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Original Article
Breast cancer
A 10-Gene Signature to Predict the Prognosis of Early-Stage Triple-Negative Breast Cancer
Chang Min Kim, Kyong Hwa Park, Yun Suk Yu, Ju Won Kim, Jin Young Park, Kyunghee Park, Jong-Han Yu, Jeong Eon Lee, Sung Hoon Sim, Bo Kyoung Seo, Jin Kyeoung Kim, Eun Sook Lee, Yeon Hee Park, Sun-Young Kong
Cancer Res Treat. 2024;56(4):1113-1125.   Published online May 10, 2024
DOI: https://doi.org/10.4143/crt.2024.100
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal-type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies.
Materials and Methods
In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing.
Results
By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor β diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores.
Conclusion
Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.

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  • Significance of Multi-Cancer Genome Profiling Testing for Breast Cancer: A Retrospective Analysis of 3326 Cases from Japan’s National Database
    Kyoka Kawabata, Hinano Nishikubo, Saki Kanei, Rika Aoyama, Yuki Tsukada, Tomoya Sano, Daiki Imanishi, Takashi Sakuma, Koji Maruo, Yurie Yamamoto, Qiang Wang, Zhonglin Zhu, Canfeng Fan, Masakazu Yashiro
    Genes.2024; 15(6): 792.     CrossRef
  • 1,091 View
  • 108 Download
  • 1 Crossref
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Review Article
Precision Oncology Clinical Trials: A Systematic Review of Phase II Clinical Trials with Biomarker-Driven, Adaptive Design
Hyerim Ha, Hee Yeon Lee, Jee Hyun Kim, Do Yeun Kim, Ho Jung An, SeungJin Bae, Hye-sung Park, Jin Hyoung Kang
Cancer Res Treat. 2024;56(4):991-1013.   Published online May 7, 2024
DOI: https://doi.org/10.4143/crt.2024.128
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration’s marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs’ efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.
  • 1,578 View
  • 86 Download
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Original Articles
Genitourinary cancer
Early Plasma Circulating Tumor DNA as a Potential Biomarker of Disease Recurrence in Non-metastatic Prostate Cancer
Xiaochen Fei, Xinxing Du, Yiming Gong, Jiazhou Liu, Liancheng Fan, Jiayi Wang, Yanqing Wang, Yinjie Zhu, Jiahua Pan, Baijun Dong, Wei Xue
Cancer Res Treat. 2023;55(3):969-977.   Published online March 2, 2023
DOI: https://doi.org/10.4143/crt.2022.1557
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
In non-metastatic prostate cancer (nmPCa) setting, it is important to early identify the patients at risk of biochemical recurrence (BCR) for immediate postoperative intervention. Our study aimed to evaluate the potential clinical utility of circulating tumor DNA (ctDNA) for predicting disease recurrence.
Materials and Methods
This real-world observational study evaluated 161 cases of nmPCa undergoing next-generation sequencing at our institution. A total of 139 ctDNA samples and 31 biopsied tumor tissue underwent genomic profiling. The study endpoint was BCR after radical prostatectomy. Relationships between the ctDNA status and the biochemical progression-free survival (bPFS) were analyzed by log-rank test and multivariate Cox regression.
Results
Of 161 enrolled patients, 19 (11.8%) harbored deleterious alterations in NCOR2, followed by BRCA2 (3.7%), ATR (2.5%), and CDK12 (2.5%). Of available pre-operative blood samples (n=139), ctDNA was detectable in 91 (65.5%). Until last follow-up, 56 of 68 patients (85.3%) with detectable ctDNA had achieved BCR, whereas only eight of 39 patients (20.5%) with undetectable ctDNA had achieved BCR. Patients who had undetectable ctDNA experienced significantly longer bPFS compared with those who had detectable ctDNA (not available vs. 8.2 months; hazard ratio, 0.14; p < 0.01). Pre-operative ctDNA status was a significant prognostic factor of disease recurrence.
Conclusion
Pre-operative ctDNA detection could identify patients at high risk of recurrence and has the potential to inform immediate postoperative interventions, but these approaches remain to be validated in prospective studies. ctDNA studies can provide insights into accurate monitoring and precise treatment rather than simply following routine clinical care.

Citations

Citations to this article as recorded by  
  • Role of Liquid Biopsy in Progressive PSA Patients after Radical Prostatectomy
    Marcel Figueras, Lourdes Mengual, Mercedes Ingelmo-Torres, Fiorella L. Roldán, Bernat Padullés, Héctor Alfambra, Sandra Herranz, Pilar Paredes, Gary Amseian, Joel Mases, Maria J. Ribal, Laura Izquierdo, Antonio Alcaraz
    Diagnostics.2024; 14(20): 2293.     CrossRef
  • Circulating Tumor DNA Is a Variant of Liquid Biopsy with Predictive and Prognostic Clinical Value in Breast Cancer Patients
    Tatiana M. Zavarykina, Polina K. Lomskova, Irina V. Pronina, Svetlana V. Khokhlova, Marina B. Stenina, Gennady T. Sukhikh
    International Journal of Molecular Sciences.2023; 24(23): 17073.     CrossRef
  • 3,313 View
  • 183 Download
  • 1 Web of Science
  • 2 Crossref
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Next-generation Proteomics-Based Discovery, Verification, and Validation of Urine Biomarkers for Bladder Cancer Diagnosis
Jungyo Suh, Dohyun Han, Ja Hyeon Ku, Hyeon Hoe Kim, Cheol Kwak, Chang Wook Jeong
Cancer Res Treat. 2022;54(3):882-893.   Published online October 9, 2021
DOI: https://doi.org/10.4143/crt.2021.642
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We aimed to identify, verify, and validate a multiplex urinary biomarker-based prediction model for diagnosis and surveillance of urothelial carcinoma of bladder, using high-throughput proteomics methods.
Materials and Methods
Label-free quantification of data-dependent and data-independent acquisition of 12 and 24 individuals was performed in each of the discovery and verification phases using mass spectrometry, simultaneously using urinary exosome and proteins. Based on five scoring system based on proteomics data and statistical methods, we selected eight proteins. Enzyme-linked immunosorbent assay on urine from 120 patients with bladder mass lesions used for validation. Using multivariable logistic regression, we selected final candidate models for predicting bladder cancer.
Results
Comparing the discovery and verification cohorts, 38% (50/132 exosomal differentially expressed proteins [DEPs]) and 44% (109/248 urinary DEPs) are consistent at statistically significance, respectively. The 20 out of 50 exosome proteins and 27 out of 109 urinary proteins were upregulated in cancer patients. From eight selected proteins, we developed two diagnostic models for bladder cancer. The area under the receiver operating characteristic curve (AUROC) of two models were 0.845 and 0.842, which outperformed AUROC of urine cytology.
Conclusion
The results showed that the two diagnostic models developed here were more accurate than urine cytology. We successfully developed and validated a multiplex urinary protein-based prediction, which will have wide applications for the rapid diagnosis of urothelial carcinoma of the bladder. External validation for this biomarker panel in large population is required.

Citations

Citations to this article as recorded by  
  • A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes
    Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri
    eLife.2024;[Epub]     CrossRef
  • A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes
    Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri
    eLife.2024;[Epub]     CrossRef
  • Comprehensive Urinary Proteome Profiling Analysis Identifies Diagnosis and Relapse Surveillance Biomarkers for Bladder Cancer
    Qi Chang, Yongqiang Chen, Jianjian Yin, Tao Wang, Yuanheng Dai, Zixin Wu, Yufeng Guo, Lingang Wang, Yufen Zhao, Hang Yuan, Dongkui Song, Lirong Zhang
    Journal of Proteome Research.2024; 23(6): 2241.     CrossRef
  • Construction of noninvasive prognostic model of bladder cancer patients based on urine proteomics and screening of natural compounds
    Shun Wan, Jinlong Cao, Siyu Chen, Jianwei Yang, Huabin Wang, Chenyang Wang, Kunpeng Li, Li Yang
    Journal of Cancer Research and Clinical Oncology.2023; 149(1): 281.     CrossRef
  • Extracellular Vesicles as Potential Bladder Cancer Biomarkers: Take It or Leave It?
    Ana Teixeira-Marques, Catarina Lourenço, Miguel Carlos Oliveira, Rui Henrique, Carmen Jerónimo
    International Journal of Molecular Sciences.2023; 24(7): 6757.     CrossRef
  • Advances in the application of label‐free quantitative proteomics techniques in malignancy research
    Xiao Meng, Dong Liu, Yan Guan
    Biomedical Chromatography.2023;[Epub]     CrossRef
  • Off the fog to find the optimal choice: Research advances in biomarkers for early diagnosis and recurrence monitoring of bladder cancer
    Jiaxin Zhao, Jinming Li, Rui Zhang
    Biochimica et Biophysica Acta (BBA) - Reviews on Cancer.2023; 1878(4): 188926.     CrossRef
  • An overview of metabolomic and proteomic profiling in bipolar disorder and its clinical value
    Henrique Caracho Ribeiro, Flávia da Silva Zandonadi, Alessandra Sussulini
    Expert Review of Proteomics.2023; 20(11): 267.     CrossRef
  • Proteome and immune responses of extracellular vesicles derived from macrophages infected with the periodontal pathogen Tannerella forsythia
    Younggap Lim, Hyun Young Kim, Dohyun Han, Bong‐Kyu Choi
    Journal of Extracellular Vesicles.2023;[Epub]     CrossRef
  • A Liquid Biopsy in Bladder Cancer—The Current Landscape in Urinary Biomarkers
    Milena Matuszczak, Adam Kiljańczyk, Maciej Salagierski
    International Journal of Molecular Sciences.2022; 23(15): 8597.     CrossRef
  • Next-generation proteomics of serum extracellular vesicles combined with single-cell RNA sequencing identifies MACROH2A1 associated with refractory COVID-19
    Takahiro Kawasaki, Yoshito Takeda, Ryuya Edahiro, Yuya Shirai, Mari Nogami-Itoh, Takanori Matsuki, Hiroshi Kida, Takatoshi Enomoto, Reina Hara, Yoshimi Noda, Yuichi Adachi, Takayuki Niitsu, Saori Amiya, Yuta Yamaguchi, Teruaki Murakami, Yasuhiro Kato, Tak
    Inflammation and Regeneration.2022;[Epub]     CrossRef
  • 7,917 View
  • 274 Download
  • 10 Web of Science
  • 11 Crossref
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Head and Neck Cancer
Outcomes and Biomarkers of Immune Checkpoint Inhibitor Therapy in Patients with Refractory Head and Neck Squamous Cell Carcinoma: KCSG HN18-12
Yun-Gyoo Lee, Hyun Chang, Bhumsuk Keam, Sang Hoon Chun, Jihyun Park, Keon Uk Park, Seong Hoon Shin, Ho Jung An, Kyoung Eun Lee, Keun-Wook Lee, Hye Ryun Kim, Sung-Bae Kim, Myung-Ju Ahn, In Gyu Hwang
Cancer Res Treat. 2021;53(3):671-677.   Published online December 7, 2020
DOI: https://doi.org/10.4143/crt.2020.824
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
This study was conducted to determine the effectiveness of immune checkpoint inhibitors (ICIs) in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after platinum-containing chemotherapy. We also identified clinical biomarkers which may be predictive of patient prognosis.
Materials and Methods
We analyzed 125 patients with R/M HNSCC who received ICIs, retrospectively. Overall response rate (ORR) was the primary study outcome. Overall survival (OS) and progression-free survival (PFS) were the secondary study outcomes.
Results
The patients received anti–programmed cell death protein-1 (PD-1) (n=73, 58%), anti–programmed death-ligand 1 (PD-L1) (n=24, 19%), or a combination of anti–PD-1/PD-L1 and anti–cytotoxic T-lymphocyte antigen 4 (n=28, 22%). The median age was 57 years (range, 37 to 87). The location of the primary tumor was in the oral cavity in 28% of the cases, followed by oropharynx (27%), hypopharynx (20%), and larynx (12%). The ORR was 15% (19/125). With 12.3 months of median follow-up, median PFS was 2.7 months. Median OS was 10.8 months. A neutrophil-to-lymphocyte ratio (NLR) > 4 was significantly associated with poor response to ICIs (odds ratio, 0.30; p=0.022). A sum of the target lesions > 40 mm (hazard ratio [HR], 1.53; p=0.046] and a NLR > 4 (HR, 1.75; p=0.009) were considered to be predictive markers of short PFS. A poor performance status (HR, 4.79; p < 0.001), a sum of target lesions > 40 mm (HR, 1.93; p=0.025), and an NLR > 4 (HR, 3.36; p < 0.001) were the significant predictors for poor survival.
Conclusion
ICIs exhibited favorable antitumor activity in R/M HNSCC. Clinically, our findings can be used to recognize patients benefit from receiving ICI.

Citations

Citations to this article as recorded by  
  • Impact of PIK3CA and cell cycle pathway genetic alterations on durvalumab efficacy in patients with head and neck squamous cell carcinoma: Post hoc analysis of TRIUMPH study
    Dong Hyun Kim, Seung Taek Lim, Hye Ryun Kim, Eun Joo Kang, Hee Kyung Ahn, Yun-Gyoo Lee, Der Sheng Sun, Jung Hye Kwon, Sang-Cheol Lee, Hyun Woo Lee, Min Kyoung Kim, Bhumsuk Keam, Keon-Uk Park, Seong-Hoon Shin, Hwan Jung Yun
    Oral Oncology.2024; 151: 106739.     CrossRef
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    Lei Liu, Qiang Liu
    Scientific Reports.2024;[Epub]     CrossRef
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    Quan Wang, Xiangzhi Yin, Shengxia Wang, Haijun Lu
    Frontiers in Oncology.2024;[Epub]     CrossRef
  • Predictive value of early dynamic changes of NLR and PLR for the efficacy of immune checkpoint inhibitor in head and neck squamous cell carcinoma
    Dong Hyun Kim, Seo Yoon Jang, Bhumsuk Keam
    Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology.2024;[Epub]     CrossRef
  • Diagnostic Predictors of Immunotherapy Response in Head and Neck Squamous Cell Carcinoma
    Piero Giuseppe Meliante, Federica Zoccali, Marco de Vincentiis, Massimo Ralli, Carla Petrella, Marco Fiore, Antonio Minni, Christian Barbato
    Diagnostics.2023; 13(5): 862.     CrossRef
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    Catherine T. Haring, Lulia A. Kana, Sarah M. Dermody, Collin Brummel, Jonathan B. McHugh, Keith A. Casper, Steven B. Chinn, Kelly M. Malloy, Michelle Mierzwa, Mark E. P. Prince, Andrew J. Rosko, Jennifer Shah, Chaz L. Stucken, Andrew G. Shuman, J. Chad Br
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  • Immunotherapy with PD-1 Inhibitor Nivolumab in Recurrent/Metastatic Platinum Refractory Head and Neck Cancers—Early Experiences from Romania and Literature Review
    Camil Ciprian Mireștean, Mihai Cosmin Stan, Michael Schenker, Constantin Volovăț, Simona Ruxandra Volovăț, Dragoș Teodor Petru Iancu, Roxana Irina Iancu, Florinel Bădulescu
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  • Integrating Cutting-Edge Methods to Oral Cancer Screening, Analysis, and Prognosis
    Sagar Dholariya, Ragini D. Singh, Amit Sonagra, Dharamveer Yadav, Bhairavi N. Vajaria, Deepak Parchwani
    Critical Reviews™ in Oncogenesis.2023; 28(2): 11.     CrossRef
  • Neutrophil–lymphocyte ratio and platelet–lymphocyte ratio as potential predictive markers of treatment response in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis
    Tibera K. Rugambwa, Omar Abdihamid, Xiangyang Zhang, Yinghui Peng, Changjing Cai, Hong Shen, Shan Zeng, Wei Qiu
    Frontiers in Oncology.2023;[Epub]     CrossRef
  • Characterization of Age-Associated, Neutrophil-to-Lymphocyte Ratio (NLR) and Systemic Immune-Inflammatory Index (SII) as Biomarkers of Inflammation in Geriatric Patients with Cancer Treated with Immune Checkpoint Inhibitors: Impact on Efficacy and Surviva
    Khalil Choucair, Caroline Nebhan, Alessio Cortellini, Stijn Hentzen, Yinghong Wang, Cynthia Liu, Raffaele Giusti, Marco Filetti, Paolo Antonio Ascierto, Vito Vanella, Domenico Galetta, Annamaria Catino, Nour Al-Bzour, Azhar Saeed, Ludimila Cavalcante, Pam
    Cancers.2023; 15(20): 5052.     CrossRef
  • A systematic review and meta-analysis of prognostic indicators in patients with head and neck malignancy treated with immune checkpoint inhibitors
    Dengxiong Kang, Siping Liu, Xin Yuan, Shenxiang Liu, Zhengrong Zhang, Zhilian He, Xudong Yin, Haiyan Mao
    Journal of Cancer Research and Clinical Oncology.2023; 149(20): 18215.     CrossRef
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    Jun-Liang Li, Tsai-Ling Hsieh, Ming-Che Ou, Frank Cheau-Feng Lin, Stella Chin-Shaw Tsai
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  • Neutrophil‐to‐lymphocyte ratio as a prognostic marker for head and neck squamous cell carcinoma treated with immune checkpoint inhibitors: Meta‐analysis
    Yukinori Takenaka, Ryohei Oya, Norihiko Takemoto, Hidenori Inohara
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  • Safety and Efficacy of Influenza Vaccination in Patients Receiving Immune Checkpoint Inhibitors. Systematic Review with Meta-Analysis
    Maria A. Lopez-Olivo, Valeria Valerio, Aliza R. Karpes Matusevich, Marianela Brizio, Michelle Kwok, Yimin Geng, Maria E. Suarez-Almazor, Ines Colmegna
    Vaccines.2022; 10(8): 1195.     CrossRef
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    Xueying Wang, Kui Cao, Erliang Guo, Xionghui Mao, Lunhua Guo, Cong Zhang, Junnan Guo, Gang Wang, Xianguang Yang, Ji Sun, Susheng Miao
    Frontiers in Immunology.2021;[Epub]     CrossRef
  • Roles of Major RNA Adenosine Modifications in Head and Neck Squamous Cell Carcinoma
    Xing-xing Huo, Shu-jie Wang, Hang Song, Ming-de Li, Hua Yu, Meng Wang, Hong-xiao Gong, Xiao-ting Qiu, Yong-fu Zhu, Jian-ye Zhang
    Frontiers in Pharmacology.2021;[Epub]     CrossRef
  • 7,015 View
  • 225 Download
  • 14 Web of Science
  • 16 Crossref
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BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy
Sung-Bae Kim, In-Gu Do, Janice Tsang, Tae-You Kim, Yoon-Sim Yap, Gerardo Cornelio, Gyungyub Gong, Soonmyung Paik, Suee Lee, Ting-Ying Ng, Sarah Park, Ho-Suk Oh, Joanne Chiu, Joohyuk Sohn, Moonhee Lee, Young-Jin Choi, Eun Mi Lee, Kyong-Hwa Park, Christos Nathaniel, Jungsil Ro
Cancer Res Treat. 2019;51(4):1527-1539.   Published online June 4, 2019
DOI: https://doi.org/10.4143/crt.2018.598
AbstractAbstract PDFPubReaderePub
Purpose
BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. Materials and Methods Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored.
Results
p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib.
Conclusion
The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.

Citations

Citations to this article as recorded by  
  • PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients
    Ju Won Kim, Ah Reum Lim, Ji Young You, Jung Hyun Lee, Sung Eun Song, Nam Kwon Lee, Seung Pil Jung, Kyu Ran Cho, Cheol Yong Kim, Kyong Hwa Park
    Cancer Research and Treatment.2023; 55(2): 531.     CrossRef
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Dynamics of Soluble Programmed Death-Ligand 1 (sPDL1) during Chemotherapy and Its Prognostic Implications in Cancer Patients: Biomarker Development in Immuno-oncology
Hyerim Ha, Ju-Hee Bang, Ah-Rong Nam, Ji-Eun Park, Mei Hua Jin, Yung-Jue Bang, Do-Youn Oh
Cancer Res Treat. 2019;51(2):832-840.   Published online October 5, 2018
DOI: https://doi.org/10.4143/crt.2018.311
AbstractAbstract PDFPubReaderePub
Purpose
The soluble programmed death-ligand 1 (sPDL1) has immunosuppressive activity and is a candidate biomarker for immuno-oncology drug development. In this study, we measured sPDL1 at pre- and post-chemotherapy and at disease progression to uncover the dynamics of sPDL1 during treatment in biliary tract cancer (BTC) patients.
Materials and Methods
From 90 BTC patients (training cohort, 53; validation cohort, 37) who were candidates for palliative first-line chemotherapy, blood was collected at pre- and post-chemotherapy (at the time of best response) and at disease progression. The sPDL1 levels were measured using an enzyme-linked immunosorbent assay. Responses to chemotherapy, overall survival (OS), and other prognostic factors including the neutrophil-lymphocyte ratio (NLR) were analyzed.
Results
The OS of all patients was 11.5 months (confidence interval [CI], 9.7 to 16.2). The best response was complete response in seven (7.8%), partial response in 20 (22.2%), stable disease in 52 (57.8%), and disease progression (PD) in 11 patients (12.2%). Patients with high pre-chemotherapy sPDL1 (≥ 1.30 ng/mL) showed worse OS than patients with low prechemotherapy sPDL1 (9.1 months vs. 12.5 months, p=0.003). In multivariate analyses, high pre-chemotherapy sPDL1 (hazard ratio [HR], 1.96; 95% CI, 1.2 to 3.9; p=0.011) and high pre-chemotherapy NLR (HR, 1.82; 95% CI, 1.1 to 3.0; p=0.020) were independent poor prognostic factors for OS. At the time of PD, sPDL1 was increased significantly compared with pre-chemotherapy sPDL1 (1.59 ng/mL vs. 0.72 ng/mL, p=0.003).
Conclusion
The sPDL1 at pre-chemotherapy confers the prognostic value for OS in BTC patients under palliative chemotherapy. The dynamics of sPDL1 during chemotherapy correlate with disease burden and have prognostic value.

Citations

Citations to this article as recorded by  
  • Prognostic significance of soluble PD-L1 in prostate cancer
    Margarita Zvirble, Zilvinas Survila, Paulius Bosas, Neringa Dobrovolskiene, Agata Mlynska, Gintaras Zaleskis, Jurgita Jursenaite, Dainius Characiejus, Vita Pasukoniene
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    Lin Chen, Yuqing Chao, Wenjing Li, Zhixia Wu, Qinchuan Wang
    Biomarker Research.2024;[Epub]     CrossRef
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    Ling Yi, Xiaojue Wang, Siyun Fu, Zhuohong Yan, Tianyu Ma, Siqi Li, Panjian Wei, Hongtao Zhang, Jinghui Wang
    Discover Oncology.2023;[Epub]     CrossRef
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    Yangyang Ding, Cheng Sun, Linhui Hu, Shudao Xiong, Zhimin Zhai
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    Vivian Peirce, Michael Paskow, Lei Qin, Ruby Dadzie, Maria Rapoport, Samantha Prince, Sukhvinder Johal
    Targeted Oncology.2023; 18(6): 837.     CrossRef
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    Magdolna Dank, Dorottya Mühl, Magdolna Herold, Lilla Hornyák, Attila Marcell Szasz, Zoltan Herold
    Journal of Clinical Medicine.2022; 11(16): 4815.     CrossRef
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    Jin Won Kim, Kyung‐Hun Lee, Ji‐Won Kim, Koung Jin Suh, Ah‐Rong Nam, Ju‐Hee Bang, Mei Hua Jin, Kyoung‐Seok Oh, Jae‐Min Kim, Tae‐Yong Kim, Do‐Youn Oh
    Liver International.2021; 41(2): 388.     CrossRef
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    Woochan Park, Ju-Hee Bang, Ah-Rong Nam, Mei Hua Jin, Hyerim Seo, Jae-Min Kim, Kyoung Seok Oh, Tae-Yong Kim, Do-Youn Oh
    Cancer Research and Treatment.2021; 53(1): 199.     CrossRef
  • The Clinical Significance of Soluble Programmed Cell Death-Ligand 1 (sPD-L1) in Patients With Gliomas
    Shujun Liu, Yadi Zhu, Chenxi Zhang, Xiangrui Meng, Bo Sun, Guojun Zhang, Yubo Fan, Xixiong Kang
    Frontiers in Oncology.2020;[Epub]     CrossRef
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    Hyunkyung Park, Ju‐Hee Bang, Ah‐Rong Nam, Ji Eun Park, Mei Hua Jin, Yung‐Jue Bang, Do‐Youn Oh
    Cancer Medicine.2020; 9(1): 43.     CrossRef
  • Soluble programmed death-1 (sPD-1) and programmed death ligand 1 (sPD-L1) as potential biomarkers for the diagnosis and prognosis of glioma patients
    Shujun Liu, Yadi Zhu, Chenxi Zhang, Jiajia Liu, Hong Lv, Guojun Zhang, Xixiong Kang
    Journal of Medical Biochemistry.2020; 39(4): 444.     CrossRef
  • Soluble PD-1: Predictive, Prognostic, and Therapeutic Value for Cancer Immunotherapy
    Muhammad Khan, Zhihong Zhao, Sumbal Arooj, Yuxiang Fu, Guixiang Liao
    Frontiers in Immunology.2020;[Epub]     CrossRef
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Immunohistochemistry Biomarkers Predict Survival in Stage II/III Gastric Cancer Patients: From a Prospective Clinical Trial
Min Hwan Kim, Xianglan Zhang, Minkyu Jung, Inkyung Jung, Hyung Soon Park, Seung-Hoon Beom, Hyo Song Kim, Sun Young Rha, Hyunki Kim, Yoon Young Choi, Taeil Son, Hyoung-Il Kim, Jae-Ho Cheong, Woo Jin Hyung, Sung Hoon Noh, Hyun Cheol Chung
Cancer Res Treat. 2019;51(2):819-831.   Published online September 27, 2018
DOI: https://doi.org/10.4143/crt.2018.331
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Identification of biomarkers to predict recurrence risk is essential to improve adjuvant treatment strategies in stage II/III gastric cancer patients. This study evaluated biomarkers for predicting survival after surgical resection.
Materials and Methods
This post-hoc analysis evaluated patients from the CLASSIC trial who underwent D2 gastrectomy with or without adjuvant chemotherapy (capecitabine plus oxaliplatin) at the Yonsei Cancer Center. Tumor expressions of thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and programmed death-ligand 1 (PD-L1) were evaluated by immunohistochemical (IHC) staining to determine their predictive values.
Results
Among 139 patients, IHC analysis revealed high tumor expression of TS (n=22, 15.8%), ERCC1 (n=23, 16.5%), and PD-L1 (n=42, 30.2%) in the subset of patients. Among all patients, high TS expression tended to predict poor disease-free survival (DFS; hazard ratio [HR], 1.80; p=0.053), whereas PD-L1 positivity was associated with favorable DFS (HR, 0.33; p=0.001) and overall survival (OS; HR, 0.38; p=0.009) in multivariate Cox analysis. In the subgroup analysis, poor DFS was independently predicted by high TS expression (HR, 2.51; p=0.022) in the adjuvant chemotherapy subgroup (n=66). High PD-L1 expression was associated with favorable DFS (HR, 0.25; p=0.011) and OS (HR, 0.22; p=0.015) only in the surgery-alone subgroup (n=73). The prognostic impact of high ERCC1 expression was not significant in the multivariate Cox analysis.
Conclusion
This study shows that high TS expression is a predictive factor for worse outcomes on capecitabine plus oxaliplatin adjuvant chemotherapy, whereas PD-L1 expression is a favorable prognostic factor in locally advanced gastric cancer patients.

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  • Utility of TMPRSS4 as a Prognostic Biomarker and Potential Therapeutic Target in Patients with Gastric Cancer
    Hirofumi Tazawa, Takahisa Suzuki, Akihisa Saito, Akira Ishikawa, Toshiaki Komo, Haruki Sada, Norimitsu Shimada, Naoto Hadano, Takashi Onoe, Takeshi Sudo, Yosuke Shimizu, Kazuya Kuraoka, Hirotaka Tashiro
    Journal of Gastrointestinal Surgery.2022; 26(2): 305.     CrossRef
  • Scoring systems for PD-L1 expression and their prognostic impact in patients with resectable gastric cancer
    Marina Alessandra Pereira, Marcus Fernando Kodama Pertille Ramos, André Roncon Dias, Renan Ribeiro, Leonardo Cardili, Bruno Zilberstein, Ivan Cecconello, Ulysses Ribeiro, Evandro Sobroza de Mello, Tiago Biachi de Castria
    Virchows Archiv.2021; 478(6): 1039.     CrossRef
  • Epstein–Barr Virus Positive Gastric Cancer: A Distinct Subtype Candidate for Immunotherapy
    Marina Alessandra Pereira, Daniel Amadeus Molon Batista, Marcus Fernando Kodama Pertille Ramos, Leonardo Cardili, Renan Ribeiro e Ribeiro, Andre Roncon Dias, Bruno Zilberstein, Ulysses Ribeiro Jr, Ivan Cecconello, Venâncio Avancini Ferreira Alves, Evandro
    Journal of Surgical Research.2021; 261: 130.     CrossRef
  • Cytotoxic T‐lymphocyte‐associated protein 4 in gastric cancer: Prognosis and association with PD‐L1 expression
    Marina Alessandra Pereira, Tiago Biachi de Castria, Marcus Fernando Kodama Pertille Ramos, André Roncon Dias, Leonardo Cardili, Rafael Dyer Rodrigues de Moraes, Bruno Zilberstein, Sergio Carlos Nahas, Ulysses Ribeiro, Evandro Sobroza de Mello
    Journal of Surgical Oncology.2021; 124(7): 1040.     CrossRef
  • Remnant gastric cancer: a neglected group with high potential for immunotherapy
    Marcus Fernando Kodama Pertille Ramos, Marina Alessandra Pereira, Tiago Biachi de Castria, Renan Ribeiro e Ribeiro, Leonardo Cardili, Evandro Sobroza de Mello, Bruno Zilberstein, Ulysses Ribeiro-Júnior, Ivan Cecconello
    Journal of Cancer Research and Clinical Oncology.2020; 146(12): 3373.     CrossRef
  • Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma
    Jose J. G. Marin, Laura Perez-Silva, Rocio I. R. Macias, Maitane Asensio, Ana Peleteiro-Vigil, Anabel Sanchez-Martin, Candela Cives-Losada, Paula Sanchon-Sanchez, Beatriz Sanchez De Blas, Elisa Herraez, Oscar Briz, Elisa Lozano
    Cancers.2020; 12(8): 2116.     CrossRef
  • Clinical Significance of CLDN18.2 Expression in Metastatic Diffuse-Type Gastric Cancer
    Seo Ree Kim, Kabsoo Shin, Jae Myung Park, Han Hong Lee, Kyo Yong Song, Sung Hak Lee, Bohyun Kim, Sang-Yeob Kim, Junyoung Seo, Jeong-Oh Kim, Sang-Young Roh, In-Ho Kim
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  • Prognostic and Predictive Factors for the Curative Treatment of Esophageal and Gastric Cancer in Randomized Controlled Trials: A Systematic Review and Meta-Analysis
    van den Ende, ter Veer, Mali, van Berge Henegouwen, Hulshof, van Oijen, van Laarhoven
    Cancers.2019; 11(4): 530.     CrossRef
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Plasma Macrophage Migration Inhibitory Factor and CCL3 as Potential Biomarkers for Distinguishing Patients with Nasopharyngeal Carcinoma from High-Risk Individuals Who Have Positive Epstein-Barr Virus Capsid Antigen-Specific IgA
Ning Xue, Jian-Hua Lin, Shan Xing, Dan Liu, Shi-Bing Li, Yan-Zhen Lai, Xue-Ping Wang, Min-Jie Mao, Qian Zhong, Mu-Sheng Zeng, Wan-Li Liu
Cancer Res Treat. 2019;51(1):378-390.   Published online May 29, 2018
DOI: https://doi.org/10.4143/crt.2018.070
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The purpose of this study was to identify novel plasma biomarkers for distinguishing nasopharyngeal carcinoma (NPC) patients from healthy individuals who have positive Epstein-Barr virus (EBV) viral capsid antigen (VCA-IgA).
Materials and Methods
One hundred seventy-four plasma cytokines were analyzed by a Cytokine Array in eight healthy individuals with positive EBV VCA-IgA and eight patients with NPC. Real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry were employed to detect the expression levels of macrophage migration inhibitory factor (MIF) and CC chemokine ligand 3 (CCL3) in NPC cell lines and tumor tissues. Plasma MIF and CCL3 were measured by ELISA in 138 NPC patients, 127 EBV VCA-IgA negative (VN) and 100 EBV VCA-IgA positive healthy donors (VP). Plasma EBV VCA-IgA was determined by immunoenzymatic techniques.
Results
Thirty-four of the 174 cytokines varied significantly between the VP and NPC group. Plasma MIF and CCL3 were significantly elevated in NPC patients compared with VN and VP. Combination of MIF and CCL3 could be used for the differential diagnosis of NPC from VN cohort (area under the curve [AUC], 0.913; sensitivity, 90.00%; specificity, 80.30%), and combination of MIF, CCL3, and VCA-IgA could be used for the differential diagnosis of NPC from VP cohort (AUC, 0.920; sensitivity, 90.00%; specificity, 84.00%), from (VN+VP) cohort (AUC, 0.961; sensitivity, 90.00%; specificity, 92.00%). Overexpressions of MIF and CCL3 were observed in NPC plasma, NPC cell lines and NPC tissues.
Conclusion
Plasma MIF, CCL3, and VCA-IgA combination significantly improves the diagnostic specificity of NPC in high-risk individuals.

Citations

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  • Nasopharyngeal carcinoma-associated inflammatory cytokines: ongoing biomarkers
    Chuwen Liang, Jun Kan, Jingli Wang, Wei Lu, Xiaoyan Mo, Bei Zhang
    Frontiers in Immunology.2024;[Epub]     CrossRef
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    Dongyu Chuo, Dapeng Lin, Mingdi Yin, Yuze Chen
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    Caihong Wei, Dan Guo, Huayun Pu
    Journal of Biomaterials and Tissue Engineering.2021; 11(7): 1388.     CrossRef
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Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma
Sun Min Lim, Sang Hee Cho, In Gyu Hwang, Jae Woo Choi, Hyun Chang, Myung-Ju Ahn, Keon Uk Park, Ji-Won Kim, Yoon Ho Ko, Hee Kyung Ahn, Byoung Chul Cho, Byung-Ho Nam, Sang Hoon Chun, Ji Hyung Hong, Jung Hye Kwon, Jong Gwon Choi, Eun Joo Kang, Tak Yun, Keun-Wook Lee, Joo-Hang Kim, Jin Soo Kim, Hyun Woo Lee, Min Kyoung Kim, Dongmin Jung, Ji Eun Kim, Bhumsuk Keam, Hwan Jung Yun, Sangwoo Kim, Hye Ryun Kim
Cancer Res Treat. 2019;51(1):300-312.   Published online May 9, 2018
DOI: https://doi.org/10.4143/crt.2018.012
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients.
Materials and Methods
Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data.
Results
Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%).
Conclusion
We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

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Negative Conversion of Progesterone Receptor Status after Primary Systemic Therapy Is Associated with Poor Clinical Outcome in Patients with Breast Cancer
Soomin Ahn, Hyun Jeong Kim, Milim Kim, Yul Ri Chung, Eunyoung Kang, Eun-Kyu Kim, Se Hyun Kim, Yu Jung Kim, Jee Hyun Kim, In Ah Kim, So Yeon Park
Cancer Res Treat. 2018;50(4):1418-1432.   Published online January 24, 2018
DOI: https://doi.org/10.4143/crt.2017.552
AbstractAbstract PDFPubReaderePub
Purpose
Alteration of biomarker status after primary systemic therapy (PST) is occasionally found in breast cancer. This study was conducted to clarify the clinical implications of change of biomarker status in breast cancer patients treated with PST.
Materials and Methods
The pre-chemotherapeutic biopsy and post-chemotherapeutic resection specimens of 442 breast cancer patients who had residual disease after PST were included in this study. The association between changes of biomarker status after PST and clinicopathologic features of tumors, and survival of the patients, were analyzed.
Results
Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status changed after PST in 18 (4.1%), 80 (18.1%), and 15 (3.4%) patients,respectively. ER and PR mainly underwent positive to negative conversion,whereas HER2 status underwent negative to positive conversion. Negative conversion of ER and PR status after PST was associated with reduced disease-free survival. Moreover, a decline in the Allred score for PR in post-PST specimens was significantly associated with poor clinical outcome of the patients. HER2 change did not have prognostic significance. In multivariate analyses, negative PR status after PST was found to be an independent adverse prognostic factor in the whole patient group, in the adjuvant endocrine therapy-treated subgroup, and also in pre-PST PR positive subgroup.
Conclusion
ER and HER2 status changed little after PST, whereas PR status changed significantly. In particular, negative conversion of PR status was revealed as a poor prognostic indicator, suggesting that re-evaluation of basic biomarkers is mandatory in breast cancer after PST for proper management and prognostication of patients.

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Phase II Study of Dovitinib in Patients with Castration-Resistant Prostate Cancer (KCSG-GU11-05)
Yoon Ji Choi, Hye Sook Kim, Se Hoon Park, Bong-Seog Kim, Kyoung Ha Kim, Hyo Jin Lee, Hong Suk Song, Dong-Yeop Shin, Ha Young Lee, Hoon-Gu Kim, Kyung Hee Lee, Jae Lyun Lee, Kyong Hwa Park
Cancer Res Treat. 2018;50(4):1252-1259.   Published online January 2, 2018
DOI: https://doi.org/10.4143/crt.2017.438
AbstractAbstract PDFPubReaderePub
Purpose
Fibroblast growth factor (FGF) signals are important in carcinogenesis and progression of prostate cancer. Dovitinib is an oral, pan-class inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor, and fibroblast growth factor receptor (FGFR). We evaluated the efficacy and toxicity of dovitinib in men with metastatic castration resistant prostate cancer (mCRPC).
Materials and Methods
This study was a single-arm, phase II, open-label, multicenter trial of dovitinib 500 mg/day (5-days-on/2-days-off schedule). The primary endpointwas 16-week progression-free survival (PFS). Secondary endpoints were overall survival (OS), toxicity and prostate-specific antigen (PSA) response rate. Biomarker analyses for VEGFR2, FGF23, and FGFR2 using multiplex enzyme-linked immunosorbent assay was performed.
Results
Forty-four men were accrued from 11 hospitals. Eighty percent were post-docetaxel. Median PSA was 100 ng/dL, median age was 69, 82% had bone metastases, and 23% had liver metastases. Median cycles of dovitinibwas 2 (range, 0 to 33). Median PFSwas 3.67 months (95% confidence interval [CI], 1.36 to 5.98) and median OS was 13.70 months (95% CI, 0 to 27.41). Chemotherapy-naïve patients had longer PFS (17.90 months; 95% CI, 9.23 to 28.57) compared with docetaxel-treated patients (2.07 months; 95% CI, 1.73 to 2.41; p=0.001) and the patients with high serum VEGFR2 level over median level (7,800 pg/mL) showed longer PFS compared with others (6.03 months [95% CI, 4.26 to 7.80] vs. 1.97 months [95% CI, 1.79 to 2.15], p=0.023). Grade 3 related adverse events were seen in 40.9% of patients. Grade 1-2 nausea, diarrhea, fatigue, anorexia, and all grade thrombocytopenia are common.
Conclusion
Dovitinib showed modest antitumor activity with manageable toxicities in men with mCRPC. Especially, patients who were chemo-naïve benefitted from dovitinib.

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Inter-alpha Inhibitor H4 as a Potential Biomarker Predicting the Treatment Outcomes in Patients with Hepatocellular Carcinoma
Eun-Jung Lee, Seung-Hyun Yang, Kyoung-Jin Kim, Hyejung Cha, Seo Jin Lee, Ji-Hye Kim, Junkyu Song, Kyung-Hee Chun, Jinsil Seong
Cancer Res Treat. 2018;50(3):646-657.   Published online July 17, 2017
DOI: https://doi.org/10.4143/crt.2016.550
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Early prediction of treatment outcomes represents an essential step towards increased treatment efficacy and survival in patients with hepatocellular carcinoma (HCC). In this study, we performed two-dimensional electrophoresis (2-DE) followed by protein profiling to identify biomarkers predictive of therapeutic outcomes in patients with HCC who received liver-directed therapy (LDTx) involving local radiotherapy (RT), and studied the underlying mechanisms of the identified proteins.
Materials and Methods
2-DE analysis was conducted by pooling sera from patients with a good or poor prognosis; serum proteomic profiles of the two groups were compared and analyzed using matrixassisted laser desorption/ionization time-of-flight mass spectrometry. Identified proteins were confirmed via enzyme-linked immunosorbent assay. An invasion assay was performed after overexpression and knockdown of target protein in Huh7 cells.
Results
Levels of inter-alpha inhibitor H4 (ITIH4), fibrinogen gamma chain, keratin 9/1 complex, carbonic anhydrase I, and carbonmonoxyhemoglobin S were changed by more than 4-fold in response to LDTx. In particular, pre-LDTx ITIH4 expression was more than 5-fold higher in patients with a good prognosis, compared to patients with a poor prognosis. The migration ability of Huh7 cells was significantly suppressed and enhanced by ITIH4 overexpression and knockdown, respectively. The tumors of patients with HCC and a good prognosis expressed high levels of ITIH4, compared to those of patients with a poor prognosis.
Conclusion
Taken together, ITIH4 may be a potential therapeutic target that could inhibit cancer metastasis, as well as a prognostic marker for patients with HCC who are receiving LDTx.

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Declined Preoperative Aspartate Aminotransferase to Neutrophil Ratio Index Predicts Poor Prognosis in Patients with Intrahepatic Cholangiocarcinoma after Hepatectomy
Lingyun Liu, Wei Wang, Yi Zhang, Jianting Long, Zhaohui Zhang, Qiao Li, Bin Chen, Shaoqiang Li, Yunpeng Hua, Shunli Shen, Baogang Peng
Cancer Res Treat. 2018;50(2):538-550.   Published online June 1, 2017
DOI: https://doi.org/10.4143/crt.2017.106
AbstractAbstract PDFPubReaderePub
Purpose
Various inflammation-based prognostic biomarkers such as the platelet to lymphocyte ratio and neutrophil to lymphocyte ratio, are related to poor survival in patients with intrahepatic cholangiocarcinoma (ICC). This study aims to investigate the prognostic value of the aspartate aminotransferase to neutrophil ratio index (ANRI) in ICC after hepatic resection.
Materials and Methods
Data of 184 patients with ICC after hepatectomy were retrospectively reviewed. The cut-off value of ANRIwas determined by a receiver operating characteristic curve. Preoperative ANRI and clinicopathological variables were analyzed. The predictive value of preoperative ANRI for prognosis of ICC was identified by univariate and multivariate analyses.
Results
The optimal cut-off value of ANRI was 6.7. ANRI was associated with tumor size, tumor recurrence, white blood cell, neutrophil count, aspartate aminotransferase, and alanine transaminase. Univariate analysis showed that ANRI, sex, tumor number, tumor size, tumor differentiation, lymph node metastasis, resection margin, clinical TNM stage, neutrophil count, and carcinoembryonic antigen were markedly correlated with overall survival (OS) and disease-free survival (DFS) in patients with ICC. Multivariable analyses revealed that ANRI, a tumor size > 6 cm, poor tumor differentiation, and an R1 resection margin were independent prognostic factors for both OS and DFS. Additionally, preoperative ANRI also had a significant value to predict prognosis in various subgroups of ICC, including serum hepatitis B surface antigen‒negative and preoperative elevated carbohydrate antigen 19-9 patients.
Conclusion
Preoperative declined ANRI is a noninvasive, simple, and effective predictor of poor prognosis in patients with ICC after hepatectomy.

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Meta-Analysis
Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis
Chiara Cremolini, Carlotta Antoniotti, Filippo Pietrantonio, Rosa Berenato, Marco Tampellini, Chiara Baratelli, Lisa Salvatore, Federica Marmorino, Beatrice Borelli, Federico Nichetti, Paolo Bironzo, Cristina Sonetto, Maria Di Bartolomeo, Filippo de Braud, Fotios Loupakis, Alfredo Falcone, Massimo Di Maio
Cancer Res Treat. 2017;49(3):834-845.   Published online November 15, 2016
DOI: https://doi.org/10.4143/crt.2016.249
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC).
Materials and Methods
A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson’s correlation coefficient (R) and the coefficient of determination (R2).
Results
Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, –2.4 to 3.4) for the median PFS and 0.7 months (range, –5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident.
Conclusion
Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

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Original Articles
FGFR4 Arg388 Is Correlated with Poor Survival in Resected Colon Cancer Promoting Epithelial to Mesenchymal Transition
Sang Hee Cho, Chang Soo Hong, Hee Nam Kim, Min Ho Shin, Ka Rham Kim, Hyun Jeong Shim, Jun Eul Hwang, Woo Kyun Bae, Ik Joo Chung
Cancer Res Treat. 2017;49(3):766-777.   Published online November 9, 2016
DOI: https://doi.org/10.4143/crt.2016.457
AbstractAbstract PDFPubReaderePub
Purpose
Fibroblast growth factor receptor 4 (FGFR4) plays an important role in cancer progression during tumor proliferation, invasion, and metastasis. This study evaluated the prognostic role of FGFR4 polymorphism in patientswith resected colon cancer, including the underlying mechanism.
Materials and Methods
FGFR4 polymorphism was characterized in patientswho received curative resection for stage III colon cancer. FGFR4-dependent signal pathways involving cell proliferation, invasion, and migration according to genotypes were also evaluated in transfected colon cancer cell lines.
Results
Among a total of 273 patients, the GG of FGFR4 showed significantly better overall survival than the AG or AA, regardless of adjuvant treatment. In the group of AG or AA, combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) resulted in better survival than fluorouracil/leucovorin or no adjuvant chemotherapy. However, in GG, there was no difference among treatment regimens. Using multivariate analyses, the Arg388 carriers, together with age, N stage, poor differentiation, absence of a lymphocyte response, and no adjuvant chemotherapy, had a significantly worse OS than patients with the Gly388 allele. In transfected colon cancer cells, overexpression of Arg388 significantly increased cell proliferation and changes in epithelial to mesenchymal transition markers compared with cells overexpressing the Gly388 allele.
Conclusion
The Arg388 allele of FGFR4 may be a biomarker and a candidate target for adjuvant treatment of patients with resected colon cancer.

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Blocking Interleukin-4 Receptor α Using Polyethylene Glycol Functionalized Superparamagnetic Iron Oxide Nanocarriers to Inhibit Breast Cancer Cell Proliferation
Abjal Pasha Shaik, Asma Sultana Shaik, Ali Al Majwal, Achraf Al Faraj
Cancer Res Treat. 2017;49(2):322-329.   Published online July 12, 2016
DOI: https://doi.org/10.4143/crt.2016.091
AbstractAbstract PDFPubReaderePub
Purpose
The specific targeting of interleukin-4 receptor α (IL4Rα) receptor offers a promising therapeutic approach for inhibition of tumor cell progression in breast cancer patients. In the current study, the in vitro efficacy of superparamagnetic iron oxide nanoparticles conjugated with anti-IL4Rα blocking antibodies (SPION-IL4Rα) via polyethylene glycol polymers was evaluated in 4T1 breast cancer cells.
Materials and Methods
Cell viability, reactive oxygen species generation, and apoptosis frequency were assessed in vitro in 4T1 cancer cell lines following exposure to SPION-IL4Rα alone or combined with doxorubicin. In addition, immunofluorescence assessments and fluorimetrywere performed to confirm the specific targeting and interaction of the developed nanocarriers with IL4Rα receptors in breast cancer cells.
Results
Blocking of IL4Rα receptors caused a significant decrease in cell viability and induced apoptosis in 4T1 cells. In addition, combined treatment with SPION-IL4Rα+doxorubicin caused significant increases in cell death, apoptosis, and oxidative stress compared to either SPION-IL4Rα or doxorubicin alone, indicating the enhanced therapeutic efficacy of this combination. The decrease in fluorescence intensity upon immunofluorescence and fluorimetry assays combined with increased viability and decreased apoptosis following the blocking of IL4Rα receptors confirmed the successful binding of the synthesized nanocarriers to the target sites on murine 4T1 breast cancerous cells.
Conclusion
These results suggest that SPION-IL4Rα nanocarriers might be used for successfulreduction of tumor growth and inhibition of progression of metastasis in vivo.

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Reactive Oxygen Species Modulator 1 (Romo1) Predicts Poor Outcomes in Advanced Non-small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy
Seung Hyeun Lee, Sue In Choi, Ji Sung Lee, Chul Hwan Kim, Won Jai Jung, Eun Joo Lee, Kyung Hoon Min, Gyu Young Hur, Seung Heon Lee, Sung Yong Lee, Je Hyeong Kim, Sang Yeub Lee, Chol Shin, Jae Jeong Shim, Kyung Ho Kang, Kwang Ho In
Cancer Res Treat. 2017;49(1):141-149.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2016.133
AbstractAbstract PDFPubReaderePub
Purpose
Reactive oxygen species modulator 1 (Romo1) is a key mediator of intracellular reactive oxygen species production. However, examination of the clinical usefulness of Romo1 in cancers has been limited. We evaluated the association of Romo1 expression with clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
Materials and Methods
Romo1 expression in tumor tissue was examined by immunohistochemistry and evaluated by histological score. Survival analyses were performed according to Romo1 expression and the association between Romo1 expression and clinical parameters was evaluated.
Results
A total of 88 tumor specimens were analyzed. Significantly shorter median progression-free survival (PFS) was observed in the high Romo1 group compared with the low Romo1 group (4.5 months vs. 9.8 months, p < 0.001), and the median overall survival (OS) of the high Romo1 group was also significantly shorter than that of the low Romo1 group (8.4 months vs. 15.5 months, p < 0.001). Results of multivariate analyses showed significant association of high Romo1 expression with both poor PFS (hazard ratio [HR], 2.75; 95% confidence interval [CI], 1.71 to 4.44) and poor OS (HR, 3.99; 95% CI, 2.36 to 6.74). Results of the subgroup analysis showed a similar association regardless of tumor histology. Romo1 expression showed no association with any clinical parameter including age, sex, smoking status, stage, differentiation, or tumor histology.
Conclusion
Romo1 overexpression was associated with poor response to treatment and shorter survival in advanced NSCLC patients treated with platinum-based chemotherapy. Romo1 could be a potential adverse predictive marker in this setting.

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Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort
Minkyu Jung, Jeeyun Lee, Tae Min Kim, Dae Ho Lee, Jin Hyung Kang, Sung Young Oh, Soo Jung Lee, Sang Joon Shin
Cancer Res Treat. 2017;49(1):44-53.   Published online April 27, 2016
DOI: https://doi.org/10.4143/crt.2016.024
AbstractAbstract PDFPubReaderePub
Purpose
Ipilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes.
Materials and Methods
Advanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes.
Results
A total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (≥5) were independent poor prognostic factors by multivariate analysis.
Conclusion
In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR.

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The Usefulness of Procalcitonin and C-Reactive Protein as Early Diagnostic Markers of Bacteremia in Cancer Patients with Febrile Neutropenia
Dae Yong Kim, Yoon-Seon Lee, Shin Ahn, Yeon Hee Chun, Kyung Soo Lim
Cancer Res Treat. 2011;43(3):176-180.   Published online September 30, 2011
DOI: https://doi.org/10.4143/crt.2011.43.3.176
AbstractAbstract PDFPubReaderePub
PURPOSE
Procalcitonin (PCT) and C-reactive protein (CRP) are well known inflammatory markers. This study was designed to determine whether PCT and CRP are useful as early diagnostic markers for bacteremia in cancer patients with febrile neutropenia (FN) in the emergency department (ED).
MATERIALS AND METHODS
In this retrospective study, 286 episodes of FN in the ED were consecutively included between June 2009 and August 2010. From medical records, clinical characteristics including PCT and CRP were extracted and analyzed.
RESULTS
Bacteremia was identified in 38 (13.3%) of the 286 episodes. The median values of PCT (2.8 ng/mL vs. 0.0 ng/mL, p=0.000) and CRP (15.9 mg/dL vs. 5.6 mg/dL, p=0.002) were significantly higher in the group with bacteremia compared to the group without bacteremia. In univariate analysis, elevated PCT (>0.5 ng/mL) and CRP (>10 mg/dL) as well as older age, hypotension, tachycardia, tachypnea, and high body temperature were significantly associated with bacteremia. On multivariate analysis, elevated PCT (>0.5 ng/mL) (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.4 to 9.2; p<0.01) and tachypnea (OR, 3.4; 95% CI, 1.4 to 8.5; p<0.01) were independent early diagnostic markers for bacteremia in FN patients. The area under the curve of PCT was 74.8% (95% CI, 65.1 to 84.6%) and that of CRP was 65.5% (95% CI, 54.8 to 76.1%). With a PCT cut-off value of 0.5 ng/mL, sensitivity and specificity were 60.5% and 82.3%, respectively, while the sensitivity and specificity were 57.6% and 67.3%, respectively, with a CRP cutoff of 10 mg/dL.
CONCLUSION
These findings suggest that PCT is a useful early diagnostic marker for the detection of bacteremia in FN at the ED and has better diagnostic value than CRP.

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