Publications by authors named "Jeeyun Lee"

426 Publications

Validation of the Combined Biomarker for Prediction of Response to Checkpoint Inhibitor in Patients with Advanced Cancer.

Cancers (Basel) 2021 May 12;13(10). Epub 2021 May 12.

Samsung Medical Center, Department of Pathology and Translational Genomics, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Although immune checkpoint inhibitors can induce durable responses in patients with multiple types of advanced cancer, only a limited number of patients have a known reliable biomarker. This study aimed to validate the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, which was developed based on a previous study of four-gene and PD-L1 level, to predict immunotherapy response. We developed a clinical assay for formalin-fixed paraffin-embedded samples using quantitative real-time polymerase chain reaction to measure the expression level of the previously published four-gene set. The predictive performance was validated in a cohort of 89 patients with several advanced tumor types. The IMAGiC score was derived from tumor samples of 89 patients consisting of eight cancer types, and 73 out of 89 patients available for clinical response were analyzed with clinicopathological factors. The IMAGiC group (responder vs. non-responder) was determined with a specific value of the IMAGiC score as a cutoff, which was set by log-rank statistics for progression-free survival (PFS) divided the patients into 56 (76.7%) non-responders and 17 (23.3%) responders. Clinical responders (complete response/partial response) were higher in the IMAGiC responder group than in the non-responder group (70.6 vs. 21.4%). The median PFS of the IMAGiC responder group and non-responder was 20.8 months (95% CI 9.1-not reached) and 6.7 months (95% CI 4.9-11.1, = 0.007), respectively. Among the 17 IMAGiC responders, 11 patients had tumor mutation burden-low and microsatellite-stable tumors. This study validated a predictive model based on a four-gene expression signature. Along with conventional biomarkers, our model could be useful for predicting response to immunotherapy in patients with advanced cancer.
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http://dx.doi.org/10.3390/cancers13102316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151730PMC
May 2021

The Right Treatment of the Right Patient: Integrating Genetic Profiling Into Clinical Decision Making in Advanced Gastric Cancer in Asia.

Am Soc Clin Oncol Educ Book 2021 Mar;41:1-8

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

Gastric cancer is a major global health burden, especially when patients are diagnosed with recurrent or metastatic gastric cancer. Despite recent advances in treatment options with palliative chemotherapy, the median overall survival of patients with gastric cancer remains within 1 or 2 years after the diagnosis of metastatic disease. Gastric cancer is significantly more prevalent in eastern Asia (e.g., Japan and Korea). Next-generation sequencing (NGS) is rapidly being adopted as part of clinical practice in Korea and Japan, especially in patients with gastric cancer. Approximately 10% to 15% of the patients with gastric cancer who undergo NGS of their tumor specimen are allocated to target-matched clinical trials in Japan and Korea. In Japan and Korea, a cell-free DNA NGS panel is also actively being investigated as an alternative NGS test for patients with gastric cancer, which may reflect the tumor heterogeneity of gastric cancer. In Japan and Korea, multiple biomarkers, such as HER2, mismatch repair, Epstein-Barr virus, PD-L1 (combined positive score), EGFR, FGFR2, and CLDN18.2, are routinely assessed through immunohistochemistry or in situ hybridization before initiation of the first-line treatment in all patients with gastric cancer. Most tertiary cancer centers in Korea routinely perform HER2, mismatch repair, Epstein-Barr virus, and PD-L1 NGS before palliative chemotherapy in patients with gastric cancer. Biomarker evaluation for all patients with metastatic gastric cancer enables clinicians to identify available biomarker-based clinical trials early during the course of treatment, which expands treatment opportunities while patients are medically fit for clinical trials, if available. Comprehensive genomic profiling using a tissue or circulating tumor DNA NGS panel is considered necessary during second-line or subsequent treatment. It is hoped that a comprehensive molecular profiling strategy will facilitate greater use of precision medicine through molecularly targeted therapies for patients with gastric cancer in the near future.
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http://dx.doi.org/10.1200/EDBK_321247DOI Listing
March 2021

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

Gut 2021 May 12. Epub 2021 May 12.

Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore

Objective: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery.

Design: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort.

Results: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022).

Conclusion: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit.

Trial Registration Number: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).
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http://dx.doi.org/10.1136/gutjnl-2021-324060DOI Listing
May 2021

Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.

Clin Cancer Res 2021 May 11. Epub 2021 May 11.

Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein.

Patients And Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel.

Results: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m on D1, D8, D15 every 28 days. The most common toxicities were neutropenia ( = 39, 68%), anemia ( = 25, 44%), and thrombocytopenia ( = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9).

Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0251DOI Listing
May 2021

ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma.

Nature 2021 May 5. Epub 2021 May 5.

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

Although RAF monomer inhibitors (type I.5, BRAF(V600)) are clinically approved for the treatment of BRAF-mutant melanoma, they are ineffective in non-BRAF mutant cells. Belvarafenib is a potent and selective RAF dimer (type II) inhibitor that exhibits clinical activity in patients with BRAF- and NRAS-mutant melanomas. Here we report the first-in-human phase I study investigating the maximum tolerated dose, and assessing the safety and preliminary efficacy of belvarafenib in BRAF- and RAS-mutated advanced solid tumours (NCT02405065, NCT03118817). By generating belvarafenib-resistant NRAS-mutant melanoma cells and analysing circulating tumour DNA from patients treated with belvarafenib, we identified new recurrent mutations in ARAF within the kinase domain. ARAF mutants conferred resistance to belvarafenib in both a dimer- and a kinase activity-dependent manner. Belvarafenib induced ARAF mutant dimers, and dimers containing mutant ARAF were active in the presence of inhibitor. ARAF mutations may serve as a general resistance mechanism for RAF dimer inhibitors as the mutants exhibit reduced sensitivity to a panel of type II RAF inhibitors. The combination of RAF plus MEK inhibition may be used to delay ARAF-driven resistance and suggests a rational combination for clinical use. Together, our findings reveal specific and compensatory functions for the ARAF isoform and implicate ARAF mutations as a driver of resistance to RAF dimer inhibitors.
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http://dx.doi.org/10.1038/s41586-021-03515-1DOI Listing
May 2021

Clinical profile of cutaneous adverse events of immune checkpoint inhibitors in a single tertiary center.

J Dermatol 2021 Apr 20. Epub 2021 Apr 20.

Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors have demonstrated their efficacy in the treatment of various malignancies. Despite their benefits, their immunomodulatory activities can cause unpredictable cutaneous adverse events (CAE). This study aimed to identify characteristics of CAE in patients treated with PD-1/PD-L1 inhibitors through the medical records, photographs, and pathology reports. Fifty CAE occurred in 47 (2.75%) of 1711 patients treated with PD-1/PD-L1 inhibitors. Pruritic, psoriasiform, urticarial, and acneiform eruptions were the four most common types. Melanoma patients showed CAE more frequently than other malignancies. Acneiform eruption occurred more often at ages under 60 years. Urticarial eruption appeared earlier, while keratoacanthoma appeared later after immunotherapy. The overall survival times were not significantly different between the two groups with and without CAE by Kaplan-Meier analysis (p = 0.055). Studies on CAE may provide more information to understand these drugs and to help manage the patients.
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http://dx.doi.org/10.1111/1346-8138.15824DOI Listing
April 2021

Determinants of Response and Intrinsic Resistance to PD-1 Blockade in Microsatellite Instability-High Gastric Cancer.

Cancer Discov 2021 Apr 12. Epub 2021 Apr 12.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Samsung Medical Center, Sungkyunkwan University School of Medicine

Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers (GC) and associated with clinical response to anti-programmed death (PD)-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in advanced MSI-H GC patients and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with anti-tumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. Additionally, increase in PD-1+ CD8+ T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H GC and may inform development of strategies to enhance responsiveness.
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http://dx.doi.org/10.1158/2159-8290.CD-21-0219DOI Listing
April 2021

EGFR Amplification in Metastatic Colorectal Cancer.

J Natl Cancer Inst 2021 Apr 7. Epub 2021 Apr 7.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.

Background: EGFR amplification occurs in about 1% of metastatic colorectal cancers (mCRCs) but is not routinely tested as a prognostic or predictive biomarker for patients treated with anti-EGFR monoclonal antibodies (mAbs). Herein, we aimed to characterize the clinical and molecular landscape of EGFR-amplified metastatic colorectal cancer (mCRC).

Methods: In this multinational cohort study, we compared clinical data of 62 patients with EGFR-amplified vs. 1459 EGFR non-amplified mCRC, as well as comprehensive genomic data of 35 EGFR-amplified vs. 439 EGFR non-amplified RAS/BRAF wild-type and microsatellite stable (MSS) tumor samples.

Results: EGFR amplification was statistically significantly associated with left primary tumor sidedness and RAS/BRAF wild-type status. All EGFR-amplified tumors were MSS and HER2 non-amplified. Overall, EGFR-amplified samples had higher median fraction of genome altered compared to EGFR non-amplified, RAS/BRAF wild-type MSS cohort. Patients with EGFR-amplified tumors reported longer overall survival (OS) (median OS = 71.3 months; 95% confidence interval [CI] = 50.7-NA) vs. EGFR non-amplified ones (24.0 months; 95% CI = 22.8-25.6; hazard ratio [HR] = 0.30, 95% CI = 0.20-0.44, P<.001; adjusted HR = 0.46, 95%CI = 0.30-0.69, P<.001). In the subgroup of patients with RAS/BRAF wild-type mCRC exposed to anti-EGFR-based therapy, EGFR amplification was again associated with better OS (median OS = 54.0 months [95% CI = 35.2-NA] vs. 29.1 months [95% CI = 27.0-31.9], respectively; HR = 0.46, 95%CI = 0.28-0.76, P=.002).

Conclusion: Patients with EGFR-amplified mCRC represent a biologically defined subgroup and merit dedicated clinical trials with novel and more potent EGFR targeting strategies beyond single-agent monoclonal antibodies.
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http://dx.doi.org/10.1093/jnci/djab069DOI Listing
April 2021

Assessment of Pembrolizumab Therapy for the Treatment of Microsatellite Instability-High Gastric or Gastroesophageal Junction Cancer Among Patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 Clinical Trials.

JAMA Oncol 2021 Apr 1. Epub 2021 Apr 1.

David Geffen School of Medicine, University of California, Los Angeles.

Importance: Immunotherapy has been associated with improved outcomes among patients who have received previous treatment for microsatellite instability-high (MSI-H) tumors.

Objective: To evaluate the antitumor activity of pembrolizumab therapy vs chemotherapy among patients with MSI-H advanced gastric or gastroesophageal junction (G/GEJ) cancer regardless of the line of therapy in which it was received.

Design, Setting, And Participants: This post hoc analysis of the phase 2 KEYNOTE-059 (third-line treatment or higher) single-arm trial and the phase 3 KEYNOTE-061 (second-line treatment) and KEYNOTE-062 (first-line treatment) randomized trials included patients with advanced G/GEJ cancer from 52 sites in 16 countries enrolled in KEYNOTE-059, 148 sites in 30 countries enrolled in KEYNOTE-061, and 200 sites in 29 countries enrolled in KEYNOTE-062. Patients were enrolled from March 2, 2015, to March 26, 2016, in KEYNOTE-059; from June 4, 2015, to July 26, 2016, in KEYNOTE-061; and from September 18, 2015, to May 26, 2017, in KEYNOTE-062, with data cutoff dates of August 8, 2018; October 26, 2017; and March 26, 2019; respectively.

Interventions: Pembrolizumab monotherapy in KEYNOTE-059, pembrolizumab monotherapy or chemotherapy (paclitaxel) in KEYNOTE-061, and pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin and 5-fluorouracil or capecitabine), or chemotherapy alone in KEYNOTE-062.

Main Outcomes And Measures: Response was assessed centrally using Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1; MSI-H status was determined centrally by polymerase chain reaction testing.

Results: At data cutoff, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 patients (5.3%) in KEYNOTE-061, and 50 of 682 patients (7.3%) in KEYNOTE-062 had MSI-H tumors. Among those with MSI-H tumors, the median overall survival was not reached (NR) for pembrolizumab in KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 or for pembrolizumab plus chemotherapy in KEYNOTE-062. The median progression-free survival (PFS) for pembrolizumab was NR (95% CI, 1.1 months to NR) in KEYNOTE-059 and 17.8 months (95% CI, 2.7 months to NR) in KEYNOTE-061 (vs 3.5 months [95% CI, 2.0-9.8 months] for chemotherapy). In KEYNOTE-062, the median PFS was 11.2 months (95% CI, 1.5 months to NR) for pembrolizumab, NR (95% CI, 3.6 months to NR) for pembrolizumab plus chemotherapy, and 6.6 months (95% CI, 4.4-8.3 months) for chemotherapy. The objective response rate (ORR) for pembrolizumab was 57.1% in KEYNOTE-059 and 46.7% (vs 16.7% for chemotherapy) in KEYNOTE-061. In KEYNOTE-062, the ORR was 57.1% for pembrolizumab , 64.7% for pembrolizumab plus chemotherapy, and 36.8% for chemotherapy.

Conclusions And Relevance: Findings from this study indicate that MSI-H status may be a biomarker for pembrolizumab therapy among patients with advanced G/GEJ cancer regardless of the line of therapy in which it was received.

Trial Registration: ClinicalTrials.gov Identifiers: NCT02335411, NCT02370498, and NCT02494583.
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http://dx.doi.org/10.1001/jamaoncol.2021.0275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017478PMC
April 2021

Programmed Death Ligand 1 Expression as a Prognostic Marker in Patients with Advanced Biliary Tract Cancer.

Oncology 2021 17;99(6):365-372. Epub 2021 Mar 17.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea,

Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients.

Patients And Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity.

Results: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer.

Conclusion: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.
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http://dx.doi.org/10.1159/000514404DOI Listing
June 2021

Clinical sequencing to assess tumor mutational burden as a useful biomarker to immunotherapy in various solid tumors.

Ther Adv Med Oncol 2021 26;13:1758835921992992. Epub 2021 Feb 26.

Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.

Background: Immune checkpoint inhibitors (ICIs) have become established as a new therapeutic paradigm in various solid cancers. Predictive biomarkers to ICIs have not yet been fully established. Tumor mutational burden (TMB) has been considered as a useful marker to indicate patients who benefit from ICIs.

Methods: We performed next-generation sequencing, including TMB analysis, as a routine clinical practice in 501 patients with advanced gastrointestinal (GI), genitourinary (GU), or rare cancers. The TruSight Oncology 500 assay from Illumina was used as a cancer panel.

Results: In total, 11.6% (58/501) were identified with tumors with high TMB and MSI-high status was confirmed in seven out of 501 cases (1.4%). High TMB was observed in 11.6% of patients with various solid tumors, including: GU cancers (36.0%, 9/25), colorectal cancer (15.2%, 23/151), biliary tract cancer (14.6%, 7/48), melanoma (14.3%, 3/21), gastric cancer (11.2%, 13/116), hepatocellular carcinoma (8.3%, 1/12), other GI tract cancers (4.5%, 1/22), and sarcoma (1.7%, 1/60). The objective response rate (ORR) to ICIs was 75% (nine out of 12) in solid tumor patients with high TMB and 25% (30 out of 40) in those with non-high TMB. Patients with high TMB had better ORR to ICIs than those with non-high TMB ( = 0.004). Univariate analysis revealed that the status of PD-L1 expression and of TMB (high non-high) had significant association in response to ICIs. However, in multivariate analysis, the status of TMB (high non-high) was only significantly related to the response to ICIs ( = 0.036).

Conclusion: In the present study, we analyzed the TMB using a cancer panel for various solid tumor patients in routine clinical practice and also demonstrated the usefulness of TMB to predict the efficacy for ICIs.
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http://dx.doi.org/10.1177/1758835921992992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917846PMC
February 2021

Chromatin accessibility of circulating CD8 T cells predicts treatment response to PD-1 blockade in patients with gastric cancer.

Nat Commun 2021 02 12;12(1):975. Epub 2021 Feb 12.

Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea.

Although tumor genomic profiling has identified small subsets of gastric cancer (GC) patients with clinical benefit from anti-PD-1 treatment, not all responses can be explained by tumor sequencing alone. We investigate epigenetic elements responsible for the differential response to anti-PD-1 therapy by quantitatively assessing the genome-wide chromatin accessibility of circulating CD8 T cells in patients' peripheral blood. Using an assay for transposase-accessible chromatin using sequencing (ATAC-seq), we identify unique open regions of chromatin that significantly distinguish anti-PD-1 therapy responders from non-responders. GC patients with high chromatin openness of circulating CD8 T cells are significantly enriched in the responder group. Concordantly, patients with high chromatin openness at specific genomic positions of their circulating CD8 T cells demonstrate significantly better survival than those with closed chromatin. Here we reveal that epigenetic characteristics of baseline CD8 T cells can be used to identify metastatic GC patients who may benefit from anti-PD-1 therapy.
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http://dx.doi.org/10.1038/s41467-021-21299-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881150PMC
February 2021

Comprehensive molecular characterization of gastric cancer patients from phase II second-line ramucirumab plus paclitaxel therapy trial.

Genome Med 2021 Jan 25;13(1):11. Epub 2021 Jan 25.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: Gastric cancer (GC) is a heterogenous disease consisted of several subtypes with distinct molecular traits. The clinical implication of molecular classification has been limited especially in association with treatment efficacy of ramucirumab or various targeted agents.

Methods: We conducted a prospective non-randomized phase II single-arm trial of ramucirumab plus paclitaxel as second-line chemotherapy in 62 patients with metastatic GC who failed to respond to first-line fluoropyrimidine plus platinum treatment. For integrative molecular characterization, all patients underwent pre-ramucirumab treatment tissue biopsy for whole-exome/whole-transcriptome sequencing to categorize patients based on molecular subtypes. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features, to identify potential molecular predictors of sensitivity and resistance to ramucirumab treatment.

Results: Sixty-two patients were enrolled in this study between May 2016 and October 2017. Survival follow-up in all patients was completed as of the date of cut-off on January 2, 2019. No patient attained complete response (CR), while 22 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 35.5% (95% CI, 23.6-47.4). According to TCGA molecular classification, there were 30 GS, 18 CIN, 3 EBV, and 0 MSI tumors. The RR was 33% in GS (10/30), 33% in CIN (6/18), and 100% in EBV-positive GC patients with significant statistical difference for EBV(+) against EBV(-) tumors (P = 0.016; chi-squared test). Moreover, responsive patients were marked by activation of angiogenesis, VEGF, and TCR-associated pathways, while non-responder patients demonstrated enrichments of sonic hedgehog signaling pathway and metabolism activity. Integrative multi-layer data analysis further identified molecular determinants, including EBV status, and somatic mutation in GNAQ to ramucirumab activity.

Conclusions: Prospective molecular characterization identified a subset of GC patients with distinct clinical response to ramucirumab therapy, and our results demonstrate the feasibility of personalized therapeutic opportunities in gastric cancer.

Trial Registration: The study was registered on ClinicalTrial.gov ( NCT02628951 ) on June 12, 2015.
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http://dx.doi.org/10.1186/s13073-021-00826-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836461PMC
January 2021

Prognostic Factors of Survival with Aflibercept and FOLFIRI (fluorouracil, leucovorin, irinotecan) as Second-line Therapy for Patients with Metastatic Colorectal Cancer.

J Cancer 2021 1;12(2):460-466. Epub 2021 Jan 1.

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

Aflibercept and fluorouracil, leucovorin, irinotecan (FOLFIRI) is commonly used as a second-line treatment for metastatic colorectal cancer (CRC). However, the biomarkers to guide the choice of this regimen from among treatment options remain unclear. We performed exploratory analyses to validate potential prognostic factors for patients receiving aflibercept plus FOLFIRI as a second-line systemic treatment for metastatic CRC between January 2015 and July 2019. Patient characteristics, histopathologic data, laboratory and radiologic data, and treatment outcomes were collected and reviewed. Included were 52 patients: 50 (96.2%) received bevacizumab plus fluorouracil, leucovorin, oxaliplatin (FOLFOX) as prior first-line treatment. Among the 52 patients receiving aflibercept and FOLFIRI, four complete responses and 21 partial responses were observed in analyzed patients for an overall response rate of 48.1%. Median progression-free survival (PFS) was 7.0 months and overall survival (OS) was 16.8 months. Response to first-line treatment (median PFS, 8.0 versus 4.2 months), left-side location of primary tumor (7.9 versus 4.9 months), low baseline CEA level (8.0 versus 5.9 months), and no RAS/RAF mutation (9.9 versus 6.4 months) were remained significant prognostic factors for PFS in the multivariate backward stepwise Cox regression model, and the latter three factors were also significantly related to OS. Significant prognostic factors for PFS with aflibercept plus FOLFIRI as second-line therapy were extracted and validated in the multivariate OS model. These findings could provide useful information for selecting patients for aflibercept plus FOLFIRI as second-line therapy.
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http://dx.doi.org/10.7150/jca.49176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739009PMC
January 2021

Impact of Radiotherapy on Kidney Function among Patients Who Received Adjuvant Treatment for Gastric Cancer: Logistic and Linear Regression Analyses.

Cancers (Basel) 2020 Dec 28;13(1). Epub 2020 Dec 28.

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

We investigated the incidence of renal function impairment after adjuvant treatment for gastric cancer and analyzed the impact of radiotherapy on estimated glomerular filtration rate (eGFR) five years after gastric surgery. We reviewed the medical records of 1490 patients with stomach cancer who underwent curative surgery and adjuvant treatment for gastric cancer. Finally, we included 663 patients who were followed up for ≥5 years without disease recurrence and whose baseline eGFR was ≥60 mL/min/1.73 m. Logistic and linear regression analyses were performed to determine independent factors associated with the five-year eGFR. A total of 13 (2.0%) patients developed renal function impairment (five-year eGFR <60 mL/min/1.73 m). In logistic regression analysis, the baseline eGFR was identified as a prognostic factor for renal function impairment (odds ratio (OR), 0.878; 95% confidence interval (CI), 0.831-0.927; < 0.001), but radiotherapy was not (OR, 1.130; 95% CI, 0.366-3.491; = 0.832). In linear regression analysis, age (B = -0.350, < 0.001), baseline eGFR (B = 0.576, < 0.001), cisplatin (B = -2.056, = 0.010), and radiotherapy (B = -2.628, < 0.001) were predictive variables for the five-year eGFR. Among patients who received adjuvant radiotherapy, age (B = -0.277, < 0.001), hypertension (B = -4.986, = 0.004), baseline eGFR (B = 0.665, < 0.001), and volume of the kidneys receiving ≥20 Gy (B = -0.209, = 0.012) were predictive variables for the five-year eGFR. Development of renal function impairment after adjuvant treatment for gastric cancer was rare among patients with normal baseline kidney function. While radiotherapy was negatively associated with the five-year eGFR, its impact would have been minimal if the kidneys were properly shielded. Further studies are needed to confirm the impact of radiotherapy in patients with poor kidney function.
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http://dx.doi.org/10.3390/cancers13010059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794775PMC
December 2020

Tolerance Patterns and Transcriptomic Response to Extreme and Fluctuating Salinities across Populations of the Intertidal Copepod .

Physiol Biochem Zool 2021 Jan/Feb;94(1):50-69

AbstractPopulations that tolerate extreme environmental conditions with frequent fluctuations can give valuable insights into physiological limits and adaptation. In some estuarine and marine ecosystems, organisms must adapt to extreme and fluctuating salinities, but not much is known about how varying salinities impact local adaptation across a wide geographic range. We used eight geographically and genetically divergent populations of the intertidal copepod to test whether northern populations have greater tolerance to low salinity stresses, as they experience greater precipitation and less evaporation. We used a common-garden experiment approach and exposed all populations to acute low (1 and 3 ppt) and high (110 and 130 ppt) salinities for 24 h and to a fluctuation between baseline salinity and moderate low (7 ppt) and high (80 ppt) salinities for over 49 h. We also performed RNA sequencing at several time points during the fluctuation between baseline and salinity of 7 ppt to understand the molecular basis of divergence between two populations with differing physiological responses. We present these novel findings: (1) acute low salinity conditions caused more deaths than high salinity; (2) molecular processes that elevate proline levels increased in salinity of 7 ppt, which contrasts with other physiological studies in that mainly associated accumulation of proline with hyperosmotic stress; and (3) tolerance to a salinity fluctuation did not follow a latitudinal trend but was instead governed by a complex interplay of factors, including population and duration of salinity stress. This highlights the importance of including a wider variety of environmental conditions in empirical studies to understand local adaptation.
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http://dx.doi.org/10.1086/712031DOI Listing
December 2020

Tumor-promoting macrophages prevail in malignant ascites of advanced gastric cancer.

Exp Mol Med 2020 12 4;52(12):1976-1988. Epub 2020 Dec 4.

Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.

Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly deteriorating clinical course with short survival following the onset of malignant ascites. Better optimized treatment strategies for this subset of patients are needed. To define the cellular characteristics of malignant ascites of GC, we used single-cell RNA sequencing to characterize tumor cells and tumor-associated macrophages (TAMs) from four samples of malignant ascites and one sample of cerebrospinal fluid. Reference transcriptomes for M1 and M2 macrophages were generated by in vitro differentiation of healthy blood-derived monocytes and applied to assess the inflammatory properties of TAMs. We analyzed 180 cells, including tumor cells, macrophages, and mesothelial cells. Dynamic exchange of tumor-promoting signals, including the CCL3-CCR1 or IL1B-IL1R2 interactions, suggests macrophage recruitment and anti-inflammatory tuning by tumor cells. By comparing these data with reference transcriptomes for M1-type and M2-type macrophages, we found noninflammatory characteristics in macrophages recovered from the malignant ascites of GC. Using public datasets, we demonstrated that the single-cell transcriptome-driven M2-specific signature was associated with poor prognosis in GC. Our data indicate that the anti-inflammatory characteristics of TAMs are controlled by tumor cells and present implications for treatment strategies for GC patients in which combination treatment targeting cancer cells and macrophages may have a reciprocal synergistic effect.
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http://dx.doi.org/10.1038/s12276-020-00538-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080575PMC
December 2020

Incorporating sarcopenia and inflammation with radiation therapy in patients with hepatocellular carcinoma treated with nivolumab.

Cancer Immunol Immunother 2021 Jun 24;70(6):1593-1603. Epub 2020 Nov 24.

Statistics and Data Center, Samsung Medical Center, Research Institute for Future Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.

Background: We investigated the combined effects of sarcopenia and inflammation on outcomes in patients with HCC treated with nivolumab.

Materials And Methods: We reviewed 102 patients treated with nivolumab between 2017 and 2018. Sarcopenia was diagnosed when the L3 skeletal muscle indices were < 42 cm/m and < 38 cm/m in men and women, respectively. Baseline neutrophil-to-lymphocyte ratio (NLR) and absolute lymphocyte count were used as surrogate markers of inflammation and immune cell reservoir. High NLR (hNLR) was defined as NLR ≥ 3, and severe lymphopenia (sLP) was defined as lymphocyte < 800/μL. The overall survival (OS) and progression-free survival (PFS) were analyzed.

Results: With a median follow-up of 21.9 (interquartile range, 8.3-58.3) months, patients with sarcopenia showed shorter OS than those without sarcopenia (median, 2.9 vs. 7.5 months, respectively). Patients with either hNLR or sLP exhibited inferior survival than those without risk factor (median OS, 2.8 vs. 14.5 months; median PFS, 1.3 vs. 3.7 months, respectively). Among 70 patients treated with RT, benefit of RT was observed in patients with sarcopenia or those without hNLR/sLP (all p < 0.05). After multivariable analysis, RT, hNLR/sLP, albumin-bilirubin (ALBI) grade, and alpha-fetoprotein were significantly associated with OS (all p < 0.05), and hNLR/sLP was also associated with decreased PFS together with ALBI grade, alpha-fetoprotein, and RT (all p < 0.05).

Conclusion: The current study hypothetically demonstrated that the risk group stratified by hNLR/sLP outweighs the significance of sarcopenia in predicting outcomes after nivolumab. Furthermore, patients with sarcopenia might benefit from RT, especially those without risk factors of hNLR/sLP.
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http://dx.doi.org/10.1007/s00262-020-02794-3DOI Listing
June 2021

Clinical and molecular distinctions in patients with refractory colon cancer who benefit from regorafenib treatment.

Ther Adv Med Oncol 2020 5;12:1758835920965842. Epub 2020 Nov 5.

Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22-79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side ( = 15, 19.8%) and the left side ( = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib ( < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6-4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib.
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http://dx.doi.org/10.1177/1758835920965842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649869PMC
November 2020

IL-7Rα CD8 T Cells from Healthy Individuals Are Anergic with Defective Glycolysis.

J Immunol 2020 12 26;205(11):2968-2978. Epub 2020 Oct 26.

Department of Anatomy and Cell Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;

Effector memory (EM) CD8 T cells expressing lower levels of IL-7R α (IL-7Rα) from healthy individuals are partly compromised in vitro, but the identity of these cells has remained unclear. In this study, we demonstrate that human IL-7Rα EM CD8 T cells are naturally occurring anergic cells in vivo and impaired in proliferation and IL-2 production but competent in IFN-γ and TNF-α production, a state that can be restored by IL-2 stimulation. IL-7Rα EM CD8 T cells show decreased expression of GATA3 and c-MYC and are defective in metabolic reprogramming toward glycolysis, a process required for the proliferation of T cells. However, IL-7Rα EM CD8 T cells can proliferate with TCR stimulation in the presence of IL-2 and IL-15, suggesting that these cells can be restored to normality or increased activity by inflammatory conditions and may serve as a reservoir for functional immunity.
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http://dx.doi.org/10.4049/jimmunol.1901470DOI Listing
December 2020

Delivering Cancer Care During the COVID-19 Pandemic: Recommendations and Lessons Learned From ASCO Global Webinars.

JCO Glob Oncol 2020 Sep;6:1461-1471

Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan.

Purpose: In response to the COVID-19 pandemic, the ASCO launched a Global Webinar Series to address various aspects of cancer care during the pandemic. Here we present the lessons learned and recommendations that have emerged from these webinars.

Methods: Fifteen international health care experts from different global regions and oncology disciplines participated in one of the six 1-hour webinars to discuss the latest data, share their experiences, and provide recommendations to manage cancer care during the COVID-19 pandemic. These sessions include didactic presentations followed by a moderated discussion and questions from the audience. All recommendations have been transcribed, categorized, and reviewed by the experts, who have also approved the consensus recommendations.

Results: The summary recommendations are divided into different categories, including risk minimization; care prioritization of patients; health care team management; virtual care; management of patients with cancer undergoing surgical, radiation, and systemic therapy; clinical research; and recovery plans. The recommendations emphasize the protection of patients and health care teams from infections, delivery of timely and appropriate care, reduction of harm from the interruption of care, and preparation to handle a surge of new COVID-19 cases, complications, or comorbidities thereof.

Conclusion: The recommendations from the ASCO Global Webinar Series may guide practicing oncologists to manage their patients during the ongoing pandemic and help organizations recover from the crisis. Implementation of these recommendations may improve understanding of how COVID-19 has affected cancer care and increase readiness to manage the current and any future outbreaks effectively.
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http://dx.doi.org/10.1200/GO.20.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529523PMC
September 2020

Single-cell transcriptome analysis of tumor and stromal compartments of pancreatic ductal adenocarcinoma primary tumors and metastatic lesions.

Genome Med 2020 09 29;12(1):80. Epub 2020 Sep 29.

Molecular Medicine Division, Translational Genomics Research Institute, 445 N. Fifth St., Phoenix, AZ, 85004, USA.

Background: Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues.

Methods: In this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets.

Results: Our single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival.

Conclusions: Taken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.
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http://dx.doi.org/10.1186/s13073-020-00776-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523332PMC
September 2020

Prognostic significance of sarcopenia in microsatellite-stable gastric cancer patients treated with programmed death-1 inhibitors.

Gastric Cancer 2021 Mar 24;24(2):457-466. Epub 2020 Sep 24.

Department of Radiology and Center for Imaging Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.

Background: Sarcopenia has been underscored as a significant predictor of poor prognosis in cancer patients undergoing immunotherapy with programmed death-1 (PD-1) inhibitors. We aimed to investigate the prognostic significance of computed tomography (CT)-determined sarcopenia in patients with microsatellite-stable (MSS) gastric cancer (GC) treated with PD-1 inhibitors.

Methods: We retrospectively assessed patients with MSS GC who had been treated with PD-1 inhibitors from March 2016 to June 2019. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index with abdominal CT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and the differences in survival probability according to sarcopenic status were compared using the log-rank test. Cox proportional hazards regression analyses were performed to identify predictors of PFS and OS.

Results: Of 149 patients with MSS GC (mean age, 57.0 ± 12.3 years; 93 men), 79 (53.0%) had sarcopenia. Patients with sarcopenia had significantly shorter PFS than patients without sarcopenia (median, 1.4 months vs. 2.6 months; P = 0.026). Sarcopenia was independently associated with shorter PFS (adjusted hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.10-2.93; P = 0.020). Patients with sarcopenia had shorter OS than patients without sarcopenia (median, 3.6 months vs. 4.9 months; P = 0.052), but sarcopenia itself was not a significant prognostic factor for OS (adjusted HR, 1.01; 95% CI, 0.58-1.75; P = 0.974).

Conclusions: CT-determined sarcopenia is an independent prognostic factor for PFS in patients with MSS GC treated with PD-1 inhibitors.
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http://dx.doi.org/10.1007/s10120-020-01124-xDOI Listing
March 2021

Mechanisms of Acquired Resistance to Savolitinib, a Selective MET Inhibitor in -Amplified Gastric Cancer.

JCO Precis Oncol 2020 24;4. Epub 2020 Mar 24.

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

Purpose: Some gastric cancers harbor gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options.

Patients And Methods: Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and -amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed.

Results: Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance D1228V/N/H and Y1230C mutations or high copy number gene amplifications that emerge when resistance to savolitinib develops in patients with -amplified gastric cancer.

Conclusion: We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.
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http://dx.doi.org/10.1200/PO.19.00386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446425PMC
March 2020

Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 10;6(10):1571-1580

Vall d'Hebron University Hospital (HUVH) and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain.

Importance: Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need.

Objective: To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater.

Design, Setting, And Participants: The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017.

Interventions: Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2 twice daily), or chemotherapy plus placebo, every 3 weeks.

Main Outcomes And Measures: Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater.

Results: A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17; P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02; P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively.

Conclusions And Relevance: This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested.

Trial Registration: ClinicalTrials.gov Identifier: NCT02494583.
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http://dx.doi.org/10.1001/jamaoncol.2020.3370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489405PMC
October 2020

Effect of baseline sarcopenia on adjuvant treatment for D2 dissected gastric cancer: Analysis of the ARTIST phase III trial.

Radiother Oncol 2020 11 31;152:19-25. Epub 2020 Jul 31.

Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Background And Purpose: This study evaluated the clinical significance of preoperative sarcopenia according to adjuvant concurrent chemo-radiotherapy (XP-RT) or chemotherapy alone (XP) in the D2 dissected gastric cancer patient cohort of the ARTIST trial.

Materials And Methods: Skeletal muscles at the L3 vertebra level from preoperative computed tomography images among the ARTIST trial participants were measured using validated in-house software. Skeletal muscle index (SMI) was defined as the measured skeletal muscle area divided by the square of the height, and sarcopenia was defined according to the Korean-specific cutoff, i.e. L3 SMI ≤ 49 cm/m for men and ≤31 cm/m for women.

Results: Among the 440 patients in whom we were able to evaluate L3 SMI, 75 (17.0%) met the definition for preoperative sarcopenia. No differences in treatment-related toxicities or treatment compliance were observed according to the presence of preoperative sarcopenia in either treatment arm. In the subgroup of patients without preoperative sarcopenia, recurrence was significantly lower in the XP-RT arm than that in the XP arm (p = 0.02). Recurrence-free survival (RFS) was also significantly higher in the XP-RT arm (p = 0.02, hazard ratio 0.633, 95% confidence interval 0.433-0.926) in this subgroup. In the multivariate analysis, and after adjusting for significant prognostic factors, the superior outcome of XP-RT arm regarding RFS was maintained in the subgroup of the patients without preoperative sarcopenia.

Conclusions: Superior clinical outcomes of adjuvant XP-RT over XP were only observed in patients without preoperative sarcopenia.
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http://dx.doi.org/10.1016/j.radonc.2020.07.043DOI Listing
November 2020

Phase I clinical trial of KML001 monotherapy in patients with advanced solid tumors.

Expert Opin Investig Drugs 2020 Sep 29;29(9):1059-1067. Epub 2020 Aug 29.

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

Background: We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors.

Research Design And Methods: With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1.

Results: A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease.

Conclusions: Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.
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http://dx.doi.org/10.1080/13543784.2020.1804855DOI Listing
September 2020

A Multi-cohort Study of the Prognostic Significance of Microsatellite Instability or Mismatch Repair Status after Recurrence of Resectable Gastric Cancer.

Cancer Res Treat 2020 Oct 4;52(4):1153-1161. Epub 2020 May 4.

Department of Surgery, Yonsei University Health System, Seoul, Korea.

Purpose: High microsatellite instability (MSI) is related to good prognosis in gastric cancer. We aimed to identify the prognostic factors of patients with recurrent gastric cancer and investigate the role of MSI as a prognostic and predictive biomarker of survival after tumor recurrence.

Materials And Methods: This retrospective cohort study enrolled patients treated for stage II/III gastric cancer who developed tumor recurrence and in whom the MSI status or mismatch repair (MMR) status of the tumor was known. MSI status and the expression of MMR proteins were evaluated using polymerase chain reaction and immunohistochemical analysis, respectively.

Results: Of the 790 patients included, 64 (8.1%) had high MSI status or MMR deficiency. The tumor-node-metastasis stage, type of recurrence, Lauren classification, chemotherapy after recurrence, and interval to recurrence were independently associated with survival after tumor recurrence. The MSI/MMR status and receiving adjuvant chemotherapy were not associated with survival after recurrence. In a subgroup analysis of patients with high MSI or MMR-deficient gastric cancer, those who did not receive adjuvant chemotherapy had better treatment response to chemotherapy after recurrence than those who received adjuvant chemotherapy.

Conclusion: Patients with high MSI/MMR-deficient gastric cancer should be spared from adjuvant chemotherapy after surgery, but aggressive chemotherapy after recurrence should be considered. Higher tumor-node-metastasis stage, Lauren classification, interval to recurrence, and type of recurrence are associated with survival after tumor recurrence and should thus be considered when establishing a treatment plan and designing clinical trials targeting recurrent gastric cancer.
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http://dx.doi.org/10.4143/crt.2020.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577808PMC
October 2020

First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients.

Ther Adv Med Oncol 2020 2;12:1758835920926796. Epub 2020 Jun 2.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea.

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy and . This is a first-in-human trial of this antibody.

Materials And Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg).

Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( = 7, 18.9%) followed by pruritis and nausea ( = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders.

Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned.

Conclusion: NCT02499224.
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http://dx.doi.org/10.1177/1758835920926796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268171PMC
June 2020

Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea.

PLoS Med 2020 06 8;17(6):e1003091. Epub 2020 Jun 8.

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

Background: Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy.

Methods And Findings: We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation.

Conclusions: Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients.

Trial Registration: Clinicaltrials.gov NCT02599012.
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http://dx.doi.org/10.1371/journal.pmed.1003091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279571PMC
June 2020