Publications by authors named "Yoon-La Choi"

302 Publications

Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome.

Nat Commun 2020 12 2;11(1):6175. Epub 2020 Dec 2.

Oncology Research & Development, Pfizer, San Diego, CA, USA.

To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.
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http://dx.doi.org/10.1038/s41467-020-19933-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710739PMC
December 2020

Clinicoradiopathological features and prognosis according to genomic alterations in patients with resected lung adenocarcinoma.

J Thorac Dis 2020 Oct;12(10):5357-5368

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Background: We investigated the clinicoradiopathological features and prognosis according to genomic alterations in patients with surgically resected lung adenocarcinoma.

Methods: Patients who underwent surgical resection for pathologic stage I, II, or IIIA lung adenocarcinoma between 2009 and 2016 and for whom results regarding mutation, ALK immunohistochemistry (IHC), and mutation were available were included. Clinicoradiopathological characteristics, genomic alterations, and disease-free survival were analyzed retrospectively.

Results: Of 164 patients, 86 (52.4%) were female and 94 (57.3%) were never-smokers. The most common imaging patterns were part-solid lesion (67.7%) followed by solid (26.2%) and non-solid (6.1%) lesions. mutation, ALK IHC, and mutation were positive in 95 (57.9%), 9 (5.5%), and 11 (6.7%) patients, respectively. mutation positivity was associated with female sex, never-smoker, subsolid pattern on radiological examination, and acinar or papillary predominant histologic subtype. ALK IHC positivity was associated with longer maximal diameter, advanced stage, solid pattern on radiological examination, solid predominant histologic subtype, and distant metastasis during follow-up. mutation positivity was associated with male sex, smoker, solid pattern on radiological examination, and invasive mucinous adenocarcinoma on histologic analysis. In multivariable analysis, ALK IHC positivity and lymph node involvement were independently associated with recurrence. However, solidity was not an independent risk factor for recurrence.

Conclusions: Genomic alterations are associated with clinicoradiopathologic features in patients with resected lung adenocarcinoma. Identifying genomic alterations could help to predict the prognosis of early-stage lung adenocarcinoma.
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http://dx.doi.org/10.21037/jtd-20-1716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656340PMC
October 2020

Nivolumab for esophageal squamous cell carcinoma and the predictive role of PD-L1 or CD8 expression in its therapeutic effect.

Cancer Immunol Immunother 2020 Oct 29. Epub 2020 Oct 29.

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.

Introduction: Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy as second-line therapy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of nivolumab therapy for ESCC patients.

Methods: ESCC patients refractory/intolerant to at least one line of chemotherapy and who received nivolumab as a subsequent line of therapy were included. The efficacy and safety of nivolumab and the predictive role of PD-L1 and CD8 expression were analyzed.

Results: Fifty-eight patients were analyzed for safety and survival outcomes, while 57 were analyzed for objective response rates (ORR) excluding one with no measurable lesions. Eleven patients achieved a partial response, leading to an ORR of 19.3%. The median response duration was 6.5 months (range 4.1-22.4). The median progression-free survival (PFS) and overall survival were 2.1 (95% confidence interval [CI] 1.8-2.3) and 7.4 (95% CI 4.8-10.0) months, respectively. Among patients with adequate samples, 56.9% (29/51), 27.5% (14/51), and 17.6% (9/51) expressed a combined positive score (CPS) ≥ 1, ≥ 10, and ≥ 20, respectively, while 24.4% (11/45) and 57.5% (23/40) were positive for intratumoral and peritumoral CD8 + T cell infiltration, respectively. A significantly longer PFS was observed in patients with a CPS ≥ 20 (7.5 [95% CI 1.8-13.1] vs. 1.9 [1.4-2.3] months, P = 0.05), and a trend towards better survival was seen in those with CPS ≥ 10 or intratumoral CD8 + T cell infiltration.

Conclusions: Nivolumab is a valuable option at subsequent treatment lines for patients with advanced ESCC.
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http://dx.doi.org/10.1007/s00262-020-02766-7DOI Listing
October 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

Clinicopathological characteristics of primary lung nuclear protein in testis carcinoma: A single-institute experience of 10 cases.

Thorac Cancer 2020 11 3;11(11):3205-3212. Epub 2020 Oct 3.

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

Background: Nuclear protein in testis (NUT) carcinoma is a rare tumor associated with NUT rearrangement that can present as poorly differentiated to undifferentiated carcinoma, with or without abrupt squamous differentiation. It is often misdiagnosed as poorly differentiated carcinoma or undifferentiated carcinoma if NUT is not suspected. In this study, we retrospectively analyzed pulmonary NUT carcinoma cases diagnosed with NUT immunohistochemical staining and discuss the differential diagnosis to provide information for this rare and aggressive entity.

Methods: Cases, diagnosed as "NUT carcinoma" in lung pleura and "metastatic NUT carcinoma from the lung" in lymph nodes were diagnosed between 2017 and 2019 at the Samsung Medical Center (SMC). Clinical features such as age, sex, treatment and follow-up period, and pathological reports were obtained by reviewing patients' electronic medical records.

Results: A total of 10 NUT carcinoma cases were found in the SMC pathology database. Seven patients were men and six were non-smokers. Tumor cells showed various cellular features such as round, squamoid, and spindle. Some cases had initially been misdiagnosed as spindle cell neoplasm, round cell sarcoma, squamous cell carcinoma and small cell carcinoma. All cases showed diffuse strong nuclear expression of NUT immunohistochemical staining, and some were positive for p63 staining and negative for CD56 staining.

Conclusions: NUT carcinoma is often misdiagnosed because of its various morphologies. It is important to consider NUT as one of the differential diagnoses when encountering lung biopsy with undifferentiated morphology.

Key Points: Due to various morphological features, NUT carcinoma can be misdiagnosed It is important to consider NUT carcinoma when diagnosing a poorly differentiated or undifferentiated tumor.
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http://dx.doi.org/10.1111/1759-7714.13648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606005PMC
November 2020

TM4SF4 and LRRK2 Are Potential Therapeutic Targets in Lung and Breast Cancers through Outlier Analysis.

Cancer Res Treat 2021 Jan 16;53(1):9-24. Epub 2020 Sep 16.

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

Purpose: To find biomarkers for disease, there have been constant attempts to investigate the genes that differ from those in the disease groups. However, the values that lie outside the overall pattern of a distribution, the outliers, are frequently excluded in traditional analytical methods as they are considered to be 'some sort of problem.' Such outliers may have a biologic role in the disease group. Thus, this study explored new biomarker using outlier analysis, and verified the suitability of therapeutic potential of two genes (TM4SF4 and LRRK2).

Materials And Methods: Modified Tukey's fences outlier analysis was carried out to identify new biomarkers using the public gene expression datasets. And we verified the presence of the selected biomarkers in other clinical samples via customized gene expression panels and tissue microarrays. Moreover, a siRNA-based knockdown test was performed to evaluate the impact of the biomarkers on oncogenic phenotypes.

Results: TM4SF4 in lung cancer and LRRK2 in breast cancer were chosen as candidates among the genes derived from the analysis. TM4SF4 and LRRK2 were overexpressed in the small number of samples with lung cancer (4.20%) and breast cancer (2.42%), respectively. Knockdown of TM4SF4 and LRRK2 suppressed the growth of lung and breast cancer cell lines. The LRRK2 overexpressing cell lines were more sensitive to LRRK2-IN-1 than the LRRK2 under-expressing cell lines.

Conclusion: Our modified outlier-based analysis method has proved to rescue biomarkers previously missed or unnoticed by traditional analysis showing TM4SF4 and LRRK2 are novel target candidates for lung and breast cancer, respectively.
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http://dx.doi.org/10.4143/crt.2020.434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812009PMC
January 2021

Earlier-Phased Cancer Immunity Cycle Strongly Influences Cancer Immunity in Operable Never-Smoker Lung Adenocarcinoma.

iScience 2020 Aug 18;23(8):101386. Epub 2020 Jul 18.

Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Electronic address:

Exome and transcriptome analyses of clinically homogeneous early-stage never-smoker female patients with lung adenocarcinoma were performed to understand tumor-T cell interactions and immune escape points. Using our novel gene panels of eight functional categories in the cancer-immunity cycle, three distinct subgroups were identified in this immune checkpoint blockade-refractory cohort by defective gene expression in two major domains, i.e., type I interferon production/signaling pathway and antigen-presenting machinery. Our approach could play a critical role in understanding immune evasion mechanisms, developing a method for effective selection of rare immune checkpoint blockade responders, and finding new treatment strategies.
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http://dx.doi.org/10.1016/j.isci.2020.101386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426575PMC
August 2020

PDX models of human lung squamous cell carcinoma: consideration of factors in preclinical and co-clinical applications.

J Transl Med 2020 08 6;18(1):307. Epub 2020 Aug 6.

Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Background: Treatment of human lung squamous cell carcinoma (LUSC) using current targeted therapies is limited because of their diverse somatic mutations without any specific dominant driver mutations. These mutational diversities preventing the use of common targeted therapies or the combination of available therapeutic modalities would require a preclinical animal model of this tumor to acquire improved clinical responses. Patient-derived xenograft (PDX) models have been recognized as a potentially useful preclinical model for personalized precision medicine. However, whether the use of LUSC PDX models would be appropriate enough for clinical application is still controversial.

Methods: In the process of developing PDX models from Korean patients with LUSC, the authors investigated the factors influencing the successful initial engraftment of tumors in NOD scid gamma mice and the retainability of the pathological and genomic characteristics of the parental patient tumors in PDX tumors.

Conclusions: The authors have developed 62 LUSC PDX models that retained the pathological and genomic features of parental patient tumors, which could be used in preclinical and co-clinical studies. Trial registration Tumor samples were obtained from 139 patients with LUSC between November 2014 and January 2019. All the patients provided signed informed consents. This study was approved by the institutional review board (IRB) of Samsung Medical Center (2018-03-110).
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http://dx.doi.org/10.1186/s12967-020-02473-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409653PMC
August 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

Dysregulation of cancer genes by recurrent intergenic fusions.

Genome Biol 2020 07 6;21(1):166. Epub 2020 Jul 6.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Background: Gene fusions have been studied extensively, as frequent drivers of tumorigenesis as well as potential therapeutic targets. In many well-known cases, breakpoints occur at two intragenic positions, leading to in-frame gene-gene fusions that generate chimeric mRNAs. However, fusions often occur with intergenic breakpoints, and the role of such fusions has not been carefully examined.

Results: We analyze whole-genome sequencing data from 268 patients to catalog gene-intergenic and intergenic-intergenic fusions and characterize their impact. First, we discover that, in contrast to the common assumption, chimeric oncogenic transcripts-such as those involving ETV4, ERG, RSPO3, and PIK3CA-can be generated by gene-intergenic fusions through splicing of the intervening region. Second, we find that over-expression of an upstream or downstream gene by a fusion-mediated repositioning of a regulatory sequence is much more common than previously suspected, with enhancers sometimes located megabases away. We detect a number of recurrent fusions, such as those involving ANO3, RGS9, FUT5, CHI3L1, OR1D4, and LIPG in breast; IGF2 in colon; ETV1 in prostate; and IGF2BP3 and SIX2 in thyroid cancers.

Conclusion: Our findings elucidate the potential oncogenic function of intergenic fusions and highlight the wide-ranging consequences of structural rearrangements in cancer genomes.
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http://dx.doi.org/10.1186/s13059-020-02076-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339451PMC
July 2020

Therapeutic Efficacy of ABN401, a Highly Potent and Selective MET Inhibitor, Based on Diagnostic Biomarker Test in -Addicted Cancer.

Cancers (Basel) 2020 Jun 15;12(6). Epub 2020 Jun 15.

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.

The receptor tyrosine kinase c-MET regulates processes essential for tissue remodeling and mammalian development. The dysregulation of c-MET signaling plays a role in tumorigenesis. The aberrant activation of c-MET, such as that caused by gene amplification or mutations, is associated with many cancers. c-MET is therefore an attractive therapeutic target, and inhibitors are being tested in clinical trials. However, inappropriate patient selection criteria, such as low amplification or expression level cut-off values, have led to the failure of clinical trials. To include patients who respond to MET inhibitors, the selection criteria must include oncogenic addiction. Here, the efficacy of ABN401, a MET inhibitor, was investigated using histopathologic and genetic analyses in -addicted cancer cell lines and xenograft models. ABN401 was highly selective for 571 kinases, and it inhibited c-MET activity and its downstream signaling pathway. We performed pharmacokinetic profiling of ABN401 and defined the dose and treatment duration of ABN401 required to inhibit c-MET phosphorylation in xenograft models. The results show that the efficacy of ABN401 is associated with MET status and they highlight the importance of determining the cut-off values. The results suggest that clinical trials need to establish the characteristics of each sample and their correlations with the efficacy of MET inhibitors.
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http://dx.doi.org/10.3390/cancers12061575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352216PMC
June 2020

An Immune-Magnetophoretic Device for the Selective and Precise Enrichment of Circulating Tumor Cells from Whole Blood.

Micromachines (Basel) 2020 May 30;11(6). Epub 2020 May 30.

Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy and Research Institute of Pharmaceutical Science, Seoul National University, Seoul 08826, Korea.

Here, we validated the clinical utility of our previously developed microfluidic device, GenoCTC, which is based on bottom magnetophoresis, for the isolation of circulating tumor cells (CTCs) from patient whole blood. GenoCTC allowed 90% purity, 77% separation rate, and 80% recovery of circulating tumor cells at a 90 μL/min flow rate when tested on blood spiked with epithelial cell adhesion molecule (EpCAM)-positive Michigan Cancer Foundation-7 (MCF7) cells. Clinical studies were performed using blood samples from non-small cell lung cancer (NSCLC) patients. Varying numbers (2 to 114) of CTCs were found in each NSCLC patient, and serial assessment of CTCs showed that the CTC count correlated with the clinical progression of the disease. The applicability of GenoCTC to different cell surface biomarkers was also validated in a cholangiocarcinoma patient using anti-EPCAM, anti-vimentin, or anti-tyrosine protein kinase MET (c-MET) antibodies. After EPCAM-, vimentin-, or c-MET-positive cells were isolated, CTCs were identified and enumerated by immunocytochemistry using anti-cytokeratin 18 (CK18) and anti-CD45 antibodies. Furthermore, we checked the protein expression of PDL1 and c-MET in CTCs. A study in a cholangiocarcinoma patient showed that the number of CTCs varied depending on the biomarker used, indicating the importance of using multiple biomarkers for CTC isolation and enumeration.
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http://dx.doi.org/10.3390/mi11060560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345362PMC
May 2020

Radial neuropathy caused by intraneural leiomyoma: A case report.

Medicine (Baltimore) 2020 May;99(22):e20196

Department of Physical and Rehabilitation Medicine.

Introduction: Leiomyoma of peripheral nerve is a rare condition characterized by neuropathy of affected nerve. We herein report a rare presentation of leiomyoma of radial nerve which presented with wrist drop.

Patient Concerns: A 37-year-old man visited our clinic with a history of sudden onset weakness of the wrist dorsiflexion/finger extension of the right side.

Diagnosis: T2-weighted with fat saturation image of MRI demonstrated a well-defined, intra-neural, round mass of about 0.8 cm × 0.5 cm within the radial nerve. Excision of mass established the pathological diagnosis of intra-neural leiomyoma.

Interventions: The patient underwent excision of mass and attached nerve tissue, followed his medial antebrachial nerve graft for repair of the defected radial nerve.

Outcomes: As of the 1-year follow-up, no symptoms of recurrence have been observed. Also, the strength of wrist dorsiflexion improved to grade 4/5 CONCLUSION:: This rare case demonstrates the importance of MR imaging to differentiate intra-neural leiomyomas from other benign peripheral nerve sheath tumors. Surgical treatment plays an important role in the treatment of patient with intraneural leiomyoma with neurologic deficits.
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http://dx.doi.org/10.1097/MD.0000000000020196DOI Listing
May 2020

Current status and future perspectives of liquid biopsy in non-small cell lung cancer.

J Pathol Transl Med 2020 May 15;54(3):204-212. Epub 2020 Apr 15.

Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea.

With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.
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http://dx.doi.org/10.4132/jptm.2020.02.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253954PMC
May 2020

Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma.

Nat Commun 2020 05 8;11(1):2285. Epub 2020 May 8.

Samsung Genome Institute, Samsung Medical Center, Seoul, 06351, Korea.

Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
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http://dx.doi.org/10.1038/s41467-020-16164-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210975PMC
May 2020

Outstanding clinical efficacy of PD-1/PD-L1 inhibitors for pulmonary pleomorphic carcinoma.

Eur J Cancer 2020 06 1;132:150-158. Epub 2020 May 1.

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

Background: We evaluated programmed death ligand 1 (PD-L1) expression and efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary pleomorphic carcinoma (PC).

Methods: We created two cohorts of patients diagnosed with pulmonary PC from 2016 to 2019, PD-L1 expression and programmed death 1 (PD-1)/PD-L1 inhibitor efficacy cohorts. The PD-L1 expression cohort included all patients evaluated for PD-L1 expression, irrespective of PD-1/PD-L1 inhibitor therapy. High PD-L1 expression was defined as ≥50% positive tumour cells (TC) for 22C3, ≥25% for SP263 or ≥10%/5% TC/immune cell (IC) for SP142. The PD-1/PD-L1 efficacy cohort included patients treated with PD-1/PD-L1 inhibitors, irrespective of PD-L1 tests.

Results: One hundred twenty-five of 175 patients diagnosed with pulmonary PCs were included in the PD-L1 expression cohort. Among them, 112 patients (89.6%) had PD-L1-positive (≥1%) tumours and 100 (80.0%) had tumours with high PD-L1 expression. A total of 49 patients were included in the efficacy cohort: 40 received pembrolizumab, 7 nivolumab and 2 atezolizumab. The objective response rate was 49.0%, with a median progression-free survival (PFS) of 7.2 months and a median overall survival of 22.2 months. In the efficacy cohort, high PD-L1 expression (n = 41) was associated with longer PFS (median: 7.2 versus 1.5 months, hazard ratio [HR]: 0.53 [0.22-1.29], p = 0.16) and overall survival (median: 22.2 versus 3.5, HR: 0.21 [0.08-0.57], p = 0.001) than low/negative/unknown PD-L1 expression (n = 8).

Conclusion: PD-1/PD-L1 inhibitors show outstanding efficacy for pulmonary PCs, and this is possibly attributable to high PD-L1 expression in these tumours.
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http://dx.doi.org/10.1016/j.ejca.2020.03.029DOI Listing
June 2020

Amplification as a Predictive Biomarker in Response to Ceritinib in Small Cell Lung Cancer.

Mol Ther Oncolytics 2020 Mar 10;16:188-196. Epub 2020 Jan 10.

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

Small cell lung cancer (SCLC) is a fast-growing and malignant cancer that responds well to chemotherapy; however, the survival rate is less than 15% after 2 years of diagnosis. Therefore, novel therapeutic agents for treating SCLC patients need to be evaluated. This study aims to identify the therapeutic targets based on the comprehensive genomic profiling of SCLC patients. Among the molecular-profiled SCLC samples obtained using targeted sequencing, the array-based comparative genomic hybridization (array CGH) identified focal () amplification in the SCLC patients. amplification was confirmed in 5% of 73 SCLC patients. To determine whether amplification could act as a therapeutic target, we generated a patient-derived xenograft (PDX) model and subsequently screened 43 targeted agents using the PDX-derived cells (PDCs). Ceritinib significantly inhibited the cell growth and impaired the tumor sphere formation in IRS2-expressing PDCs. Its effects were confirmed in various assays and were further validated in the mouse xenograft models. In this study, we present that amplification and/or expression serve as preclinical implications for a novel therapeutic target in SCLC progression. Furthermore, we suggest that insulin-like growth factor-1 (IGF-1) receptor inhibitor-based therapy could be used for treating SCLC with amplification.
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http://dx.doi.org/10.1016/j.omto.2019.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029374PMC
March 2020

Characteristics and outcomes of RET-rearranged Korean non-small cell lung cancer patients in real-world practice.

Jpn J Clin Oncol 2020 May;50(5):594-601

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

Objective: Since the first discovery of rearranged during transfection (RET) fusion in lung adenocarcinoma in 2011, two tyrosine kinase inhibitors, namely vandetanib and cabozantinib, are currently available. Despite favorable outcomes in systemic control, the intracranial therapeutic response remains insufficient. In this study, the clinical characteristics and outcomes of non-small cell lung cancer (NSCLC) patients with RET rearrangements were analyzed.

Methods: Patients with NSCLC harboring RET fusion who received treatment between January 2006 and January 2018 were analyzed. RET rearrangement was identified by FISH or NGS.

Results: A total of 59 patients were identified. About half of the patients were female (47.5%) and never smokers (50.9%). Most patients had adenocarcinoma (89.8%). A total of 17 patients (28.8%) had an intracranial lesion at the initial diagnosis of stage IV disease, and 11 additional patients (18.6%) developed intracranial metastases during follow-up. The median time to development of intracranial metastases was 19.0 months (95% CI: 9.6-28.5), resulting in a >60% cumulative incidence of brain metastasis at 24 months. The systemic efficacy of pemetrexed-based regimens was favorable with progression-free survival of 9.0 (95% CI: 6.9-11.2) and OS of 24.1 (95% CI: 15.2-33.0) months. The median progression-free survival for vandetanib and immunotherapy was 2.9 (95% CI: 2.0-3.8) and 2.1 (95% CI: 1.6-2.6) months, respectively.

Conclusions: Given the likelihood of RET-rearranged NSCLC progressing to intracranial metastases and the absence of apparent clinical benefit of currently available targeted or immunotherapeutic agents, development of novel treatment with higher selectivity and better penetration of the blood-brain barrier remains a priority.
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http://dx.doi.org/10.1093/jjco/hyaa019DOI Listing
May 2020

UBE2C Overexpression Aggravates Patient Outcome by Promoting Estrogen-Dependent/Independent Cell Proliferation in Early Hormone Receptor-Positive and HER2-Negative Breast Cancer.

Front Oncol 2019 23;9:1574. Epub 2020 Jan 23.

Laboratory of Molecular Pathology and Cancer Genomics, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, South Korea.

We previously showed that mRNA expression is significantly associated with poor prognosis only in patients with hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer. In this study, we further reanalyzed the correlation between mRNA expression and clinical outcomes in patients with HR+/HER2- breast cancer, and we investigated the molecular mechanism underlying the role of UBE2C modulation in disease progression in this subgroup of patients. Univariate and multivariate analyses showed that high expression was associated with significantly shorter survival of breast cancer patients with pN0 and pN1 tumors but not pN2/N3 tumors ( < 0.05). functional experiments in HR+/HER2- breast cancer cells showed that UBE2C expression is a tumorigenic factor, and that estrogen upregulated mRNA and protein by directly binding to the promoter region. UBE2C knockdown inhibited cell proliferation by affecting cell cycle progression, and UBE2C overexpression was associated with estrogen-independent growth. UBE2C depletion markedly increased the cytotoxicity of tamoxifen by inducing apoptosis. The present findings suggest that UBE2C overexpression is correlated with relapse and promotes estrogen-dependent/independent proliferation in early HR+/HER2- breast cancer.
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http://dx.doi.org/10.3389/fonc.2019.01574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989552PMC
January 2020

Development of Human Monoclonal Antibody for Claudin-3 Overexpressing Carcinoma Targeting.

Biomolecules 2019 12 28;10(1). Epub 2019 Dec 28.

Laboratory of Molecular Pathology and Cancer Genomics, Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 08826, Korea.

Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell-cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of antibodies against specific CLDN proteins is difficult, because CLDNs are four-transmembrane domain proteins with high homology among CLDN family members and species. Here, we developed a human IgG1 monoclonal antibody (h4G3) against CLDN3 through scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. The h4G3 recognized the native conformation of human and mouse CLDN3 without cross-reactivity to other CLDNs. The binding kinetics of h4G3 demonstrated a sub-nanomolar affinity for CLDN3 expressed on the cell surface. The h4G3 showed antibody-dependent cellular cytotoxicity (ADCC) according to CLDN3 expression levels in various cancer cells by the activation of FcγRIIIa (CD16a). The biodistribution of h4G3 was analyzed by intravenous injection of fluorescence-conjugated h4G3 which showed that it localized to the tumor site in xenograft mice bearing CLDN3-expressing tumors. These results indicate that h4G3 recognizes CLDN3 specifically, suggesting its value for cancer diagnosis, antibody-drug conjugates, and potentially as a chimeric antigen receptor (CAR) for CLDN3-expressing pan-carcinoma.
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http://dx.doi.org/10.3390/biom10010051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022679PMC
December 2019

High CD3 and ICOS and low TIM-3 expression predict favourable survival in resected oesophageal squamous cell carcinoma.

Sci Rep 2019 12 27;9(1):20197. Epub 2019 Dec 27.

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

With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. The value of immune markers, including programmed cell death ligand-1, programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-dominant containing-3 (TIM-3), is not well known. Using tissue microarrays of 396 patients who underwent surgery for oesophageal squamous cell carcinoma (ESCC), infiltrated T-cell subsets (CD3, CD8, and Foxp3) and checkpoint protein expression were scored. With a median follow-up of 24.8 months, CD3 TIL subsets (50.0%) had longer median recurrence-free survival (RFS, 55.0 vs 21.4 months) and overall survival (OS, 77.7 vs 35.8 months). Patients with high ICOS expression (46.5%) had longer median RFS (53.9 vs 25.3 months) and OS (88.8 vs 36.9 months). For PD-1, RFS (hazard ratio [HR] 0.67) and OS (HR 0.66) were significantly longer in the high-expression group (45.2%). In the multivariate analysis, high TIM-3 expression (50.8%) had a significant relationship with shorter RFS (HR = 1.52) and OS (HR = 1.60). High CD3 TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade.
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http://dx.doi.org/10.1038/s41598-019-56828-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934772PMC
December 2019

Junction Location Identifier (JuLI): Accurate Detection of DNA Fusions in Clinical Sequencing for Precision Oncology.

J Mol Diagn 2020 03 25;22(3):304-318. Epub 2019 Dec 25.

Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea; Geninus Inc., Seoul, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea; Department of Digital Health, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Republic of Korea; Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address:

Accurate detection of genomic fusions by high-throughput sequencing in clinical samples with inadequate tumor purity and formalin-fixed, paraffin-embedded tissue is an essential task in precise oncology. We developed the fusion detection algorithm Junction Location Identifier (JuLI) for optimization of high-depth clinical sequencing. Novel filtering steps were implemented to minimize false positives in the clinical setting. The algorithm was comprehensively validated using high-depth sequencing data from cancer cell lines and clinical samples and genome sequencing data from NA12878. JuLI showed improved performance mainly in positive predictive value over state-of-the-art fusion callers in cases with high-depth clinical sequencing and rescued a driver fusion from false negative in plasma cell-free DNA using joint calling.
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http://dx.doi.org/10.1016/j.jmoldx.2019.10.015DOI Listing
March 2020

Benefit of Targeted DNA Sequencing in Advanced Non-Small-Cell Lung Cancer Patients Without EGFR and ALK Alterations on Conventional Tests.

Clin Lung Cancer 2020 05 21;21(3):e182-e190. Epub 2019 Nov 21.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea. Electronic address:

Background: Genetic sequencing testing has become widely used to inform treatment decisions for advanced non-small-cell lung cancer (NSCLC) patients. We analyzed benefits of genetic sequencing testing in real practice.

Patients And Methods: We retrospectively reviewed 209 NSCLC patients who had no EGFR and ALK alterations on routine molecular tests and underwent next-generation targeted DNA sequencing of 380 cancer-related genes between November 2013 and October 2016. Median patient age was 59 years. A total of 96 patients (46%) were never smokers, and 195 patients (93%) had adenocarcinoma.

Results: Among 209 total patients, 64 (31%) demonstrated actionable genetic alterations; 20 had EGFR mutations (6 L858R, 8 exon 19 deletions, 1 L861Q, 1 G719S, 4 exon 20 duplications), 4 ALK fusions, 9 ROS1 fusions, 6 BRAF V600E mutations, 15 RET fusions, 1 MET high-level amplification, 6 MET exon 14 skipping mutations, and 3 ERBB2 exon 20 insertion mutations. Of the 64 patients harboring actionable alterations, 28 patients received therapy targeted to their own actionable alterations (15 EGFR, 3 ALK, 1 ROS1, 8 RET, 1 BRAF). There were significant differences in overall survival between individuals with no actionable alterations, those with actionable alterations but no targeted therapy, and those with actionable alterations and targeted therapy (20.1 vs. 17.1 vs. 66.2 months, P < .001).

Conclusion: The results of targeted DNA sequencing testing could provide improved treatment options for some NSCLC patients and result in a survival benefit to NSCLC patients with no EGFR and ALK alterations on routine tests who are treated with targeted therapy.
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http://dx.doi.org/10.1016/j.cllc.2019.11.006DOI Listing
May 2020

High expression of NR1D1 is associated with good prognosis in triple-negative breast cancer patients treated with chemotherapy.

Breast Cancer Res 2019 11 28;21(1):127. Epub 2019 Nov 28.

College of Pharmacy, Bio-MAX, and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.

Background: Nuclear receptor subfamily 1, group D, member 1 (NR1D1) is a ligand-regulated nuclear receptor and transcriptional factor. Although recent studies have implicated NR1D1 as a regulator of DNA repair and proliferation in breast cancers, its potential as a therapeutic target for breast cancer has not been assessed in terms of clinical outcomes. Thus, this study aims to analyze NR1D1 expression in breast cancer patients and to evaluate its potential prognostic value.

Methods: NR1D1 expression was analyzed by immunohistochemistry using an anti-NR1D1 antibody in 694 breast cancer samples. Survival analyses were performed using the Kaplan-Meier method with the log-rank test to investigate the association of NR1D1 expression with clinical outcome.

Results: One hundred thirty-nine of these samples exhibited high NR1D1 expression, mostly in the nucleus of breast cancer cells. NR1D1 expression correlated significantly with histological grade and estrogen receptor status. Overall survival (OS) and disease-free survival (DFS) did not correlate significantly with NR1D1 expression in breast cancer patients regardless of whether they had received chemotherapy. Subgroup analysis performed according to molecular subtype of breast cancer showed a significant influence of high NR1D1 expression on OS (P = 0.002) and DFS (P = 0.007) in patients with triple-negative breast cancer (TNBC) treated with chemotherapy.

Conclusions: High NR1D1 expression level had a favorable impact on OS and DFS in patients with TNBC treated with chemotherapy. NR1D1 should be investigated further as a possible prognostic marker in TNBC patients receiving chemotherapeutic treatment and as a target in the development of chemotherapeutic approaches to treating TNBC.
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http://dx.doi.org/10.1186/s13058-019-1197-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883674PMC
November 2019

Nomogram for prediction of lymph node metastasis in patients with superficial esophageal squamous cell carcinoma.

J Gastroenterol Hepatol 2020 Jun 15;35(6):1009-1015. Epub 2019 Dec 15.

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

Background And Aim: Knowledge of lymph node metastasis (LNM) status is crucial to determine whether patients with superficial esophageal squamous cell carcinoma (ESCC) can be cured with endoscopic resection alone, without the need for additional esophagectomy. The present study aimed to identify predictive factors and develop a prediction model for LNM in patients with superficial ESCC.

Methods: Clinicopathologic data from 501 patients with superficial ESCC treated with radical esophagectomy were reviewed. Stepwise logistic regression analysis determined the predictors of LNM. Using these predictors, a nomogram for predicting the risk of LNM was constructed and internally validated using a bootstrap resampling method.

Results: LNM rates of tumors invading the lamina propria, muscularis mucosa, and SM1 layers were 3.7%, 15.5%, and 40.7%, respectively. Deep tumor invasion depth, moderately or poorly differentiated histology, and lymphovascular invasion were independent predictors of LNM. ESCC with muscularis mucosa and SM1 invasion had odds ratios of 3.635 and 11.834, respectively, compared with that for ESCC confined to the lamina propria. Large tumor size (>2.0 cm) and presence of tumor budding showed borderline significance for LNM prediction. These five variables were incorporated into a nomogram. A constructed nomogram showed good calibration and good discrimination with an area under the receiver-operating characteristic curve (area under the curve [AUC]) of 0.812. After bootstrapping, AUC was 0.811.

Conclusions: We developed a nomogram that can facilitate individualized prediction of risk of LNM in patients with superficial ESCC. This model can aid in decision-making for the need for additional esophagectomy after endoscopic resection for superficial ESCC.
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http://dx.doi.org/10.1111/jgh.14915DOI Listing
June 2020

Interobserver Reproducibility of PD-L1 Biomarker in Non-small Cell Lung Cancer: A Multi-Institutional Study by 27 Pathologists.

J Pathol Transl Med 2019 Nov 28;53(6):347-353. Epub 2019 Oct 28.

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

Background: Assessment of programmed cell death-ligand 1 (PD-L1) immunohistochemical staining is used for treatment decisions in non-small cell lung cancer (NSCLC) regarding use of PD-L1/programmed cell death protein 1 (PD-1) immunotherapy. The reliability of the PD-L1 22C3 pharmDx assay is critical in guiding clinical practice. The Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists investigated the interobserver reproducibility of PD-L1 staining with 22C3 pharmDx in NSCLC samples.

Methods: Twenty-seven pathologists individually assessed the tumor proportion score (TPS) for 107 NSCLC samples. Each case was divided into three levels based on TPS: <1%, 1%-49%, and ≥50%.

Results: The intraclass correlation coefficient for TPS was 0.902±0.058. Weighted κ coefficient for 3-step assessment was 0.748±0.093. The κ coefficients for 1% and 50% cut-offs were 0.633 and 0.834, respectively. There was a significant association between interobserver reproducibility and experience (formal PD-L1 training, more experience for PD-L1 assessment, and longer practice duration on surgical pathology), histologic subtype, and specimen type.

Conclusions: Our results indicate that PD-L1 immunohistochemical staining provides a reproducible basis for decisions on anti-PD-1 therapy in NSCLC.
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http://dx.doi.org/10.4132/jptm.2019.09.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877442PMC
November 2019

Soft tissue sarcoma: DWI and DCE-MRI parameters correlate with Ki-67 labeling index.

Eur Radiol 2020 Feb 18;30(2):914-924. Epub 2019 Oct 18.

Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul, 06351, South Korea.

Objectives: To examine the correlation of diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters with Ki-67 labeling index (LI) in soft tissue sarcoma (STS).

Methods: The institutional review board approved this retrospective study, and the requirement for informed consent was waived. Thirty-six patients with STS who underwent 3.0-T MRI, including diffusion-weighted and dynamic contrast-enhanced MRI, between July 2011 and February 2018, were included in this study. The mean and minimum apparent diffusion coefficients (ADCs) (ADC and ADC, respectively), volume transfer constant, reflux rate, and volume fraction of the extravascular extracellular matrix of each lesion were independently analyzed by two readers. Their relationship with the Ki-67 LI was examined using Spearman's correlation analyses. Differences between low- and high-proliferation groups based on Ki-67 LI were evaluated statistically. Optimal cut-off points were determined using the area under the curve analysis for significant parameters. Interobserver agreement was assessed with the intraclass correlation coefficient.

Results: ADC (ρ = - 0.333, p = 0.047) was significantly and inversely correlated with Ki-67 LI. The high-proliferation group showed a significantly lower ADC than did the low-proliferation group (median, 1.08 vs. 1.20; p = 0.048). When a cut-off ADC value of 1.16 × 10 mm/s was used, the sensitivity, specificity, and area under the curve for differentiating low- and high-proliferation groups were 75.0%, 60.0%, and 0.712, respectively. Interobserver agreements between the two readers were almost perfect for all parameters.

Conclusions: ADC was correlated with Ki-67 LI and could help differentiate between STS with low and high proliferation potential.

Key Points: • ADC was significantly and inversely correlated with Ki-67 labeling index in soft tissue sarcoma. • In the high-proliferation group, ADC values were significantly lower than those of the low-proliferation group.
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http://dx.doi.org/10.1007/s00330-019-06445-9DOI Listing
February 2020

Association with PD-L1 Expression and Clinicopathological Features in 1000 Lung Cancers: A Large Single-Institution Study of Surgically Resected Lung Cancers with a High Prevalence of EGFR Mutation.

Int J Mol Sci 2019 Sep 26;20(19). Epub 2019 Sep 26.

Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.

Programmed cell death ligand 1 (PD-L1) expression is an important biomarker for predicting response to immunotherapy in clinical practice. Hence, identification and characterization of factors that predict high expression of PD-L1 in patients is critical. Various studies have reported the association of PD-L1 expression with driver genetic status in non-small cell cancer; however, the results have been conflicting and inconclusive. We analyzed the relationship between PD-L1 expression and clinicopathological factors including driver genetic alterations in 1000 resected lung cancers using a clinically validated PD-L1 immunohistochemical assay. PD-L1 expression was significantly higher in squamous cell carcinoma (SCC) compared to adenocarcinomas. PD-L1 expression in adenocarcinoma was associated with higher N-stage, solid histologic pattern, wild type, and positive, but no significant association with the clinicopathological factors in SCC. mutant adenocarcinomas with distinctive clinicopathologic features, especially solid histologic pattern and higher stage showed higher PD-L1 expression. To the best of our knowledge, this study is the largest to evaluate the association between PD-L1 expression and clinicopathological and molecular features in lung cancer with a highly prevalent mutation. Therefore, our results are useful to guide the selection of lung cancer, even -mutated adenocarcinoma patients with PD-L1 expression, for further immunotherapy.
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http://dx.doi.org/10.3390/ijms20194794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801455PMC
September 2019

Genomic scoring to determine clinical benefit of immunotherapy by targeted sequencing.

Eur J Cancer 2019 10 4;120:65-74. Epub 2019 Sep 4.

Division of Hematology-Oncology, Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, South Korea. Electronic address:

Aims: Immune checkpoint inhibitors (ICIs) induce durable responses, but their clinical benefits apply to only a subset of patients. Therefore, precisely predicting a patient's response before ICI treatment is crucial.

Methods: A total of 248 patients with anti-Programmed cell death protein 1/Programmed death-ligand 1 (PD1/PD-L1)-treated advanced non-small cell lung cancer were enrolled, and clinical outcomes were collected with a minimum 6-month follow-up period. Tumour tissues were used for PD-L1 staining, targeted sequencing of 380 cancer-related genes and whole-exome sequencing (WES).

Results: The tumour mutation burden (TMB) obtained from targeted sequencing was higher among patients with a partial response (PR) than those with progressive disease (PD)/stable disease (SD) (P = 0.01) and in those with durable clinical benefit (DCB) than nondurable benefit (NDB) (P = 0.05). The somatic copy number alteration (SCNA) was lower in patients with a PR than those with PD/SD (P = 0.02) and in those with DCB than NDB (P = 0.02). The accuracy of the TMB and SCNA results from the targeted sequencing was confirmed by testing the correlation of the TMB and SCNA results from the targeted sequencing against those results from WES (r = 0.87, r = 0.62, respectively). To improve prediction score, TMB, SCNA and PD-L1 were integrated. New prediction scores reached Area under the ROC Curve (AUC) = 0.71 from TMB (AUC = 0.63), SCNA (AUC = 0.52) or PD-L1 (AUC = 0.57) with our cohort, and validation set from other cohorts also showed improved prediction scores with our new model.

Conclusion: We report TMB, SCNA and PD-L1 as ICI biomarkers. Combining all these factors improved the prediction accuracy of ICI response compared with using individual factors. Tumour molecular features, TMB and SCNA, were efficiently obtained by targeted sequencing.
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http://dx.doi.org/10.1016/j.ejca.2019.08.001DOI Listing
October 2019

Comparison of GenesWell BCT Score With Oncotype DX Recurrence Score for Risk Classification in Asian Women With Hormone Receptor-Positive, HER2-Negative Early Breast Cancer.

Front Oncol 2019 24;9:667. Epub 2019 Jul 24.

Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, South Korea.

The GenesWell Breast Cancer Test (BCT) is a recently developed multigene assay that predicts the risk of distant recurrence in patients with early breast cancer. Here, we analyzed the concordance of the BCT score with the Oncotype DX recurrence score (RS) for risk stratification in Asian patients with pN0-N1, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Formalin-fixed, paraffin-embedded breast cancer tissues previously analyzed using the Oncotype DX test were assessed using the GenesWell BCT test. The risk stratification by the two tests was then compared. A total of 771 patients from five institutions in Korea were analyzed. According to the BCT score, 527 (68.4%) patients were classified as low risk, and 244 (31.6%) as high risk. Meanwhile, 134 (17.4%), 516 (66.9%), and 121 (15.7%) patients were categorized into the low-, intermediate-, and high-risk groups, respectively, according to the RS ranges used in the TAILORx. The BCT high-risk group was significantly associated with advanced lymph node status, whereas no association between RS risk groups and nodal status was observed. The concordance between the two risk stratification methods in the overall population was 71.9% when the RS low-risk, and intermediate-risk groups were combined into one group. However, poor concordance was observed in patients aged ≤50 years and in those with lymph node-positive breast cancer. The concordance between the BCT score and RS was low in women aged ≤50 years or with lymph node-positive breast cancer. Further studies are necessary to identify more accurate tests for predicting prognosis and chemotherapy benefit in this subpopulation.
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http://dx.doi.org/10.3389/fonc.2019.00667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670782PMC
July 2019