Publications by authors named "Jin Seok Ahn"

332 Publications

Deep Learning-Based Prediction Model for Breast Cancer Recurrence Using Adjuvant Breast Cancer Cohort in Tertiary Cancer Center Registry.

Front Oncol 2021 4;11:596364. Epub 2021 May 4.

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

Several prognosis prediction models have been developed for breast cancer (BC) patients with curative surgery, but there is still an unmet need to precisely determine BC prognosis for individual BC patients in real time. This is a retrospectively collected data analysis from adjuvant BC registry at Samsung Medical Center between January 2000 and December 2016. The initial data set contained 325 clinical data elements: baseline characteristics with demographics, clinical and pathologic information, and follow-up clinical information including laboratory and imaging data during surveillance. Weibull Time To Event Recurrent Neural Network (WTTE-RNN) by Martinsson was implemented for machine learning. We searched for the optimal window size as time-stamped inputs. To develop the prediction model, data from 13,117 patients were split into training (60%), validation (20%), and test (20%) sets. The median follow-up duration was 4.7 years and the median number of visits was 8.4. We identified 32 features related to BC recurrence and considered them in further analyses. Performance at a point of statistics was calculated using Harrell's C-index and area under the curve (AUC) at each 2-, 5-, and 7-year points. After 200 training epochs with a batch size of 100, the C-index reached 0.92 for the training data set and 0.89 for the validation and test data sets. The AUC values were 0.90 at 2-year point, 0.91 at 5-year point, and 0.91 at 7-year point. The deep learning-based final model outperformed three other machine learning-based models. In terms of pathologic characteristics, the median absolute error (MAE) and weighted mean absolute error (wMAE) showed great results of as little as 3.5%. This BC prognosis model to determine the probability of BC recurrence in real time was developed using information from the time of BC diagnosis and the follow-up period in RNN machine learning model.
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http://dx.doi.org/10.3389/fonc.2021.596364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129587PMC
May 2021

Long-Term Survival in Non-Small Cell Lung Cancer Patients with Metachronous Brain-Only Oligorecurrence Who Underwent Definitive Treatment.

Cancer Res Treat 2021 May 6. Epub 2021 May 6.

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

Purpose: Metachronous brain-only oligorecurrence in patients with non-small cell lung cancer (NSCLC) is a rare event with favorable prognosis, but the clinical outcome has not been fully determined. We retrospectively analyzed clinical outcomes and prognostic factors in metachronous brain-only oligorecurrence in patients with NSCLC who underwent definitive treatment.

Materials And Methods: We reviewed 4,437 NSCLC patients without oncogenic driver mutations who underwent definitive treatment between 2008 and 2018. Among them, we identified 327 patients who developed 1 to 5 brain metastases with or without systemic metastasis. Of the 327 patients, 71 had metachronous brain-only oligorecurrence without extracranial progression and were treated with local therapy to the brain. Overall survival (OS), progression-free survival (PFS), and prognostic factors affecting OS were analyzed.

Results: The median OS was 38.9 months (95% CI, 21.8 to 56.1 months) in 71 patients. The 2-year OS rate was 67.8% and the 5-year OS rate was 33.1%. The median PFS was 25.5 months (95% CI, 12.2 to 14.4 months). The longest surviving patient had a survival period of 115 months. Through multivariate analysis, ECOG ≥ 1 (HR: 5.33, p=0.005) was associated with poor survival. There was no significant difference in OS between patients with local therapy and those with local plus systemic therapy (18.5 vs. 34.7 months, p=0.82).

Conclusion: Metachronous brain-only oligorecurrence NSCLC patients who underwent definitive treatment experienced long-term survival with local therapy, highlighting the unique patient population. The role of systemic chemotherapy in this patient population requires further investigation.
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http://dx.doi.org/10.4143/crt.2021.306DOI Listing
May 2021

Validation of the Korean Version of the Patient-Reported Outcomes Measurement Information System 29 Profile V2.1 among Cancer Survivors.

Cancer Res Treat 2021 Apr 9. Epub 2021 Apr 9.

Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, Korea.

Purpose: The purpose of the study was to validate the Korean version of Patient-Reported Outcomes Measurement Information System 29 Profile V2.1 (K-PROMIS-29 V2.1) among cancer survivors.

Materials And Methods: Participants were recruited from outpatient clinics of the Comprehensive Cancer Center at the Samsung Medical Center in Seoul, South Korea, from September to October 2018. Participants completed a survey questionnaire that included the K-PROMIS-29 V2.1 and the European Organisation for Research and Treatment of Cancer Quality Of Life Core Questionnaire (EORTC QLQ-C30). Principal component analysis and confirmatory factor analysis (Principal Component Analysis, confirmatory factor analysis) and Pearson's correlations were used to evaluate the reliability and validity of the K-PROMIS-29 V2.1.

Results: The mean age of the study participants was 54.4 years, the mean time since diagnosis was 1.2 (± 2.4) years, and 349 (87.3%) completed the entire questionnaire. The Cronbach's alpha coefficients of the seven domains in the K-PROMIS-29 V2.1 ranged from 0.81 to 0.96, indicating satisfactory internal consistency. In the CFA, the goodness-of-fit indices for the K-PROMIS-29 V2.1 were high (comparative fit index, 0.91 and standardized root-mean-squared residual, 0.06). High to moderate correlations were found between comparable subscales of the K-PROMIS-29 V2.1 and subscales of the EORTC QLQ-C30 (r=0.52-0.73).

Conclusion: The K-PROMIS-29 V2.1 is a reliable and valid measure for assessing the health-related quality of life domains in a cancer population, thus supporting their use in studies and oncology trials.
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http://dx.doi.org/10.4143/crt.2020.1200DOI Listing
April 2021

High concordance of actionable genomic alterations identified between circulating tumor DNA-based and tissue-based next-generation sequencing testing in advanced non-small cell lung cancer: The Korean lung liquid versus invasive biopsy program.

Cancer 2021 Apr 7. Epub 2021 Apr 7.

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

Background: Because of the growing number of actionable biomarkers in non-small cell lung cancer (NSCLC), sufficient tissue availability for testing is becoming a greater challenge. Liquid biopsy offers a potential solution by complementing standard tissue-based methods. In this study, the authors analyzed the concordance of actionable genomic alterations sequenced from circulating tumor DNA (ctDNA; Guardant360) and tissue (Oncomine Focus Assay).

Methods: From September 2015 to May 2018, 421 paired plasma and tissue samples from patients with advanced NSCLC who had previously undergone tissue testing by standard methods were collected. Both types of samples were available for 287 patients (262 in cohort 1 [treatment-naive] and 25 in cohort 2 [treatment failure]), and only 1 sample type was available for 134 patients (50 in cohort 3 [plasma only] and 84 in cohort 4 [tissue only]).

Results: In cohort 1, 198 samples (77.6%) showed concordance between tissue and plasma next-generation sequencing (NGS). Among the discordant cases, plasma testing detected additional genomic alterations in 11 patients (4.2%). In 50 patients without tissue-based NGS results (cohort 3), the ctDNA-based test detected genomic alterations in 20 samples (40.0%). The median allele frequency (AF) of mutations identified with ctDNA-based NGS (0.74%) was lower than that identified with the tissue-based NGS test (13.90%). Clinical responses to matched targeted therapy occurred, regardless of the ctDNA AF. Upfront ctDNA-based testing identified 60.4% of patients with genomic alterations. In addition, ctDNA-based testing uncovered 12.0% more actionable alterations when it was performed after tissue-based NGS testing.

Conclusions: The results indicate that a ctDNA-based test identifies additional patients with actionable genomic alterations and could, therefore, be used to complement traditional tissue-based testing for NSCLC.

Lay Summary: Circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) testing is becoming essential as the number of actionable genomic biomarker increases for the treatment selection of non-small cell lung cancer. This study demonstrates the additive value of ctDNA-based testing in addition to tissue-based NGS and standard of care-based biomarker testing for detecting additional patients with actionable genomic alterations. Clinical responses have also been observed in patients with a low allele frequency detected by ctDNA-based NGS testing.
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http://dx.doi.org/10.1002/cncr.33571DOI Listing
April 2021

The Role of Chemotherapy in Patients With HER2-Negative Isolated Locoregional Recurrence of Breast Cancer: A Multicenter Retrospective Cohort Study.

Front Oncol 2021 5;11:653243. Epub 2021 Mar 5.

Division of Hemato-Oncology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, South Korea.

The role of chemotherapy for isolated locoregional recurrence (iLRR) of breast cancer has not been firmly established after local therapies. We performed a multicenter, retrospective analysis to evaluate the clinical implications of chemotherapy in breast cancer patients with HER2-negative iLRR. Of a total of 277 patients, 146 (52.7%) received chemotherapy for iLRR. Median follow-up duration was 56.1 months. Eighty-six (31.0%) patients had luminal B-like and 100 (36.1%) had TNBC iLRR. There was a trend of longer disease free survival (DFS) in the chemotherapy group (4-year DFS: 70.4 vs. 59.5%, HR = 0.68, 95% CI 0.45-1.02, log-rank = 0.059). When adjusted with clinically relevant factors, DFS was significantly prolonged with chemotherapy (adjusted HR = 0.61, 95% CI 0.40-0.94, = 0.023). Subgroup analyses for DFS showed patients with disease free interval (DFI) <5 years or prior chemotherapy had a benefit from chemotherapy (adjusted HR = 0.57, = 0.018; adjusted HR = 0.51, = 0.005, respectively). Regarding the molecular subtypes, a longer DFS with chemotherapy was observed both in luminal B-like (4-year DFS: 77.8 vs. 55.0%, HR = 0.51, 95% CI 0.27-0.99, log-rank = 0.048) and in TNBC patients (4-year DFS: 61.9 vs. 42.8%, HR = 0.49, 95% CI 0.24-1.02, log-rank = 0.056), but not in luminal A-like. The chemotherapy for iLRR of breast cancer should be individualized for each patient, considering DFI, prior chemotherapy, and molecular subtypes.
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http://dx.doi.org/10.3389/fonc.2021.653243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973367PMC
March 2021

Comprehensive evaluation of the clinical utility of plasma EGFR test in non-small cell lung cancer patients with acquired resistance to first-line EGFR inhibitors.

Transl Lung Cancer Res 2021 Feb;10(2):878-888

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

Background: Plasma epidermal growth factor receptor (EGFR) mutation tests are widely used when non-small cell lung cancer (NSCLC) patients acquire resistance to EGFR inhibitors. We comprehensively evaluated the clinical utility of plasma EGFR test.

Methods: We screened NSCLC patients who had a plasma EGFR test upon acquiring resistance to first- or second-generation EGFR inhibitors. Plasma EGFR tests were performed with the EGFR mutation test.

Results: A total of 355 patients were tested for plasma EGFR mutations, and T790M was detected in 83 patients (23%). Of 79 patients who were tested multiple times, T790M was newly detected in 13 subsequent plasma tests. When initial plasma tests did not detect any EGFR mutation types, the detection rate of T790M in subsequent tests was very low (9%, 5/56), while detection rates of T790M in subsequent tests increased (35%, 8/23) in those individuals in whom sensitizing mutations had been detected in the initial plasma test (P=0.005). Paired plasma and tissue EGFR test results were available for 235 patients. Sensitivity and specificity of the plasma tests for T790M were 14% and 87%, respectively. Among 235 patients, 140 patients had tissue EGFR tests performed after T790M-negative plasma results were reported. The subsequent tissue test detected T790M in 61% (44/72) of these patients when any EGFR mutations were not detected in prior plasma tests, while the detection rate of T790M in subsequent tissue tests was 37% (25/68) when sensitizing mutations were detected in prior plasma tests (P=0.004).

Conclusions: Because the sensitivity of plasma EGFR test for T790M is low, follow-up tissue or plasma tests are necessary. Presence or absence of a sensitizing mutation in the initial plasma tests can be used to determine which samples (tissue or plasma) should be submitted for further testing.
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http://dx.doi.org/10.21037/tlcr-20-1128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947405PMC
February 2021

Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea.

Diagnostics (Basel) 2021 Feb 22;11(2). Epub 2021 Feb 22.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.'s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. "Discordant: Opposite classification" was observed for only one among 27 (3.7%). This discrepancy was due to the detection of a deleterious large genomic rearrangement of by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 patients. "Discordant: Laboratory's uncertain classification" was found in 22.2% of the sample (six patients). All discrepancies were generated during interpretation of gene sequencing. Further studies and standardization of genetic testing for genes are required.
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http://dx.doi.org/10.3390/diagnostics11020370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926822PMC
February 2021

Ventriculoperitoneal Shunt for CNS Metastasis in Breast Cancer: Clinical Outcomes Based on Intrinsic Subtype.

Clin Breast Cancer 2021 Jan 6. Epub 2021 Jan 6.

Division of Hematology-Oncology, Departments of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address:

Background: Leptomeningeal metastasis (LM) is associated with a grave prognosis in breast cancer (BC) and can be controlled with a ventriculoperitoneal shunt (VPS). Information regarding LM and VPS based on intrinsic subtype is limited; thus, we investigated the clinical outcomes of BC treated with VPS.

Patients And Methods: The present retrospective study comprised 70 patients diagnosed with LM who received a VPS. The patients were divided into 4 groups based on BC subtype: hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2), HR/HER2, HR/HER2, and triple negative BC (TNBC).

Results: The most common indications for VPS were uncontrolled intracranial pressure (57.1%) and uncontrolled headache (55.7%), which improved in 54 (77.1%) of 70 patients after VPS. The median overall survival (OS) after brain or LM and overall survival after VPS were 7.6 and 2.3 months, respectively. Anti-HER2 treatment was a significant prognostic factor for better OS after brain or LM based on multivariate analysis (hazard ratio, 0.15; 95% confidence interval, 0.04-0.57; P = .005), whereas TNBC was correlated with shorter OS after central nervous system metastasis (hazard ratio, 2.82; 95% confidence interval, 1.46-5.48; P = .002).

Conclusions: There were significant differences in clinical outcome based on the intrinsic subtype of patients with BC with LM who received a VPS. Anti-HER2 treatment in patients with HER2 BC was associated with better survival in patients with metastatic BC with VPS insertion compared with those without. Survival of metastatic BC with VPS remained poor, especially in the TNBC subgroup.
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http://dx.doi.org/10.1016/j.clbc.2020.12.013DOI Listing
January 2021

Tumor infiltrated immune cell types support distinct immune checkpoint inhibitor outcomes in patients with advanced non-small cell lung cancer.

Eur J Immunol 2021 Apr 22;51(4):956-964. Epub 2021 Feb 22.

Division of Hematology-Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.

The evaluation of PD-L1 expression alone has limitations in predicting clinical outcome in immune-checkpoint inhibitors (ICI). This study aimed to evaluate the predictive and prognostic effects of the presence of various immune cells in pretreatment tissue samples and to identify determinants associated with response in patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1 blockade. Immune cell distribution was heterogeneous and the most dominant immune cell type was T cells. Patients with durable clinical benefit (DCB) showed significantly higher PD-L1 expression. The ratio of tumor/stroma region of T cell, B cell, and macrophage was significantly higher in patient with DCB. High intratumoral T- and B-cell density (≥median) was associated with DCB in the low PD-L1 expression (<50%) group. In univariate analyses, the overall survival (OS) benefit was shown according to intratumoral B-cell density (p = 0.0337). The incidence of hyperprogressive disease (HPD) was 13.0%. The Chi-square test revealed that HPD was significantly associated with intratumoral B-cell density but not T-cell or macrophage density. Our results demonstrate different predictive and prognostic values for infiltrating immune cells in tumor tissue, which may help in selecting patients for ICI.
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http://dx.doi.org/10.1002/eji.202048966DOI Listing
April 2021

Treatment Patterns and Clinical Outcomes in Korean Cancer Patients With Venous Thromboembolism: A Retrospective Cohort Study.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:1076029620979575

Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea.

This study assessed epidemiologic data and clinical outcomes, including venous thromboembolism (VTE) recurrence and bleeding events, in patients with cancer-associated VTE, and assessed factors associated with clinical outcomes. Data were extracted from retrospective medical-chart review of adult patients diagnosed with cancer-associated deep vein thrombosis or pulmonary embolism who received anticoagulation treatment for ≥3 months. Patients were classified by: low-molecular-weight heparin (LMWH), direct oral anticoagulants (DOACs), and other anticoagulants. First VTE recurrence and bleeding events, and factors associated with their occurrence, were assessed during the initial 6 months of treatment. Overall, 623 patients (age: 63.7 ± 11.3 years, 49.3% male) were included (119, 132, and 372 patients in LMWH, DOACs and other anticoagulants groups, respectively). The cumulative 6-month incidence of VTE recurrence was 16.6% (total), 8.3% (LMWH), 16.7% (DOACs), and 20.7% (other); respective bleeding events were 22.5%, 11.0%, 12.3%, and 30.7%). VTE recurrence and bleeding rates differed only between LMWH and other anticoagulants (HR 2.4, 95% CI: 1.2-5.0 and 3.6, 1.9-6.8, respectively). These results highlight the importance of initial VTE treatment choice for preventing VTE recurrence and bleeding events. LMWH or DOACs for ≥3 months can be considered for effective VTE management in cancer patients.
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http://dx.doi.org/10.1177/1076029620979575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960896PMC
January 2021

Immunological Characteristics of Hyperprogressive Disease in Patients with Non-small Cell Lung Cancer Treated with Anti-PD-1/PD-L1 Abs.

Immune Netw 2020 Dec 21;20(6):e48. Epub 2020 Dec 21.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea.

Hyperprogressive disease (HPD) is a distinct pattern of progression characterized by acceleration of tumor growth after treatment with anti-PD-1/PD-L1 Abs. However, the immunological characteristics have not been fully elucidated in patients with HPD. We prospectively recruited patients with metastatic non-small cell lung cancer treated with anti-PD-1/PD-L1 Abs between April 2015 and April 2018, and collected peripheral blood before treatment and 7-days post-treatment. HPD was defined as ≥2-fold increase in both tumor growth kinetics and tumor growth rate between pre-treatment and post-treatment. Peripheral blood mononuclear cells were analyzed by multi-color flow cytometry to phenotype the immune cells. Of 115 patients, 19 (16.5%) developed HPD, 52 experienced durable clinical benefit (DCB; partial response or stable disease ≥6 months), and 44 experienced non-hyperprogressive progression (NHPD). Patients with HPD had significantly lower progression-free survival (p<0.001) and overall survival (p<0.001). When peripheral blood immune cells were examined, the pre-treatment frequency of CD39 cells among CD8 T cells was significantly higher in patients with HPD compared to those with NHPD, although it showed borderline significance to predict HPD. Other parameters regarding regulatory T cells or myeloid derived suppressor cells did not significantly differ among patient groups. Our findings suggest high pre-treatment frequency of CD39CD8 T cells might be a characteristic of HPD. Further investigations in a larger cohort are needed to confirm our results and better delineate the immune landscape of HPD.
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http://dx.doi.org/10.4110/in.2020.20.e48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779871PMC
December 2020

Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery.

J Korean Neurosurg Soc 2021 Mar 4;64(2):271-281. Epub 2020 Dec 4.

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

Objective: Immune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC.

Methods: We retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27).

Results: The median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1-77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5-27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004).

Conclusion: GKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.
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http://dx.doi.org/10.3340/jkns.2020.0135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969051PMC
March 2021

The different central nervous system efficacy among gefitinib, erlotinib and afatinib in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer.

Transl Lung Cancer Res 2020 Oct;9(5):1749-1758

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

Background: Brain metastasis is common in non-small cell lung cancer (NSCLC) and has an even higher incidence in epidermal growth factor receptor (EGFR)-mutant cancers. Although EGFR tyrosine kinase inhibitors (TKIs) are effective against brain metastases, it is unknown which first- or second-generation EGFR TKI is most effective.

Methods: Patients treated with first-line gefitinib, erlotinib, or afatinib for advanced EGFR-mutant NSCLC were included. The efficacy against brain metastasis was evaluated by comparing the response rates of measurable and non-irradiated brain metastases, central nervous system progression-free survival (CNS-PFS), and the cumulative incidence of CNS failure.

Results: Among the 559 patients who received EGFR-TKIs (gefitinib, n=299; erlotinib, n=93; afatinib, n=167), 198 had initial brain metastasis before starting EGFR-TKIs. The CNS response rates of gefitinib, erlotinib, and afatinib were 64.7%, 68.2%, and 72.9%, respectively (P=0.78). In the overall study population, irrespective of initial CNS metastasis, the median CNS-PFS was 17.3 months for gefitinib, 12.4 months for erlotinib, and 23.3 months for afatinib (P<0.001). In multivariate analysis for CNS-PFS, the hazard ratio (HR) of afatinib was 0.63 (95% CI, 0.47-0.83) compared with gefitinib or erlotinib. In the competing risk analysis for cumulative incidence of CNS failure, afatinib showed a lower cumulative incidence of CNS failure compared with gefitinib or erlotinib after adjusting for both EGFR mutation type and preexisting CNS metastases (HR 0.51, 95% CI, 0.34-0.75, P=0.0007).

Conclusions: Through there are some limitation as a retrospective study, afatinib showed similar CNS response rates, superior CNS-PFS and cumulative incidence of CNS failure, compared with gefitinib or erlotinib.
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http://dx.doi.org/10.21037/tlcr-20-379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653133PMC
October 2020

Regulatory (FoxP3) T cells and TGF-β predict the response to anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

Sci Rep 2020 11 4;10(1):18994. Epub 2020 Nov 4.

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-ro, Gangnam-gu, Seoul, Republic of Korea.

Antitumor immune responses induced by immune checkpoint inhibitors anti-PD-1 or anti-PD-L1 have been used as therapeutic strategies in advanced non-small cell lung cancer (NSCLC) patients over the last decade. Favorable antitumor activity to immune checkpoint inhibitors is correlated with high PD-L1 expression, increased tumor-infiltrating lymphocytes, and decreased suppressive immune cells including Treg cells, myeloid-derived suppressor cells, or tumor-associated macrophages in various cancer types. In this study, we investigated the potential correlation between clinical outcomes and peripheral blood immune cell profiles, specifically focused on FoxP3 Treg cells, collected at baseline and one week after anti-PD-1 therapy in two independent cohorts of patients with NSCLC: a discovery cohort of 83 patients and a validation cohort of 49 patients. High frequencies of circulating Treg cells one week after anti-PD-1 therapy were correlated with a high response rate, longer progression-free survival, and overall survival. Furthermore, high levels of TGF-β and Treg cells were associated with favorable clinical outcomes. Our results suggest that higher levels of FoxP3 Treg cells and TGF-β can predict a favorable response to anti-PD-1 immunotherapy in patients with advanced NSCLC.
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http://dx.doi.org/10.1038/s41598-020-76130-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642363PMC
November 2020

Characteristics of female lung cancer in Korea: analysis of Korean National Lung Cancer Registry.

J Thorac Dis 2020 Sep;12(9):4612-4622

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Backgrounds: The present study evaluated Korean women with lung cancer and compared the clinical characteristics of ever-smoker and never-smoker groups using the National Lung Cancer Registry.

Methods: In affiliation with the Korean Central Cancer Registry, the Korean Association for Lung Cancer constructed a registry into which 10% of the lung cancer cases in Korea were registered. Female lung cancer patients with valid smoking history were evaluated.

Results: Among 735 female lung cancer patients, 643 (87.5%) were never-smokers and 92 (12.5%) were smokers. The median survival was significantly longer in the never-smoker group (28 14 months; P<0.001). Among 683 patients with non-small cell lung cancer (NSCLC), the never-smoker group showed significantly longer median survival (29 14 months; P=0.002) and a higher proportion of stage I cancer (40.3% 25.7%; P<0.001). Survival analysis of the NSCLC patients showed that smoking status, receiving only supportive care, EGFR mutation status, lung cancer stage, and forced vital capacity (FVC) (%) were significantly associated with mortality in the multivariate analysis (P=0.025, HR 2.39, 95% CI: 1.12-5.11; P=0.017, HR 3.14, 95% CI: 1.22-8.06; P=0.033, HR 0.63, 95% CI: 0.41-0.96; P<0.001, HR 11.88, 95% CI: 5.79-24.38; P=0.002, HR 0.98, 95% CI: 0.96-0.99, respectively).

Conclusions: In Korean women with NSCLC, smoking status, not receiving active anticancer treatment, EGFR mutation status, lung cancer stage, and pulmonary function were significantly associated with mortality.
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http://dx.doi.org/10.21037/jtd-20-1671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578488PMC
September 2020

Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity.

J Immunother Cancer 2020 10;8(2)

Samsung Genome Institute, Samsung Medical Center, Seoul, Korea

Background: Tumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.

Methods: We comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker's predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).

Results: Low tumor purity was common (range 30%-45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016).

Conclusions: Our data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
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http://dx.doi.org/10.1136/jitc-2020-001199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574938PMC
October 2020

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon Mutations: Are They Different from Those with Common Mutations?

Biology (Basel) 2020 Oct 7;9(10). Epub 2020 Oct 7.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Approximately 10% of the epidermal growth factor receptor () mutations in non-small-cell lung cancer (NSCLC) are uncommon mutations. Although the efficacy of second (2G) or third generation (3G) tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8-13.5), 11.7 months (95% CI: 6.6-16.7), 7.7 months (95% CI: 4.9-17.4), and 5.0 months (95% CI: 3.7-6.1) for major uncommon mutation (G719X, L861Q), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9-34.2), 28.8 (95% CI: 24.4-33.4), 13.5 months (95% CI: 7.4-27.8), and 9.4 months (95% CI: 3.4-10.5) for major uncommon mutation (G719X), compound mutation with major mutation (Del 19 or exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6-16.9), and 37.5 months (95% CI: 35.4-39.6) for common mutation-positive NSCLC. After failing 1L -TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G -TKI after failing the first-line -TKI, the ORR and PFS for 3G -TKI were 80% and 8.9 months (95% CI: 8.0-9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8-39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common mutations. T790M was detected in 28.6% of the uncommon mutation-positive patients for whom prior 1G/2G -TKIs failed and underwent repeat biopsy at the time of progression.
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http://dx.doi.org/10.3390/biology9100326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600176PMC
October 2020

A return-to-work intervention protocol directed at cancer patients (self-assessment, tailored information & lifestyle management for returning to work among cancer patients, START): A multi-center, randomized controlled trial.

Contemp Clin Trials Commun 2020 Sep 12;19:100633. Epub 2020 Aug 12.

Department of Clinical Research Design & Evaluation, SAIHST, Sungkyunkwan University, Seoul, South Korea.

Purpose: This study describes the protocol for the design and evaluation of a self-assessment based educational program supporting cancer patients' return-to-work (RTW), prior to its complete and ongoing implementation.

Methods: We designed a multi-center, randomized controlled trial with three follow-up points. The study population (N = 239) includes recently diagnosed cancer patients who plan to receive active treatment at two university hospitals in Korea. A pre-test is conducted at the point of enrollment for both groups. The intervention group receives a leaflet clarifying misconceptions about RTW and is shown a video clip of patient interviews concerning RTW. The control group receives a booklet about cancer and nutrition, and is not provided with further intervention. After active treatment, the intervention group receives a one-time, face-to-face education session with an oncology nurse. Following the education session, both groups receive three follow-up phone calls. The first follow-up call occurs at the end of intervention and at the end of active treatment for intervention and control groups, respectively. The next two follow-up calls will be conducted one month and a year following the post-test. The primary outcome is whether the patient has RTW or has plans to RTW, and the secondary outcome is knowledge of RTW.

Results: As of April 2020, 239 patients have been enrolled in the trial. Statistical analyses will be conducted upon trial completion in December 2020.

Discussion: We hypothesize that the provision of RTW education near diagnosis will not only enhance patients' intentions to RTW, but also effectively encourage them to RTW.
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http://dx.doi.org/10.1016/j.conctc.2020.100633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451719PMC
September 2020

Prognostication of a 13-immune-related-gene signature in patients with early triple-negative breast cancer.

Breast Cancer Res Treat 2020 Nov 18;184(2):325-334. Epub 2020 Aug 18.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea.

Purpose: We investigated the expression profiles of immune genes in patients with triple-negative breast cancer (TNBC) to identify the prognostic value of immune genes and their clinical implications.

Methods: NanoString nCounter Analysis of 770 immune-related genes was used to measure immune gene expression in patients with TNBC who underwent curative surgery followed by adjuvant chemotherapy at Samsung Medical Center between 2000 and 2004. Statistical analyses were conducted to identify the associations between gene expression and distant recurrence-free survival (DRFS).

Results: Of 1189 patients who underwent curative BC surgery, 200 TNBC patients were included and stage was the only clinical factor predictive of DRFS. In terms of immune genes, 155 of 770 genes were associated with DRFS (p < 0.01). Further multivariate analysis revealed that 13 genes, CD1B, CD53, CT45A1, GTF3C1, IL11RA, IL1RN, LRRN3, MAPK1, NEFL, PRKCE, PTPRC, SPACA3 and TNFSF11, were associated with patient prognosis (p < 0.05). The prognostic value of stage and expression levels of 13 immune genes was analyzed and the area under the receiver operating characteristic curve (AUC) was 0.923. Based on the AUC, we divided patients into three genetic risk groups and DRFS rate was significantly different according to genetic risk groups, even in the same stage (p < 0.001).

Conclusions: In this study, a 13-gene expression profile in combination with stage precisely predicted distant recurrence of early TNBC. Therefore, this 13-immune-gene signature could help predict TNBC prognosis and provide guidance for treatment as well as the opportunity to develop new targets for immunotherapy in TNBC patients.
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http://dx.doi.org/10.1007/s10549-020-05874-1DOI Listing
November 2020

Are there any ethnic differences in the efficacy and safety of immune checkpoint inhibitors for treatment of lung cancer?

J Thorac Dis 2020 Jul;12(7):3796-3803

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

Immunotherapy, especially immune checkpoint inhibitors, has revolutionized the treatment of non-small cell lung cancer. However, data on ethnic differences in response to these treatments are still lacking. We reviewed the currently available clinical data on immune checkpoint inhibitors and analyzed the ethnic difference in terms of treatment efficacies and side effects. Despite different epidemiology, genetic susceptibility and molecular profiles, Asian lung cancer patients demonstrated comparable outcomes to Western patients in terms of response rates and survival benefits. The incidence of immune-related adverse events has been reported with a higher incidence in Japanese patients, but was not consistent across other Asian patient populations, and warrants further investigation.
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http://dx.doi.org/10.21037/jtd.2019.08.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399433PMC
July 2020

Metabolic radiogenomics in lung cancer: associations between FDG PET image features and oncogenic signaling pathway alterations.

Sci Rep 2020 08 6;10(1):13231. Epub 2020 Aug 6.

Department of Nuclear Medicine and Molecular Imaging, Samsung Medical Center, Seoul, Republic of Korea.

This study investigated the associations between image features extracted from tumor F-fluorodeoxyglucose (FDG) uptake and genetic alterations in patients with lung cancer. A total of 137 patients (age, 62.7 ± 10.2 years) who underwent FDG positron emission tomography/computed tomography (PET/CT) and targeted deep sequencing analysis for a tumor lesion, comprising 61 adenocarcinoma (ADC), 31 squamous cell carcinoma (SQCC), and 45 small cell lung cancer (SCLC) patients, were enrolled in this study. From the tumor lesions, 86 image features were extracted, and 381 genes were assessed. PET features were associated with genetic mutations: 41 genes with 24 features in ADC; 35 genes with 22 features in SQCC; and 43 genes with 25 features in SCLC (FDR < 0.05). Clusters based on PET features showed an association with alterations in oncogenic signaling pathways: Cell cycle and WNT signaling pathways in ADC (p = 0.023, p = 0.035, respectively); Cell cycle, p53, and WNT in SQCC (p = 0.045, 0.009, and 0.029, respectively); and TGFβ in SCLC (p = 0.030). In addition, SUV and SUV were associated with a mutation of the TGFβ signaling pathway in ADC (FDR = 0.001, < 0.001). In this study, PET image features had significant associations with alterations in genes and oncogenic signaling pathways in patients with lung cancer.
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http://dx.doi.org/10.1038/s41598-020-70168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411040PMC
August 2020

Evaluating entrectinib as a treatment option for non-small cell lung cancer.

Expert Opin Pharmacother 2020 Nov 31;21(16):1935-1942. Epub 2020 Jul 31.

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

Introduction: Entrectinib, an oral pan-TRK, ALK, and ROS1 inhibitor is approved as a first-line treatment for NTRK-rearranged solid tumors and ROS1-rearranged non-small cell lung cancer (NSCLC). It has demonstrated clinical efficacy for patients harboring the relevant gene rearrangement in both systemic and intracranial disease, regardless of the tumor type.

Areas Covered: In this review, the authors analyzed data from preclinical and clinical studies, the characteristics of entrectinib compared to those of other relevant inhibitors (currently available and/or under investigation), and the emerging resistance mechanisms. The authors then provide the readers with their future perspectives.

Expert Opinion: Entrectinib has been well studied across many tumor types, including NSCLC with ALK, ROS1, and NTRK rearrangements. The drug has demonstrated favorable properties with oral administration, prolonged response duration, high intracranial efficacy, and a favorable toxicity profile. However, with acquisition of resistance and the development of newer generation TKIs, the optimal place for entrectinib in the landscape of targeted therapies for NSCLC warrants further validation.
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http://dx.doi.org/10.1080/14656566.2020.1798932DOI 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

Osimertinib Improves Overall Survival in Patients With EGFR-Mutated NSCLC With Leptomeningeal Metastases Regardless of T790M Mutational Status.

J Thorac Oncol 2020 11 9;15(11):1758-1766. Epub 2020 Jul 9.

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

Introduction: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, efficiently penetrates the blood-brain barrier. This study explored whether treatment with osimertinib leads to improved overall survival (OS) for patients with EGFR-mutated NSCLC with leptomeningeal metastases (LM) compared with those not treated with osimertinib.

Methods: From October 2008 to October 2019, patients with EGFR-mutated NSCLC and cytologically confirmed LM were retrospectively analyzed for OS according to osimertinib treatment and T790M mutational status. The OS was defined as the time from the diagnosis of LM to death.

Results: For the 351 patients with LM included in the analysis, the median OS (mOS) was 8.1 months (95% confidence interval [CI]: 7.2-9.0). T790M mutation was detected in 88 of 197 patients tested, and a total of 110 patients were treated with osimertinib after LM. No difference in mOS according to T790M mutational status (10.1 mo [95% CI: 4.31-15.82] versus 9.0 [95% CI: 6.81-11.21], p = 0.936) was found. Nevertheless, patients treated with osimertinib had a superior OS of 17.0 months (95% CI: 15.13-18.94) compared with those not treated with osimertinib who had a mOS of 5.5 months (95% CI: 4.34-6.63), regardless of T790M mutational status (hazard ratio: 0.36 [95% CI: 0.28-0.47], p < 0.001). This was also considerably longer even than the mOS of 8.7 months (95% CI: 7.01-10.39) of those who were never treated with osimertinib but had first- or second-generation EGFR tyrosine kinase inhibitors.

Conclusions: Osimertinib is a promising treatment option for EGFR-mutated NSCLC with LM regardless of T790M mutational status.
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http://dx.doi.org/10.1016/j.jtho.2020.06.018DOI Listing
November 2020

EGFR C797S as a Resistance Mechanism of Lazertinib in Non-small Cell Lung Cancer with EGFR T790M Mutation.

Cancer Res Treat 2020 Oct 22;52(4):1288-1290. Epub 2020 Jun 22.

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

The non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutation eventually acquires resistant to either first or second-generation EGFR tyrosine kinase inhibitor (TKI). As the following option, targeting EGFR T790M with third-generation EGFR TKI is now established as a standard treatment option. In this study, we are reporting the first case of resistance mechanism to the novel third-generation EGFR TKI, lazertinib, which showed promising clinical efficacy in phase 1-2 study. The patients showed resistance to the treatment by acquiring the additional EGFR C797S mutation in cis which is also confirmed from the patient-derived cell lines.
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http://dx.doi.org/10.4143/crt.2020.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577810PMC
October 2020

Biomarker-driven phase 2 umbrella trial study for patients with recurrent small cell lung cancer failing platinum-based chemotherapy.

Cancer 2020 09 25;126(17):4002-4012. Epub 2020 Jun 25.

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

Background: A high percentage of small cell lung cancer (SCLC) cases harbor cell cycle-related gene mutations and RICTOR amplification. Based on underlying somatic mutations, the authors have conducted a phase 2 biomarker-driven, multiarm umbrella study.

Methods: The SCLC Umbrella Korea StudiES (SUKSES) is an adaptive platform trial that undergoes continual modification according to the observed outcomes. This study included 286 patients with SCLC who failed platinum therapy and who had known genomic profiles based on a predesigned screening trial. Patients with MYC amplification or CDKN2A and TP53 co-alterations were allocated to adavosertib (SUKSES protocol C [SUKSES-C]; 7 patients) and those with RICTOR amplification were allocated to vistusertib (SUKSES-D; 4 patients). Alternatively, patients who were without any predefined biomarkers were assigned to a non-biomarker-selected arm: adavosertib (SUKSES-N1; 21 patients) or AZD2811NP (SUKSES-N3; 15 patients).

Results: Patients in the SUKSES-C and SUKSES-N1 arms demonstrated no objective response. Three patients presented with stable disease (SD) in SUKSES-C and 6 patients in SUKSES-N1. The median progression-free survival (PFS) was 1.3 months (95% confidence interval, 0.9 months to not available) for SUKSES-C and 1.2 months (95% CI, 1.1-1.4 months) for SUKSES-N1. Patients in the SUKSES-D arm demonstrated no objective response and no SD, with a PFS of 1.2 months (95% CI, 1.0 months to not available). The SUKSES-N3 arm had 5 patients with SD and a PFS of 1.6 months (95% CI, 0.9-1.7 months), without an objective response. Grade≥3 adverse events (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) were observed as follows: 3.2% in the SUKSES-C and SUKSES-N1 arms and 50.0% in the SUKSES-D arm. Target-related neutropenia (grade≥3) was observed in approximately 60.0% of patients in the AZD2811NP arm using the current dosing schedule.

Conclusions: To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.
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http://dx.doi.org/10.1002/cncr.33048DOI Listing
September 2020

Clinical Characteristics and Exploratory Genomic Analyses of Germline BRCA1 or BRCA2 Mutations in Breast Cancer.

Mol Cancer Res 2020 09 17;18(9):1315-1325. Epub 2020 Jun 17.

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

gBRCA1/2 mutations increase the incidence of breast cancer by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 breast cancer have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 breast cancer. Sanger sequencing to identify gBRCA1/2 mutations was conducted in 2,720 patients, and gBRCA1 ( = 128) and gBRCA2 ( = 126) mutations were analyzed. Within this population, deep target sequencing and matched whole-transcriptome sequencing (WTS) results were available for 46 and 34 patients, respectively. An internal database of patients with breast cancer with wild-type gBRCA was used to compile a target sequencing ( = 195) and WTS ( = 137) reference dataset. Three specific mutation sites, p.Y130X ( = 14) and p.1210Afs ( = 13) in gBRCA1 and p.R294X ( = 22) in gBRCA2, were comparably frequent. IHC subtyping determined that the incidence of triple-negative breast cancer was higher among those with a gBRCA1 mutation (71.9%), and estrogen receptor-positive breast cancer was dominant in those with a gBRCA2 mutation (76.2%). gBRCA1/2 mutations were mutually exclusive with somatic mutations ( < 0.05), and gBRCA1 frequently cooccurred with somatic mutations ( < 0.05). The median tumor mutation burden was 6.53 per megabase (MB) in gBRCA1 and 6.44 per MB in gBRCA2. The expression of , and was significantly upregulated with gBRCA2 mutation compared with gBRCA1 mutation. gBRCA1 and gBRCA2 breast cancer have similar clinical characteristics, but they have different molecular subtypes, coaltered somatic mutations, and gene expression patterns. IMPLICATIONS: Even though gBRCA1 and gBRCA2 mutations both alter HRR pathways, our results suggest that they generate different molecular characteristics and different mechanisms of carcinogenesis.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-1108DOI Listing
September 2020

Ten-year patient journey of stage III non-small cell lung cancer patients: A single-center, observational, retrospective study in Korea (Realtime autOmatically updated data warehOuse in healTh care; UNIVERSE-ROOT study).

Lung Cancer 2020 08 31;146:112-119. Epub 2020 May 31.

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

Introduction: Until the recent approval of immunotherapy after completing concurrent chemoradiotherapy (CCRT), there has been little progress in treating unresectable stage III non-small cell lung cancer (NSCLC). This prompted us to search real-world data (RWD) to better understand diagnosis and treatment patterns, and outcomes.

Methods: This non-interventional observational study used a unique, novel algorithm for big data analysis to collect and assess anonymized patient electronic medical records from a clinical data warehouse (CDW) over a 10-year period to capture real-world patterns of diagnosis, treatment, and outcomes of stage III NSCLC patients. We describe real-world patterns of diagnosis and treatment of patients with newly-diagnosed stage III NSCLC, and patients' characteristics, and assessment of treatment outcomes.

Results: We analyzed clinical variables from 23,735 NSCLC patients. Stage III patients (N = 4138, 18.2 %) were diagnosed as IIIA (N = 2,547, 11.2 %) or IIIB (N = 1,591. 7.0 %). Treated stage III patients (N = 2530, 61.1 %) had a median age of 64.2 years, were mostly male (78.5 %) and had an ECOG performance status of 1 (65.2 %). Treatment comprised curative-intent surgery (N = 1,254, 49.6 %) with 705 receiving neoadjuvant therapy; definitive CRT (N = 648, 25.6 %); palliative CT (N = 270, 10.7 %), or thoracic RT (N = 170, 6.7 %). Median OS (range) for neoadjuvant, surgery, CRT, palliative chemotherapy, lung RT alone, and supportive care was 49.2 (42.0-56.5), 52.5 (43.1-61.9), 30.3 (26.6-34.0), 14.7 (13.0-16.4), 8.8 (6.2-11.3), and 2.0 (1.0-3.0) months, respectively.

Conclusions: This unique in-house algorithm enabled a rapid and comprehensive analysis of big data through a CDW, with daily automatic updates that documented real-world PFS and OS consistent with the published literature, and real-world treatment patterns and clinical outcomes in stage III NSCLC patients.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.033DOI Listing
August 2020

MDSC subtypes and CD39 expression on CD8 T cells predict the efficacy of anti-PD-1 immunotherapy in patients with advanced NSCLC.

Eur J Immunol 2020 11 9;50(11):1810-1819. Epub 2020 Jul 9.

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.

The major suppressive immune cells in tumor sites are myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and Treg cells, and the major roles of these suppressive immune cells include hindering T-cell activities and supporting tumor progression and survival. In this study, we analyzed the pattern of circulating MDSC subtypes in patients with non-small cell lung cancer (NSCLC) whether those suppressive immune cells hinder T-cell activities leading to poor clinical outcomes. First, we verified PMN-MDSCs, monocytic-MDSCs (M-MDSCs), and Treg cells increased according to the stages of NSCLC, and MDSCs effectively suppressed T-cell activities and induced T-cell exhaustion. The analysis of NSCLC patients treated with anti-PD-1 immunotherapy demonstrated that low PMN-MDSCs, M-MDSCs, and CD39 CD8 T cells as an individual and all together were associated with longer progression free survival and overall survival, suggesting PMN-MDSCs, M-MDSCs, and CD39 CD8 T cells frequencies in peripheral blood might be useful as potential predictive and prognostic biomarkers.
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http://dx.doi.org/10.1002/eji.202048534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689686PMC
November 2020