Publications by authors named "Yeul Hong Kim"

200 Publications

Clinical Implication of Liquid Biopsy in Colorectal Cancer Patients Treated with Metastasectomy.

Cancers (Basel) 2021 May 6;13(9). Epub 2021 May 6.

Division of Medical Oncology and Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Korea.

Background & Aims: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA level before and after metastasectomy in patients with mCRC to explore its potential as a predictive biomarker.

Methods: We collected data on 98 metastasectomies for mCRC performed from March 2017 to February 2020. Somatic mutations in the primary and metastatic tumors were identified and tumor-informed ctDNAs were selected by ultra-deep targeted sequencing. Plasma samples were mandatorily collected before and 3-4 weeks after metastasectomy and serially, if patients agreed.

Results: Data on 67 of 98 metastasectomies (58 patients) meeting the criteria were collected. ctDNA was detected in 9 (29%) of 31 cases treated with upfront metastasectomy and in 7 (19.4%) of 36 cases treated with metastasectomy after upfront chemotherapy. The detection rate of ctDNA was higher in liver metastasis ( = 0.0045) and tumors measuring ≥1 cm ( = 0.0183). ctDNA was less likely to be detected if the response to chemotherapy was good. After metastasectomy, ctDNA was found in 4 (6%) cases with rapid progressive disease.

Conclusion: The biological factors affecting the ctDNA shedding from the tumor should be considered when applying ctDNA assays in a clinical setting. After metastasectomy for oligometastatic lesions in good responders of chemotherapy, most ctDNA was cleared or existed below the detection level. To assist clinical decision making after metastasectomy for mCRC using ctDNA, further studies for improving specific outcomes are needed.
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http://dx.doi.org/10.3390/cancers13092231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125778PMC
May 2021

Comparison of the Data of a Next-Generation Sequencing Panel from K-MASTER Project with that of Orthogonal Methods for Detecting Targetable Genetic Alterations.

Cancer Res Treat 2021 May 20. Epub 2021 May 20.

Division of Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.

Purpose: K-MASTER project is a Korean national precision medicine platform that screened actionable mutations by analyzing next-generation sequencing (NGS) of solid tumor patients. We compared gene analyses between NGS panel from the K-MASTER project and orthogonal methods.

Materials And Methods: Colorectal, breast, non-small-cell lung, and gastric cancer patients were included. We compared NGS results from K-MASTER projects with those of non-NGS orthogonal methods (KRAS, NRAS, and BRAF mutations in colorectal cancer (CRC); EGFR, ALK fusion, and ROS1 fusion in non-small-cell lung cancer (NSCLC), and ERBB2 positivity in breast and gastric cancers).

Results: In the CRC cohort (n=225), the sensitivity and specificity of NGS were 87.4% and 79.3% (KRAS); 88.9% and 98.9% (NRAS); and 77.8% and 100.0% (BRAF), respectively. In the NSCLC cohort (n=109), the sensitivity and specificity of NGS for EGFR were 86.2% and 97.5%, respectively. The concordance rate for ALK fusion was 100%, but ROS1 fusion was positive in only one of three cases that were positive in orthogonal tests. In the breast cancer cohort (n=260), ERBB2 amplification was detected in 45 by NGS. Compared with orthogonal methods that integrated immunohistochemistry and in situ hybridization, sensitivity and specificity were 53.7% and 99.4%, respectively. In the gastric cancer cohort (n=64), ERBB2 amplification was detected in six by NGS. Compared with orthogonal methods, sensitivity and specificity were 62.5% and 98.2%, respectively.

Conclusion: The results of the K-MASTER NGS panel and orthogonal methods showed a different degree of agreement for each genetic alteration, but generally showed a high agreement rate.
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http://dx.doi.org/10.4143/crt.2021.218DOI Listing
May 2021

Tumor Suppressor miR-584-5p Inhibits Migration and Invasion in Smoking Related Non-Small Cell Lung Cancer Cells by Targeting YKT6.

Cancers (Basel) 2021 Mar 8;13(5). Epub 2021 Mar 8.

Cancer Research Institute, Korea University College of Medicine, Goryeodae-ro 73, Seongbuk-gu, Seoul 02841, Korea.

Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate the change of miRNA expression pattern and to identify tumor suppressor miRNAs by smoking in lung carcinogenesis, we used lung carcinogenesis model cell lines that, derived from a murine xenograft model with human bronchial epithelial cells (BEAS-2B), exposed CS or not. The microarray analysis revealed that miR-584-5p expression was downregulated with cancer progression in lung carcinogenesis model cell lines. We confirmed by pyrosequencing that the methylation level of the miR-584-5p promoter increased with cancer progression. In vitro and in vivo experiments showed that miR-584-5p suppressed migration and invasion in non-small cell lung cancer (NSCLC) cells by targeting YKT6. Furthermore, we showed that high level of YKT6 was associated with a poor survival rate in NSCLC patients with a history of smoking. These results suggest that miR-584-5p acts as a tumor suppressor and is a potential molecular biomarker for smoking-related NSCLC.
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http://dx.doi.org/10.3390/cancers13051159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962648PMC
March 2021

Clathrin-mediated EGFR endocytosis as a potential therapeutic strategy for overcoming primary resistance of EGFR TKI in wild-type EGFR non-small cell lung cancer.

Cancer Med 2021 01 12;10(1):372-385. Epub 2020 Dec 12.

Cancer Research Institute, Korea University College of Medicine, Seoul, Republic of Korea.

Objectives: Oncogenic alterations of epidermal growth factor receptor (EGFR) signaling are frequently noted in non-small cell lung cancer (NSCLC). In recent decades, EGFR tyrosine kinase inhibitors (TKIs) have been developed, although the therapeutic efficacy of these inhibitor is restricted to EGFR-mutant patients. In this study, we investigated that clathrin-mediated EGFR endocytosis hampers the effects of gefitinib and sustains NSCLC cells with wild-type EGFR.

Materials And Methods: NSCLC cell lines (H358, Calu-3, SNU-1327, and H1703) were stimulated with the EGF and treated with gefitinib and endocytosis inhibitors (phenylarsine oxide (PAO) and Filipin III). Growth inhibition and apoptosis were evaluated. Immunofluorescence, immunoprecipitation, and western blot assay were performed to investigate EGFR endocytosis and determine the signaling pathway. Xenograft mouse models were used to verify the combination effect of gefitinib and PAO in vivo.

Results: We confirmed the differences in EGFR endocytosis according to gefitinib response in wild-type EGFR NSCLC cell lines. EGFR in gefitinib-sensitive and -refractory cell lines tended to internalize through distinct routes, caveolin-mediated endocytosis (CVE), and clathrin-mediated endocytosis (CME). Interestingly, while suppressing CME and CVE did not affect cell survival in sensitive cell lines significantly, CME inhibition combined with gefitinib treatment decreased cell survival and induced apoptosis in gefitinib-refractory cell lines. In addition, blocking CME in the refractory cell lines led to downregulate of p-STAT3 and inhibit nuclear localization of STAT3 in vivo, combination treatment with gefitinib and a CME inhibitor resulted in tumor regression accompanying apoptosis in xenograft mouse models.

Conclusion: Clathrin-mediated EGFR endocytosis contribute primary resistance of gefitinib treatment and CME inhibition combined with gefitinib could be an option in treatment of wild-type EGFR NSCLC.
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http://dx.doi.org/10.1002/cam4.3635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826488PMC
January 2021

HSP90 Inhibitor, 17-DMAG, Alone and in Combination with Lapatinib Attenuates Acquired Lapatinib-Resistance in ER-positive, HER2-Overexpressing Breast Cancer Cell Line.

Cancers (Basel) 2020 Sep 15;12(9). Epub 2020 Sep 15.

Division of Oncology/Hematology, Department of Internal Medicine, Korea University College Medicine, Seoul 02841, Korea.

Lapatinib, a Human Epidermal growth factor Receptor 2 (HER2)-targeting therapy in HER2-overexpressing breast cancer, has been widely used clinically, but the prognosis is still poor because most patients acquire resistance. Therefore, we investigated mechanisms related to lapatinib resistance to evaluate new therapeutic targets that may overcome resistance. Lapatinib-resistant cell lines were established using SKBR3 and BT474 cells. We evaluated cell viability and cell signal changes, gene expression and protein changes. In the xenograft mouse model, anti-tumor effects were evaluated using drugs. Analysis of the protein interaction network in two resistant cell lines with different lapatinib resistance mechanisms showed that HSP90 protein was commonly increased. When Heat Shock Protein 90 (HSP90) inhibitors were administered alone to both resistant cell lines, cell proliferation and protein expression were effectively inhibited. However, inhibition of cell proliferation and protein expression with a combination of lapatinib and HSP90 inhibitors showed a more synergistic effect in the LR-BT474 cell line than the LR-SKBR3 cell line, and the same result was exhibited with the xenograft model. These results suggest that HSP90 inhibitors in patients with lapatinib-resistant Estrogen Receptor (ER) (+) HER2 (+) breast cancer are promising therapeutics for future clinical trials.
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http://dx.doi.org/10.3390/cancers12092630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564044PMC
September 2020

The Clinical Significance of RAS, PIK3CA, and PTEN Mutations in Non-Small Cell Lung Cancer Using Cell-Free DNA.

J Clin Med 2020 Aug 14;9(8). Epub 2020 Aug 14.

Division of Oncology/Hematology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Korea.

Mutations in the EGFR gene downstream signaling pathways may cause receptor-independent pathway activation, making tumors unresponsive to EGFR inhibitors. However, the clinical significance of RAS, PIK3CA or PTEN mutations in NSCLC is unclear. In this study, patients who were initially diagnosed with NSCLC or experienced recurrence after surgical resection were enrolled, and blood samples was collected. Ultra-deep sequencing analysis of cfDNA using Ion AmpliSeq Cancer Hotspot Panel v2 with Proton platforms was conducted. RAS/PIK3CA/PTEN mutations were frequently detected in cfDNA in stage IV NSCLC (58.1%), and a high proportion of the patients (47.8%) with mutations had bone metastases at diagnosis. The frequency of RAS/PIK3CA/PTEN mutations in patients with activating EGFR mutation was 61.7%. The median PFS for EGFR-TKIs was 15.1 months in patients without RAS/PIK3CA/PTEN mutations, and 19.9 months in patients with mutations ( = 0.549). For patients with activating EGFR mutations, the overall survival was longer in patients without RAS/PIK3CA/PTEN mutations (53.8 months vs. 27.4 months). For the multivariate analysis, RAS/PIK3CA/PTEN mutations were independent predictors of poor prognosis in patients with activating EGFR mutations. In conclusion, RAS, PIK3CA and PTEN mutations do not hamper EGFR-TKI treatment outcome; however, they predict a poor OS when activating EGFR mutations coexist.
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http://dx.doi.org/10.3390/jcm9082642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465200PMC
August 2020

Clinical Application of Targeted Deep Sequencing in Metastatic Colorectal Cancer Patients: Actionable Genomic Alteration in K-MASTER Project.

Cancer Res Treat 2021 Jan 18;53(1):123-130. Epub 2020 Aug 18.

Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.

Purpose: Next-generation sequencing (NGS) can facilitate precision medicine approaches in metastatic colorectal cancer (mCRC) patients. We investigated the molecular profiling of Korean mCRC patients under the K-MASTER project which was initiated in June 2017 as a nationwide precision medicine oncology clinical trial platform which used NGS assay to screen actionable mutations.

Materials And Methods: As of 22 January 2020, total of 994 mCRC patients were registered in K-MASTER project. Targeted sequencing was performed using three platforms which were composed of the K-MASTER cancer panel v1.1 and the SNUH FIRST Cancer Panel v3.01. If tumor tissue was not available, cell-free DNA was extracted and the targeted sequencing was performed by Axen Cancer Panel as a liquid biopsy.

Results: In 994 mCRC patients, we found 1,564 clinically meaningful pathogenic variants which mutated in 71 genes. Anti-EGFR therapy candidates were 467 patients (47.0%) and BRAF V600E mutation (n=47, 4.7%), deficient mismatch repair/microsatellite instability-high (n=15, 1.5%), HER2 amplifications (n=10, 1.0%) could be incorporated with recently approved drugs. The patients with high tumor mutation burden (n=101, 12.7%) and DNA damaging response and repair defect pathway alteration (n=42, 4.2%) could be enrolled clinical trials with immune checkpoint inhibitors. There were more colorectal cancer molecular alterations such as PIK3CA, KRAS G12C, atypical BRAF, and HER2 mutations and even rarer but actionable genes that approved or ongoing clinical trials in other solid tumors.

Conclusion: K-MASTER project provides an intriguing background to investigate new clinical trials with biomarkers and give therapeutic opportunity for mCRC patients.
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http://dx.doi.org/10.4143/crt.2020.559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812021PMC
January 2021

Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.

Lancet Oncol 2020 08 9;21(8):1066-1076. Epub 2020 Jul 9.

MacroGenics, Rockville, MD, USA.

Background: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma.

Methods: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing.

Findings: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients.

Interpretation: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab).

Funding: MacroGenics.
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http://dx.doi.org/10.1016/S1470-2045(20)30326-0DOI Listing
August 2020

Innovative countermeasures can maintain cancer care continuity during the coronavirus disease-2019 pandemic in Korea.

Eur J Cancer 2020 09 3;136:69-75. Epub 2020 Jul 3.

Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea. Electronic address:

Background: Even though Korea was known to have the highest number of coronavirus disease-2019 (COVID-19) infection in the early phase of the pandemic, Korea was able to successfully flatten the curve in a short period of time without extreme measures. We compared the status of cancer management before and after COVID-19 and analysed how cancer care continuity was maintained in Korea.

Patients And Methods: We investigated the medical records on the number of cancer diagnosis, cancer surgery, radiation therapy and scheduled chemotherapy conducted in Korea University Anam Hospital from January 1 to April 30, 2019 and from the same period in 2020. We also collected the data of metastatic cancer patients who were hospitalised due to respiratory disease.

Results: Of all diagnoses, 1694 cancer diagnoses were made in the study period of 2019, and 1445 diagnoses in 2020 (decreased by 14.7%); the cancer surgery performed 830 and 800 cases; the set-up for radiation therapy decreased from 185 to 140 cases; the number of systemic chemotherapies for metastatic cancer patients treated in department of medical oncology increased from 2555 to 2878 cases. Among hospitalised patients, emergency centre visit, intensive care unit admission, discharge after recovery and death reveal no drastic changes.

Conclusions: Routine cancer care for patients with metastatic cancer has been maintained without significant difference before and after the COVID-19 pandemic. The Korean government's innovative countermeasures in the early phase of outbreak made it possible for cancer care practitioners to provide cancer patients with regular care under the standard infection control protocol.
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http://dx.doi.org/10.1016/j.ejca.2020.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332944PMC
September 2020

A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair-Deficient/Microsatellite Instability-High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer.

Cancer Res Treat 2020 Oct 24;52(4):1135-1144. Epub 2020 Apr 24.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations.

Materials And Methods: In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1.

Results: The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in four and two patients, respectively, with no treatment-related deaths.

Conclusion: Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.
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http://dx.doi.org/10.4143/crt.2020.218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577804PMC
October 2020

Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial.

Eur J Cancer 2020 05 13;130:51-62. Epub 2020 Mar 13.

Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea. Electronic address:

Background: Cancer-related fatigue (CRF) is a common symptom and has a negative impact on prognosis in cancer patients. CRF could be improved by Korean red ginseng (KRG).

Patients And Methods: For this randomised and double-blinded trial, colorectal cancer patients who received mFOLFOX-6 were randomly assigned to either KRG 2000 mg/day (n = 219) or placebo (n = 219) for 16 weeks. CRF was evaluated using the mean area under the curve (AUC) change from baseline of brief fatigue inventory (BFI) as the primary endpoint. Fatigue-related quality of life, stress, and adverse events were evaluated as secondary endpoints.

Results: In the full analysis group, KRG up to 16 weeks improved CRF by the mean AUC change from baseline of BFI compared to placebo, particularly in "Mood" and "Walking ability" (P = 0.038, P = 0.023, respectively). In the per-protocol group, KRG led to improved CRF in the global BFI score compared with the placebo (P = 0.019). Specifically, there were improvements in "Fatigue right now," "Mood," "Relations with others," "Walking ability," and "Enjoyment of life" at 16 weeks (P = 0.045, P = 0.006, P = 0.028, P = 0.003, P = 0.036, respectively). In subgroups of female patients, ≥60 years old, with high compliance (≥80%) or more baseline fatigue, the beneficial effects of KRG were more enhanced than that of placebo. Although neutropenia was more frequent in KRG than placebo, the incidence of all adverse events was similar.

Conclusions: KRG could be safely combined with mFOLFOX-6 chemotherapy in colorectal cancer patients, and reduced CRF compared with placebo.
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http://dx.doi.org/10.1016/j.ejca.2020.02.018DOI Listing
May 2020

Clinical Implication of Concordant or Discordant Genomic Profiling between Primary and Matched Metastatic Tissues in Patients with Colorectal Cancer.

Cancer Res Treat 2020 Jul 16;52(3):764-778. Epub 2020 Feb 16.

Division of Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea.

Purpose: The purpose of this study was to identify the concordant or discordant genomic profiling between primary and matched metastatic tumors in patients with colorectal cancer (CRC) and to explore the clinical implication.

Materials And Methods: Surgical samples of primary and matched metastatic tissues from 158 patients (335 samples) with CRC at Korea University Anam Hospital were evaluated using the Ion AmpliSeq Cancer Hotspot Panel. We compared genetic variants and classified them as concordant, primary-specific, and metastasis-specific variants. We used a combination of principal components analysis and clustering to find genomic groups. Kaplan-Meier curves were used to appraise survival between genomic groups. We used machine learning to confirm the correlation between genetic variants and metastatic sites.

Results: A total of 282 types of deleterious non-synonymous variants were selected for analysis. Of a total of 897 variants, an average of 40% was discordant. Three genomic groups were yielded based on the genomic discrepancy patterns. Overall survival differed significantly between the genomic groups. The poorest group had the highest proportion of concordant KRAS G12V and additional metastasis-specific SMAD4. Correlation analysis between genetic variants and metastatic sites suggested that concordant KRAS mutations would have more disseminated metastases.

Conclusion: Driver gene mutations were mostly concordant; however, discordant or metastasis-specific mutations were present. Clinically, the concordant driver genetic changes with additional metastasis-specific variants can predict poor prognosis for patients with CRC.
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http://dx.doi.org/10.4143/crt.2020.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373863PMC
July 2020

Completion rate of physician orders for life-sustaining treatment for patients with metastatic or recurrent cancer: a preliminary, cross-sectional study.

BMC Palliat Care 2019 Oct 22;18(1):84. Epub 2019 Oct 22.

Division of Oncology/Hematology, Department of Internal medicine, Korea University Anam Hospital, 73 Goryeodae-ro Seongbuk-gu, Seoul, 02841, South Korea.

Background: "End of life" is a difficult topic of conversation in East Asian cultures, even among patients and doctors who share a good rapport. In 2016, the Hospice, Palliative Care, and Life-Sustaining Treatment Decision-Making Act, which took the form of "Physician Orders for Life-Sustaining Treatment," was introduced in South Korea. This study was conducted to investigate the completion rate of Physician Orders for Life-Sustaining Treatment in patients with advanced cancer on the active recommendation of physicians, as well as patients' general attitudes toward end-of-life care.

Methods: We conducted a preliminary, cross-sectional descriptive survey on patients with advanced cancer. A total of 101 patients with advanced solid cancer agreed to participate in the study. The primary endpoint was the rate of completion of Physician Orders for Life-Sustaining Treatment based on a doctor's suggestion. Written interviews were conducted to understand the perceptions and factors influencing patients' decisions.

Results: Of the 101 patients, 72 (71.3%) agreed to prepare Physician Orders for Life-Sustaining Treatment. Patients who had an educational level of high school or higher were more likely to agree to complete Physician Orders for Life-Sustaining Treatment documentation as compared to the lower educational status group. More than half of the respondents who completed Physician Orders for Life-Sustaining Treatment documentation reported that they had more than a fair understanding of "life-sustaining care" or "Physician Orders for Life-Sustaining Treatment." Participants' reasons for Physician Orders for Life-Sustaining Treatment completion were diverse.

Conclusions: We found that highly educated patients, who understood the concept behind the policy well, tended to accept Physician Orders for Life-Sustaining Treatment without hesitation. Better education, information shared through the media, and conversations with health care providers might improve understanding of Physician Orders for Life-Sustaining Treatment in patients with cancer.
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http://dx.doi.org/10.1186/s12904-019-0475-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806497PMC
October 2019

Clinical implications of circulating cell-free DNA quantification and metabolic tumor burden in advanced non-small cell lung cancer.

Lung Cancer 2019 08 13;134:158-166. Epub 2019 Jun 13.

Division of Medical Oncology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, Seoul, Republic of Korea; Cancer Research Institute, Korea University, Seoul, Republic of Korea. Electronic address:

Objectives: This study unravels the significance of cell-free DNA (cfDNA) quantification as a promising measure of the biological behavior/aggressiveness of tumors. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) measured by positron emission tomography/computed tomography scan enable a precise assessment of metabolic tumor burden. However, their clinical implications in identifying patients who need more aggressive treatment in advanced non-small cell lung cancer (NSCLC) are not fully understood.

Materials And Methods: In the current prospective trial, we analyzed 101 newly diagnosed advanced NSCLC (stage III-IV) patients with measurable baseline MTV, TLG, and cfDNA quantification. The best cut-offs for cfDNA levels, MTV, and TLG to predict progression-free survival and overall survival were determined using X-tile analysis.

Results: There were significant positive correlations between cfDNA and MTV (r = 0.488, p <  0.001) and between cfDNA and TLG (r = 0.554, p <  0.001). High-cfDNA levels and high-MTV/TLG negatively correlated with overall survival (OS) (all p <  0.001). Patients with high-MTV showed similar median OS irrespective of their cfDNA levels (low-cfDNA vs. high-cfDNA=9.2 vs 6.6 months; p >  0.05). However, patients with low-MTV and low-cfDNA levels showed longer OS than those with low-MTV and high-cfDNA levels (low-cfDNA vs. high-cfDNA=49.3 vs 11.5 months; p <  0.001). The patient group with low-TLG also showed similar trends. The cfDNA level was an independent prognostic factor for OS by Cox-proportional hazard analysis.

Conclusion: Although the patients with high metabolic tumor burden had a poor prognosis, regardless of the biological behavior/aggressiveness of the tumor, patients with low metabolic tumor burden and high cfDNA levels showed a poor prognosis. Taken together, this study indicates a stronger prognostic value of baseline cfDNA levels in identifying patients with advanced NSCLC and personalizing their treatment strategies for better survival.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.014DOI Listing
August 2019

ERRATUM: Caveolin-1 Modulates Docetaxel-Induced Cell Death in Breast Cancer Cell Subtypes through Different Mechanisms.

Cancer Res Treat 2019 07 5;51(3):1257. Epub 2019 Jun 5.

Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.4143/crt.2015.227.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639225PMC
July 2019

Tuberculosis infection and lung adenocarcinoma: Mendelian randomization and pathway analysis of genome-wide association study data from never-smoking Asian women.

Genomics 2020 03 12;112(2):1223-1232. Epub 2019 Jul 12.

Guangdong Lung Cancer Institute, Medical Research Center and Cancer Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.
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http://dx.doi.org/10.1016/j.ygeno.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954985PMC
March 2020

A Selective FGFR inhibitor AZD4547 suppresses RANKL/M-CSF/OPG-dependent ostoclastogenesis and breast cancer growth in the metastatic bone microenvironment.

Sci Rep 2019 06 19;9(1):8726. Epub 2019 Jun 19.

The BK21 Plus Program, Korea University College of Medicine, Seongbuk-Gu, Seoul, Republic of Korea.

Aberrant activation of fibroblast growth factor receptor (FGFR) signalling contributes to progression and metastasis of many types of cancers including breast cancer. Accordingly, FGFR targeted tyrosine kinase inhibitors (TKIs) are currently under development. However, the efficacy of FGFR TKIs in the bone microenvironment where breast cancer cells most frequently metastasize and also where FGFR is biologically active, has not been clearly investigated. We investigated the FGFR-mediated interactions among cancer and the bone microenvironment stromal cells (osteoblasts and osteoclasts), and also the effects of FGFR inhibition in bone metastasis. We showed that addition of culture supernatant from the MDA-MB-134-VI FGFR-amplified breast cancer cells-activated FGFR siganalling in osteoblasts, including increased expression of RANKL, M-CSF, and osteoprotegerin (OPG). Further in vitro analyses showed that AZD4547, an FGFR TKI currently in clinical trials for breast cancer, decreased RANKL and M-CSF, and subsequently RANKL and M-CSF-dependent osteoclastogenesis of murine bone marrow monocytes. Moreover, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis in an orthotopic breast cancer bone metastasis mouse model using FGFR non-amplified MDA-MB-231 cells. Collectively, our results support that FGFR inhibitors inhibit the bone microenvironment stromal cells including osteoblasts and osteoclasts, and effectively suppress both tumor and stromal compartments of bone metastasis.
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http://dx.doi.org/10.1038/s41598-019-45278-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584658PMC
June 2019

Behaviors and Attitudes toward the Use of Complementary and Alternative Medicine among Korean Cancer Patients.

Cancer Res Treat 2019 Jul 7;51(3):851-860. Epub 2019 Jun 7.

Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.

Purpose: A cross-sectional survey was conducted to explore the current awareness and use of complementary and alternative medicine (CAM), as well as attitudes toward CAM, in patients with cancer and their family members in South Korea.

Materials And Methods: Between September 21 and October 31, 2017, a 25-item questionnaire regarding CAM experiences among cancer patients and their family members was conducted in 10 oncology clinics in South Korea after institutional review board approval at each institution.

Results: In total, 283/310 patients were analyzed. The median age was 60 years, and 60% were male. Most of the patients were actively receiving anticancer treatment at the time of the survey. A total of 106 patients (37%) had experienced a median of two types (interquartile range, 1 to 3) of CAM. Belief in CAM (odds ratio [OR], 3.015; 95% confidence interval [CI], 1.611 to 5.640) and duration of disease (OR, 1.012; 95% CI, 1.004 to 1.020) were independent factors for using CAM in multivariable analysis. Belief in CAM was significantly associated with current use of CAM (OR, 3.633; 95% CI, 1.567 to 8.424). Lay referral was the most common reason for deciding to use CAM, and only 25% of patients (72/283) discussed CAM with their physicians.

Conclusion: Patient attitudes toward and confidence in CAM modalities were strongly associated with their CAM experiences, and only a small number of patients had an open discussion about CAM with their physicians. A patient education program for CAM is needed.
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http://dx.doi.org/10.4143/crt.2019.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639220PMC
July 2019

A phase I/II study of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer.

Gastric Cancer 2019 11 3;22(6):1206-1214. Epub 2019 Apr 3.

Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Background: Poziotinib (HM781-36B) is an irreversible pan-HER tyrosine kinase inhibitor which targets EGFR, HER2, and HER4. This prospective, multicenter, open-label, phase I/II study determined the maximum tolerated dose (MTD) and evaluated the safety and efficacy of poziotinib combined with paclitaxel and trastuzumab in patients with HER2-positive advanced gastric cancer (GC).

Methods: Patients with HER2-positive GC previously treated with one line of chemotherapy received oral poziotinib (8 mg or 12 mg) once daily for 14 days, followed by 7 days off. Paclitaxel (175 mg/m infusion) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg infusion) were administered concomitantly with poziotinib on day 1 every 3 weeks.

Results: In the phase I part, 12 patients were enrolled (7 at dose level 1, 5 at dose level 2). One patient receiving poziotinib 8 mg and 2 receiving poziotinib 12 mg had dose-limiting toxicities (DLTs); all DLTs were grade 4 neutropenia, one with fever. The most common poziotinib-related adverse events were diarrhea, rash, stomatitis, pruritus and loss of appetite. The MTD of poziotinib was determined to be 8 mg/day and this was used in the phase II part which enrolled 32 patients. Two patients (6.3%) had complete responses and 5 (15.6%) had partial responses (objective response rate 21.9%). Median progression-free survival and overall survival were 13.0 weeks (95% CI 9.8-21.9) and 29.5 weeks (95% CI 17.9-59.2), respectively.

Conclusions: The MTD of poziotinib combined with paclitaxel and trastuzumab was 8 mg/day. This combination yielded promising anti-tumor efficacy with manageable toxicity in previously treated patients with HER2-positive GC.
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http://dx.doi.org/10.1007/s10120-019-00958-4DOI Listing
November 2019

Accuracy and Prognostic Significance of Oncologists' Estimates and Scenarios for Survival Time in Advanced Gastric Cancer.

Oncologist 2019 11 1;24(11):e1102-e1107. Epub 2019 Apr 1.

NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia.

Background: Worst-case, typical, and best-case scenarios for survival, based on simple multiples of an individual's expected survival time (EST), estimated by their oncologist, are a useful way of formulating and explaining prognosis. We aimed to determine the accuracy and prognostic significance of oncologists' estimates of EST, and the accuracy of the resulting scenarios for survival time, in advanced gastric cancer.

Materials And Methods: Sixty-six oncologists estimated the EST at baseline for each of the 152 participants they enrolled in the INTEGRATE trial. We hypothesized that oncologists' estimates of EST would be unbiased (∼50% would be longer or shorter than the observed survival time [OST]); imprecise (<33% within 0.67-1.33 times the OST); independently predictive of overall survival (OS); and accurate at deriving scenarios for survival time with approximately 10% of patients dying within a quarter of their EST (worst-case scenario), 50% living within half to double their EST (typical scenario), and 10% living three or more times their EST (best-case scenario).

Results: Oncologists' estimates of EST were unbiased (45% were shorter than the OST, 55% were longer); imprecise (29% were within 0.67-1.33 times observed); moderately discriminative (Harrell's C-statistic 0.62, = .001); and an independently significant predictor of OS (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; = .001) in a Cox model including performance status, number of metastatic sites, neutrophil-to-lymphocyte ratio ≥3, treatment group, age, and health-related quality of life (EORTC-QLQC30 physical function score). Scenarios for survival time derived from oncologists' estimates were remarkably accurate: 9% of patients died within a quarter of their EST, 57% lived within half to double their EST, and 12% lived three times their EST or longer.

Conclusion: Oncologists' estimates of EST were unbiased, imprecise, moderately discriminative, and independently significant predictors of OS. Simple multiples of the EST accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer.

Implications For Practice: Results of this study demonstrate that oncologists' estimates of expected survival time for their patients with advanced gastric cancer were unbiased, imprecise, moderately discriminative, and independently significant predictors of overall survival. Simple multiples of the expected survival time accurately estimated worst-case, typical, and best-case scenarios for survival time in advanced gastric cancer.
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http://dx.doi.org/10.1634/theoncologist.2018-0613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853097PMC
November 2019

Identification of different gene expressions between diffuse- and intestinal-type spheroid-forming gastric cancer cells.

Gastric Cancer 2019 09 6;22(5):967-979. Epub 2019 Feb 6.

Brain Korea 21 Plus Project for Biomedical Science, Korea University College of Medicine, Seoul, 02841, Republic of Korea.

Background: Three-dimensional in vitro spheroid models are unique because they are considered for enrichment of specific cell populations with self-renewal ability. In this study, we explored the different mechanisms of gastric cancer spheroid-forming cells according to the Lauren classification.

Methods: We isolated and enriched cells with self-renewal ability using spheroid-forming methods from gastric cancer cell lines. The expression of candidate target genes was investigated using western blot and qRT-PCR analysis. Lentiviral shRNA knockdown of target gene expression was performed and the effects on spheroid, colony forming, and tumorigenic ability were analyzed.

Results: The SNU-638, SNU-484, MKN-28, and NCI-N87 successfully formed spheroid from single cell and enriched for self-renewal ability from 11 gastric cancer cell lines, including diffuse and intestinal types. The expression of SOX2 and E-cadherin increased in spheroid-forming cells in a diffuse-type cell line (SNU-638 and SNU-484), but not in the intestinal type (MKN-28 and NCI-N87). In contrast, ERBB3 expression was only increased in intestinal-type spheroid cells. The depletion of each candidate target gene expression suppressed self-renewal ability to grow as spheroids and colonies in a soft agar assay. In particular, down-regulated ERBB3 in the intestinal-type cell lines inhibited tumor growth in a mouse xenograft model. We found that high ERBB3 gene expression correlates with decreased survival in the intestinal type of gastric cancer.

Conclusions: Our results suggest that diffuse- and intestinal-type spheroid-forming cells express genes differently. Our data suggest that these candidate genes from spheroid-forming cells can be used in applications in targeted therapy.
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http://dx.doi.org/10.1007/s10120-019-00935-xDOI Listing
September 2019

Isolation of spheroid-forming single cells from gastric cancer cell lines: enrichment of cancer stem-like cells.

Biotechniques 2018 10;65(4):197-203

Brain Korea 21 Plus Project for Biomedical Science, Korea University College of Medicine, Seoul 02841, Republic of Korea.

Isolation of spheroid-forming cells is important to investigate cancer stem cell (CSC) characteristics. However, conventional tumor spheroid culture methods have not proven suitable because the aggregated spheroids generally maintain their original heterogeneity and harbor multiple cells with various characteristics. Here we cultured spheroids using a polydimethylsiloxane microwell-based method and a limiting dilution protocol. We then isolated and enriched for CSCs that formed single cell-derived spheroids from gastric cancer cell lines. Cells from the microwell demonstrated higher self-renewal, increased expression of stem cell markers and resistance to apoptosis compared with spheroid cells made by the traditional method. This novel approach allows efficient cancer stem cell isolation and represents a step forward in cancer stem cell studies.
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http://dx.doi.org/10.2144/btn-2018-0046DOI Listing
October 2018

A Phase III Study to Compare the Efficacy and Safety of Paclitaxel Versus Irinotecan in Patients with Metastatic or Recurrent Gastric Cancer Who Failed in First-line Therapy (KCSG ST10-01).

Oncologist 2019 01 20;24(1):18-e24. Epub 2018 Aug 20.

Department of Medical Oncology, Division of Internal Medicine, Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Korea

Lessons Learned: Irinotecan could not be proven noninferior to paclitaxel as a second-line treatment for patients with metastatic or recurrent gastric cancer.The failure to demonstrate noninferiority may have been a result of insufficient patient enrollment.Both agents were tolerable but showed different toxicity profiles.

Background: This phase III study compared the efficacy and safety of paclitaxel versus irinotecan in patients with metastatic or recurrent gastric cancer (MRGC) who had experienced disease progression following first-line chemotherapy.

Methods: Patients were randomized to receive either paclitaxel (70 mg/m; days 1, 8, 15, every 4 weeks) or irinotecan (150 mg/m every other week). The primary endpoint was progression-free survival (PFS).

Results: This study was stopped early due to low accrual rate. A total of 112 patients were enrolled; 54 were allocated to paclitaxel and 58 to irinotecan. Median PFS for the paclitaxel and irinotecan groups was 3.5 and 2.1 months, respectively (hazard ratio [HR], 1.27; 95% confidence interval [CI], 0.86-1.88; = .234). Noninferiority of irinotecan to paclitaxel was not proved because the upper boundary of the 95% CI (1.88) exceeded the predefined upper margin of noninferiority (1.32). Median overall survival (OS) was 8.6 months in the paclitaxel group and 7.0 months in the irinotecan group (HR, 1.39; 95% CI, 0.91-2.11; = .126). Among toxicities greater than or equal to grade 3, neutropenia (11.5%) was the most common, followed by peripheral neuropathy (7.7%) in the paclitaxel group, and neutropenia (34.5%) followed by nausea, vomiting, and anemia (8.6%, respectively) in the irinotecan group.

Conclusion: Although paclitaxel showed numerically longer PFS and OS compared with irinotecan, this was statistically insignificant. Both irinotecan and paclitaxel are valid second-line treatment options in MRGC.
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http://dx.doi.org/10.1634/theoncologist.2018-0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324622PMC
January 2019

Helicobacter pylori and Prevention of Gastric Cancer.

N Engl J Med 2018 06;378(23):2244

Korea University, Seoul, South Korea

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http://dx.doi.org/10.1056/NEJMc1805129DOI Listing
June 2018

Incidence and risk factors for congestive heart failure in patients with early breast cancer who received anthracycline and/or trastuzumab: a big data analysis of the Korean Health Insurance Review and Assessment service database.

Breast Cancer Res Treat 2018 Aug 8;171(1):181-188. Epub 2018 May 8.

Division of Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.

Purpose: We aimed to analyze the incidence, time to occurrence, and congestive heart failure (CHF) risk factors for early breast cancer patients treated with anthracycline (AC)-based chemotherapy and/or trastuzumab (T) therapy in Korea.

Methods: We included female patients > 19 years old from the Health Insurance Review and Assessment Service database who had no prior CHF history and had been diagnosed with early breast cancer between January 2007 and October 2016.

Results: We included 83,544 patients in our analysis. In terms of crude incidence for CHF, AC followed by T showed the highest incidence (6.3%). However, 3.1 and 4.2% of the patients had CHF due to AC-based chemotherapy and non-AC followed by T, respectively. The median times to occurrence of CHF were different according to adjuvant treatments, approximately 2 years (701.0 days) in the AC-based chemotherapy group vs 1 year (377.5 days) AC followed by T group. T therapy was associated with earlier development of CHF irrespective of previous chemotherapy, but late risk of CHF 1.2 years after T therapy rapidly decreased in both chemotherapy groups. Multivariate Cox regression analysis revealed that the adjusted hazard ratio for CHF was increased in the group of older patients (≥ 65 years old) who underwent AC followed by T therapy, with Charlson comorbidity index scores of ≥ 2.

Conclusions: Our study showed that neo-/adjuvant chemotherapy using T irrespective of previous chemotherapy (AC or non-AC) was associated with significantly increased risk of CHF compared with AC-based chemotherapy in Korean patients with early breast cancer.
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http://dx.doi.org/10.1007/s10549-018-4809-8DOI Listing
August 2018

Landscape of Actionable Genetic Alterations Profiled from 1,071 Tumor Samples in Korean Cancer Patients.

Cancer Res Treat 2019 Jan 23;51(1):211-222. Epub 2018 Apr 23.

Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data.

Materials And Methods: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared.

Results: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration.

Conclusion: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.
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http://dx.doi.org/10.4143/crt.2018.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333975PMC
January 2019

Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG).

Gastric Cancer 2018 09 9;21(5):819-830. Epub 2018 Feb 9.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP).

Methods: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen.

Results: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS.

Conclusion: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.
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http://dx.doi.org/10.1007/s10120-018-0806-1DOI Listing
September 2018

Detection of somatic variants and mutations in cell-free DNA from non-small cell lung cancer patients by ultra-deep sequencing using the ion ampliseq cancer hotspot panel and droplet digital polymerase chain reaction.

Oncotarget 2017 Dec 15;8(63):106901-106912. Epub 2017 Nov 15.

Cancer Research Institute, Korea University, Seoul, Republic of Korea.

Highly sensitive genotyping assays can detect mutations in cell-free DNA (cfDNA) from cancer patients, reflecting the biology of each patient's cancer. Because circulating tumor DNA comprises a small, variable fraction of DNA circulating in the blood, sensitive parallel multiplexing tests are required to determine mutation profiles. We prospectively examined the clinical utility of ultra-deep sequencing analysis of cfDNA from 126 non-small cell lung cancer (NSCLC) patients using the Ion AmpliSeq Cancer Hotspot Panel v2 (ICP) and validated these findings with droplet digital polymerase chain reaction (ddPCR). ICP results were compared with tumor tissue genotyping (TTG) results and clinical outcomes. A total of 853 variants were detected, with a median of four variants per patient. Overall concordance of ICP and TTG analyses was 90% for EGFR exon 19 deletion and 88% for the L858R mutation. Of 34 patients with a well-defined activating mutation defined based on the results of ICP and TTG, 31 (81.6%) showed long-term disease control with EGFR TKI treatment. Of 56 patients treated with an EGFR tyrosine kinase inhibitor (TKI), the presence of the T790M mutation was confirmed in 28 (50%). Presence of this mutation did not have a negative effect on EGFR TKI treatment. Ultra-deep sequencing analysis of cfDNA using ICP combined with confirmatory ddPCR was effective at defining driver genetic changes in NSCLC patients. Comprehensive analysis of tumor DNA and cfDNA can increase the specificity of molecular diagnosis, which could translate into tailored treatment.
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http://dx.doi.org/10.18632/oncotarget.22456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739783PMC
December 2017

Quantification of circulating cell-free DNA to predict patient survival in non-small-cell lung cancer.

Oncotarget 2017 Nov 10;8(55):94417-94430. Epub 2017 Oct 10.

Division of Medical Oncology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, Seoul, Republic of Korea.

We used computed tomography (CT) to explore the prognostic value of cell-free (cf) DNA quantification and its predictive efficacy over time after chemotherapy in non-small-cell lung cancer (NSCLC) patients. In total, 177 NSCLC patients were enrolled in a prospective biomarker trial. Consecutive paired blood collection was performed to determine cfDNA concentrations at baseline CT and throughout serial follow-ups. The best cfDNA cut-off value to predict progression-free and overall survival was determined using X-tile analysis. Among 112 chemo-naive patients with stage IV adenocarcinoma, 43 were available for follow-up analysis. Cox regression multivariate analysis indicated that a high cfDNA concentration was an independent negative prognostic factor for progression-free survival (hazard ratio: 2.60; 95% confidence interval: 1.65-4.10; p = 0.008) and overall survival (hazard ratio: 2.63; 95% confidence interval: 1.66-4.17; p < 0.001). However, cfDNA concentration changes during treatment did not correlate with radiological CT responses at first follow-up or best response. No pattern was noted in the percent change in the cfDNA concentration from baseline or subsequently measured level to progression. The serum cfDNA concentration is thus associated with NSCLC patient prognosis, but does not appear to be a clinically valid marker for tumor responses.
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http://dx.doi.org/10.18632/oncotarget.21769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706884PMC
November 2017

A non-randomized, open-label, single-arm, Phase 2 study of emibetuzumab in Asian patients with MET diagnostic positive, advanced gastric cancer.

Cancer Chemother Pharmacol 2017 Dec 25;80(6):1197-1207. Epub 2017 Oct 25.

National Cancer Center Hospital East, 5-1, Kashiwanoha 6-chome, Kashiwa, Chiba, 277-8577, Japan.

Purpose: Mesenchymal-epithelial transition factor (MET) is expressed in gastric cancer and associated with poor clinical outcomes. We assessed activity, safety, and pharmacokinetics of emibetuzumab, a bivalent monoclonal anti-MET antibody that blocks ligand-dependent and ligand-independent MET signaling.

Methods: This non-randomized, single-arm, Phase 2 study enrolled Asian patients with MET diagnostic positive advanced gastric adenocarcinoma. Emibetuzumab (2000 mg, intravenous) was given on days 1 and 15 (28-day cycle). The primary endpoint was 8-week progression-free survival rate. Secondary objectives included safety, pharmacokinetics, overall survival, and change in tumor size.

Results: Tumors from 65 patients were immunohistochemically screened to enroll 15 MET diagnostic positive patients (23% positivity; 8 Japanese, 7 Korean; 10 male). Eight-week progression-free survival rate was 0.47 (70% CI, 0.33-0.59). Disease control rate was 40% (target lesion decreases, three patients; no complete/partial responses according to RECIST). Median overall survival was 17.1 weeks (95% CI, 6.3-not achievable). No serious emibetuzumab-related adverse events or new safety signals emerged. Grade ≥ 3 possibly drug-related adverse events were hyperkalemia, hyponatremia, and hyperuricemia (one each). Emibetuzumab's pharmacokinetics profile was similar to that observed previously. MET expression and clinical outcomes were not obviously associated.

Conclusion: Emibetuzumab was well tolerated with limited single-agent activity in advanced gastric adenocarcinoma.
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http://dx.doi.org/10.1007/s00280-017-3445-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686250PMC
December 2017
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