cancer patients
Huilin Wang, Hongliang Liu, Xiaozhun Tang, Guojun Lu, Sheng Luo, Mulong Du, David C. Christiani, Qingyi Wei
International Journal of Cancer.2024;[Epub] CrossRef
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Yanning Sun, Li Ma, Xiaofei Zhang, Zhaoxia Wang
OncoTargets and Therapy.2024; Volume 17: 1095. CrossRef
Discoidin Domain Receptor 2: A New Target in Cancer
Xiaoxiao Xu, Tong Yu, Zhenxing Wang
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Sungbin An, Hyun Hee Koh, Eun Sol Chang, Juyoung Choi, Ji-Young Song, Mi-Sook Lee, Yoon-La Choi
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Squamous cell lung cancer: Current landscape and future therapeutic options
Sally C.M. Lau, Yuanwang Pan, Vamsidhar Velcheti, Kwok Kin Wong
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Complex roles of discoidin domain receptor tyrosine kinases in cancer
V. Mehta, H. Chander, A. Munshi
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Sandra Majo, Patrick Auguste
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Charles Ricordel, Alexandra Lespagnol, Francisco Llamas-Gutierrez, Marie de Tayrac, Mallorie Kerjouan, Alice Fievet, Houda Hamdi-Rozé, Amyrat Aliouat, Benoit Desrues, Jean Mosser, Hervé Léna
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Martin Götte, Ilona Kovalszky
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Zahra Fathi, Seyed Ali Javad Mousavi, Raheleh Roudi, Farideh Ghazi, Sumitra Deb
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Patient-Derived Xenograft Models of Epithelial Ovarian Cancer for Preclinical Studies: Eun Jin Heo, Young Jae Cho, William Chi Cho, Ji Eun Hong, Hye-Kyung Jeon, Doo-Yi Oh, Yoon-La Choi, Sang Yong Song, Jung-Joo Choi, Duk-Soo Bae, Yoo-Young Lee, Chel Hun Choi, Tae-Joong Kim, Woong-Yang Park, Byoung-Gie Kim, Jeong-Won Lee; Cancer Res Treat. 2017;49(4):915-926. Published online January 4, 2017; DOI: https://doi.org/10.4143/crt.2016.322

Abstract PDF Supplementary Material PubReader ePub

Purpose
Patient-derived tumor xenografts (PDXs) can provide more reliable information about tumor biology than cell line models. We developed PDXs for epithelial ovarian cancer (EOC) that have histopathologic and genetic similarities to the primary patient tissues and evaluated their potential for use as a platform for translational EOC research.
Materials and Methods
We successfully established PDXs by subrenal capsule implantation of primary EOC tissues into female BALB/C-nude mice. The rate of successful PDX engraftment was 48.8% (22/45 cases). Hematoxylin and eosin staining and short tandem repeat analysis showed histopathological and genetic similarity between the PDX and primary patient tissues.
Results
Patients whose tumors were successfully engrafted in mice had significantly inferior overall survival when compared with those whose tumors failed to engraft (p=0.040). In preclinical tests of this model, we found that paclitaxel-carboplatin combination chemotherapy significantly deceased tumor weight in PDXs compared with the control treatment (p=0.013). Moreover, erlotinib treatment significantly decreased tumor weight in epidermal growth factor receptor–overexpressing PDX with clear cell histology (p=0.023).
Conclusion
PDXs for EOC with histopathological and genetic stability can be efficiently developed by subrenal capsule implantation and have the potential to provide a promising platform for future translational research and precision medicine for EOC.

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Case Report

SEC31A-ALK Fusion Gene in Lung Adenocarcinoma: Ryong Nam Kim, Yoon-La Choi, Mi-Sook Lee, Maruja E. Lira, Mao Mao, Derrick Mann, Joshua Stahl, Abel Licon, So Jung Choi, Michael Van Vrancken, Joungho Han, Iwona Wlodarska, Jhingook Kim; Cancer Res Treat. 2016;48(1):398-402. Published online February 17, 2015; DOI: https://doi.org/10.4143/crt.2014.254

Abstract PDF Supplementary Material PubReader ePub

Anaplastic lymphoma kinase (ALK) fusion is a common mechanism underlying pathogenesis of non-small cell lung carcinoma (NSCLC) where these rearrangements represent important diagnostic and therapeutic targets. In this study, we found a new ALK fusion gene, SEC31A-ALK, in lung carcinoma from a 53-year-old Korean man. The conjoined region in the fusion transcript was generated by the fusion of SEC31A exon 21 and ALK exon 20 by genomic rearrangement, which contributed to generation of an intact, in-frame open reading frame. SEC31A-ALK encodes a predicted fusion protein of 1,438 amino acids comprising the WD40 domain of SEC31A at the N-terminus and ALK kinase domain at the C-terminus. Fluorescence in situ hybridization studies suggested that SEC31A-ALK was generated by an unbalanced genomic rearrangement associated with loss of the 3′-end of SEC31A. This is the first report of SEC31A-ALK fusion transcript in clinical NSCLC, which could be a novel diagnostic and therapeutic target for patients with NSCLC.

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