Cancer Research and Treatment

Original Articles

Lung and Thoracic cancer

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

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

Citations

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

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Gastrointestinal cancer

Circulating Tumor DNA Dynamics and Treatment Outcome of Regorafenib in Metastatic Colorectal Cancer: Dae-Won Lee, Yoojoo Lim, Hwang-Phill Kim, Su Yeon Kim, Hanseong Roh, Jun-Kyu Kang, Kyung‑Hun Lee, Min Jung Kim, Seung-Bum Ryoo, Ji Won Park, Seung-Yong Jeong, Kyu Joo Park, Gyeong Hoon Kang, Sae-Won Han, Tae-You Kim; Cancer Res Treat. 2023;55(3):927-938. Published online March 7, 2023; DOI: https://doi.org/10.4143/crt.2023.268

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Purpose
Circulating tumor DNA (ctDNA) is emerging as a valuable non-invasive tool to identify tumor heterogeneity and tumor burden. This study investigated ctDNA dynamics in metastatic colorectal cancer patients treated with regorafenib.
Materials and Methods
In this prospective biomarker study, plasma cell-free DNA (cfDNA) samples obtained at baseline, at the first response evaluation after 2 cycles of treatment, and at the time of progressive disease were sequenced using a targeted next-generation sequencing platform which included 106 genes.
Results
A total of 285 blood samples from 110 patients were analyzed. Higher baseline cfDNA concentration was associated with worse progression-free survival (PFS) and overall survival (OS). After 2 cycles of treatment, variant allele frequency (VAF) in the majority of ctDNA mutations decreased with a mean relative change of –31.6%. Decreases in the VAF of TP53, APC, TCF7L2, and ROS1 after 2 cycles of regorafenib were associated with longer PFS. We used the sum of VAF at each time point as a surrogate for the overall ctDNA burden. A reduction in sum (VAF) of ≥ 50% after 2 cycles was associated with longer PFS (6.1 vs. 2.7 months, p=0.002), OS (11.3 vs. 5.9 months, p=0.001), and higher disease control rate (86.3% vs. 51.1%, p < 0.001). VAF of the majority of the ctDNA mutations increased at the time of disease progression, and VAF of BRAF increased markedly.
Conclusion
Reduction in ctDNA burden as estimated by sum (VAF) could be used to predict treatment outcome of regorafenib.

Citations

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Adjuvant therapy for stage IIB + IIC melanoma
Parisa Malekzadeh, Mary S. Brady
Journal of Surgical Oncology.2024; 129(1): 91. CrossRef
Variant allele frequency in circulating tumor DNA correlated with tumor disease burden and predicted outcomes in patients with advanced breast cancer
Jianxin Zhong, Hanfang Jiang, Xiaoran Liu, Hao Liao, Feng Xie, Bin Shao, Shidong Jia, Huiping Li
Breast Cancer Research and Treatment.2024; 204(3): 617. CrossRef
Stage-Specific Plasma Metabolomic Profiles in Colorectal Cancer
Tetsuo Ishizaki, Masahiro Sugimoto, Yu Kuboyama, Junichi Mazaki, Kenta Kasahara, Tomoya Tago, Ryutaro Udo, Kenichi Iwasaki, Yutaka Hayashi, Yuichi Nagakawa
Journal of Clinical Medicine.2024; 13(17): 5202. CrossRef
Nivolumab plus anlotinib hydrochloride in advanced gastric adenocarcinoma and esophageal squamous cell carcinoma: the phase II OASIS trial
Jing Wu, Shilong Zhang, Shan Yu, Guo An, Yi Wang, Yiyi Yu, Li Liang, Yan Wang, Xiaojing Xu, YanShi Xiong, Di Shao, Zhun Shi, Nannan Li, Jingyuan Wang, Dawei Jin, Tianshu Liu, Yuehong Cui
Nature Communications.2024;[Epub] CrossRef
Mutational evolution after chemotherapy‐progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis
Sheehyun Kim, Yongjun Cha, Yoojoo Lim, Hanseong Roh, Jun‐Kyu Kang, Kyung‐Hun Lee, Min Jung Kim, Ji Won Park, Seung‐Bum Ryoo, Hwang‐Phill Kim, Seung‐Yong Jeong, Kyu Joo Park, Sae‐Won Han, Tae‐You Kim
International Journal of Cancer.2023; 153(3): 571. CrossRef
A Phase II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients with Metastatic Colorectal Cancer Who Have Failed First-Line Therapy
Karen Gambaro, Maud Marques, Suzan McNamara, Mathilde Couetoux du Tertre, Cyrla Hoffert, Archana Srivastava, Anna Schab, Thierry Alcindor, Adrian Langleben, Lucas Sideris, Mahmoud Abdelsalam, Mustapha Tehfe, Felix Couture, Gerald Batist, Petr Kavan
International Journal of Molecular Sciences.2023; 25(1): 43. CrossRef

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Case Report

Efficacy of Olaparib in Treatment-Refractory, Metastatic Breast Cancer with Uncommon Somatic BRCA Mutations Detected in Circulating Tumor DNA: Jung-Ki Yoon, Jongseong Ahn, Sheehyun Kim, Hwang-Phil Kim, Jun-kyu Kang, Duhee Bang, Yoojoo Lim, Tae-You Kim; Cancer Res Treat. 2023;55(3):1048-1052. Published online January 31, 2023; DOI: https://doi.org/10.4143/crt.2022.1529

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Poly(ADP-ribose) polymerase inhibitors have been shown dramatic responses in patients with BRCAness. However, clinical studies have been limited to breast cancer patients with germline mutations. Here, we describe a patient with metastatic breast cancer who had a rare BRCA1 somatic mutation (BRCA1 c.4336G>T (p.E1446*)) detected by cell-free DNA analysis after failing standard therapies. This tier III variant of unknown significance was predicted to be a pathogenic variant in our assessment, leading us to consider off-label treatment with olaparib. The patient responded well to olaparib for several months, with a decrease in allele frequency of this BRCA1 somatic mutation in cell-free DNA. Olaparib resistance subsequently developed with an increase in the allele frequency and new BRCA1 reversion mutations. To our knowledge, this is the first report confirming BRCA1 c.4336G>T (p.E1446*) as a mutation sensitive to olaparib in breast cancer and describing the dynamic changes in the associated mutations using liquid biopsy.

Citations

Citations to this article as recorded by

Circulating tumor DNA validity and potential uses in metastatic breast cancer
Ottavia Amato, Nefeli Giannopoulou, Michail Ignatiadis
npj Breast Cancer.2024;[Epub] CrossRef
DNA damage targeted therapy for advanced breast cancer
Vanessa Patel, Sandra Casimiro, Catarina Abreu, Tiago Barroso, Rita Teixeira de Sousa, Sofia Torres, Leonor Abreu Ribeiro, Gonçalo Nogueira-Costa, Helena Luna Pais, Conceição Pinto, Leila Costa, Luís Costa
Exploration of Targeted Anti-tumor Therapy.2024; 5(3): 678. CrossRef
Practical Utility of Liquid Biopsies for Evaluating Genomic Alterations in Castration-Resistant Prostate Cancer
Seung-Hwan Jeong, Dongsoo Kyung, Hyeong Dong Yuk, Chang Wook Jeong, Wookjae Lee, Jung-Ki Yoon, Hwang-Phill Kim, Duhee Bang, Tae-You Kim, Yoojoo Lim, Cheol Kwak
Cancers.2023; 15(10): 2847. CrossRef

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Original Article

Korean Cancer Patients’ Awareness of Clinical Trials, Perceptions on the Benefit and Willingness to Participate: Yoojoo Lim, Jee Min Lim, Won Jae Jeong, Kyung-Hun Lee, Bhumsuk Keam, Tae-Yong Kim, Tae Min Kim, Sae-Won Han, Do Youn Oh, Dong-Wan Kim, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2017;49(4):1033-1043. Published online April 7, 2017; DOI: https://doi.org/10.4143/crt.2016.413

Abstract PDF PubReader ePub

Purpose
The purpose of this study was to assess current levels of awareness of clinical trials (CTs), perceptions regarding their benefits and willingness to participate to CTs among Korean cancer patients.
Materials and Methods
From December 2012 to August 2015, we distributed questionnaires to cancer patients receiving systemic anti-cancer therapy at Seoul National University Hospital, Seoul, Korea.
Results
A total of 397 out of 520 requested patients (76.3%) responded to the survey. Among the 397 patients, 62.5% were female and the median age was 52 years. Overall, 97.4% (387/397) answered that they have at least heard of CTs. When asked about their level of awareness, 23.8% (92/387) answered that they could more than roughly explain about CTs. The average visual analogue scale score of CT benefit in all patients was 6.43 (standard deviation, 2.20). Patients who were only familiar with the term without detailed knowledge of the contents had the least expectation of benefit from CTs (p=0.015). When asked about their willingness to participate in CTs, 56.7% (225/397) answered positively. Patients with higher levels of awareness of CTs showed higher willingness to participate (p < 0.001). Heavily treated patients and patients with previous experience regarding CTs also showed a higher willingness to participate (p < 0.001). The perceived benefit of CTs was higher in the group willing to participate (p=0.026).
Conclusion
The patient’s level of awareness regarding CTs was positively related to the positive perception and willingness to participate. Although the general awareness of CTs was high, a relatively large proportion of patients did not have accurate knowledge; therefore, proper and accurate patient education is necessary.

Citations

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Depression and anxiety among hemophilia patients enrolled in clinical trials: a multi-center cohort study
Zhen Peng, Xiaoyu Zhu, Chongwei Wang, Mingfeng Zhou, Xiaoling Xu, Yin Chen
Annals of Hematology.2023; 102(7): 1927. CrossRef
Depression and anxiety in cancer patient enrolled in clinical trials with serious adverse events
Zhen Peng, Chongwei Wang, Yubei Sun, Yan Ma, Jumei Wang, Fei Xu, Xiaoling Xu, Yin Chen
Cancer Medicine.2023; 12(19): 20015. CrossRef
Acceptance Factors and Psychological Investigation of Clinical Trials in Cancer Patients
Jiangjie Sun, Jingyi Fang, Chenchen Zhang, Nannan Jia, Weiming Zhao, Jinjian Gao, Yingying Huang, Jiqing Hao, Liping Zhang, Carmen M Galvez-Sánchez
Behavioural Neurology.2023; 2023: 1. CrossRef
Understanding and attitudes of the Jordanian public about clinical research ethics
Mera A Ababneh, Sayer I Al-Azzam, Karem Alzoubi, Abeer Rababa’h, Saddam Al Demour
Research Ethics.2021; 17(2): 228. CrossRef
A patient-focused, theory-guided approach to survey design identified barriers to and drivers of clinical trial participation
Jamie C. Brehaut, Kelly Carroll, Justin Presseau, Dawn P. Richards, Jenn Gordon, Angèle Bénard, Natasha Hudek, Ian D. Graham, Dean A. Fergusson, Susan Marlin
Journal of Clinical Epidemiology.2021; 132: 106. CrossRef
Awareness of breast cancer patients in Poland about clinical trials as available treatment options
Mikołaj Bartoszkiewicz, Joanna Kufel-Grabowska, Maria Litwiniuk
Breast Disease.2021; 40(1): 33. CrossRef
Results from a Theory-Guided Survey to Support Breast Cancer Trial Participation: Barriers, Enablers, and What to Do about them
Jamie C. Brehaut, Kelly Carroll, Jenn Gordon, Justin Presseau, Dawn P. Richards, Dean A. Fergusson, Ian D. Graham, Susan Marlin
Current Oncology.2021; 28(3): 2014. CrossRef
Regional Differences in Access to Clinical Trials for Cancer in Korea
Woorim Kim, Seongkyeong Jang, Yoon Jung Chang
Quality Improvement in Health Care.2021; 27(1): 20. CrossRef
How Cancer Patients Perceive Clinical Trials (CTs) in the Era of CTs: Current Perception and Its Differences Between Common and Rare Cancers
Ji Hyun Park, Ji Sung Lee, HaYeong Koo, Jeong Eun Kim, Jin-Hee Ahn, Min-Hee Ryu, Sook-ryun Park, Shin-kyo Yoon, Jae Cheol Lee, Yong-Sang Hong, Sun Young Kim, Kyo-Pyo Kim, Chang-Hoon Yoo, Jung Yong Hong, Jae Lyun Lee, Kyung Hae Jung, Baek-Yeol Rhyoo, Tae W
Journal of Cancer Education.2020; 35(3): 545. CrossRef
Colorectal cancer survivors’ willingness to participate in a hypothetical clinical trial of Korean medicine: A cross-sectional study
Yown Hwangbo, Gyung Mo Son, Kyung Hee Kim, Myeong Sook Kwon, Kun Hyung Kim
European Journal of Integrative Medicine.2020; 33: 101033. CrossRef
Perception and Satisfaction of Anticancer Drug Clinical Trials in Cancer Patients
Ju Kyung Jeon, Jeong Hye Kim
Asian Oncology Nursing.2019; 19(1): 18. CrossRef
Challenges in informed consent decision-making in Korean clinical research: A participant perspective
Im-Soon Choi, Eun Young Choi, Iyn-Hyang Lee, Dermot Cox
PLOS ONE.2019; 14(5): e0216889. CrossRef
Clinical Trials: What, Where, When?
Olga S. Kobyakova, Ivan A. Deev, Evgeny S. Kulikov, Roman I. Shtykh, Igor D. Pimenov, Olga I. Zvonareva, Igor V. Mareev
Annals of the Russian academy of medical sciences.2018; 73(5): 314. CrossRef

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