Cancer Research and Treatment

Original Articles

Histological Assessment and Interobserver Agreement in Major Pathologic Response for Non–Small Cell Lung Cancer with Neoadjuvant Therapy: Sungjin Kim, Jeonghyo Lee, Jin-Haeng Chung; Received July 19, 2024 Accepted September 8, 2024 Published online September 9, 2024; DOI: https://doi.org/10.4143/crt.2024.670 [Epub ahead of print]

Abstract PDF Supplementary Material PubReader ePub: Purpose
Major pathologic response (MPR), defined as ≤ 10% of residual viable tumor (VT), is a prognostic factor in non–small cell lung cancer (NSCLC) after neoadjuvant therapy. This study evaluated interobserver reproducibility in assessing MPR, compared area-weighted and unweighted VT (%) calculation, and determined optimal VT (%) cutoffs across histologic subtypes for survival prediction.
Materials and Methods
This retrospective study included 108 patients with NSCLC who underwent surgical resection after neoadjuvant chemotherapy or chemoradiation at Seoul National University Bundang Hospital between 2009-2018. Three observers with varying expertise independently assessed tumor bed and VT (%) based on digital whole-slide images.
Results
Reproducibility in tumor bed delineation was reduced in squamous cell carcinoma (SqCC) with smaller tumor bed, although overall concordance was high (Dice coefficient, 0.96; intersection-over-union score, 0.92). Excellent agreement was achieved for VT (%) (intraclass correlation coefficient=0.959) and MPR using 10% cutoff (Fleiss’ kappa=0.911). Shifting between area-weighted and unweighted VT (%) showed only one case differing in MPR status out of 81 cases. The optimal cutoff was 10% for both adenocarcinoma (ADC) and SqCC. MPR+ was observed in 18 patients (17%), with SqCC showing higher MPR+ rates (p=0.044), lower VT (%) (p < 0.001), and better event-free survival (p=0.015) than ADC. MPR+ significantly improved overall survival (p=0.023), event-free survival (p=0.001), and lung cancer-specific survival (p=0.012).
Conclusion
While MPR assessment demonstrated robust reproducibility with minimal impact from the tumor bed, attention is warranted when evaluating smaller tumor beds in SqCC. A 10% cutoff reliably predicted survival across histologic subtypes with higher interobserver reproducibility.

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Lung and Thoracic cancer

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma: Hyun Jung Kwon, Sejoon Lee, Yeon Bi Han, Jeonghyo Lee, Soohyeon Kwon, Hyojin Kim, Jin-Haeng Chung; Cancer Res Treat. 2024;56(2):442-454. Published online November 14, 2023; DOI: https://doi.org/10.4143/crt.2023.764

Abstract PDF Supplementary Material PubReader ePub

Purpose
Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non–small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples.
Materials and Methods
A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed.
Results
TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs.
Conclusion
Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.

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PD-L1 Expression and Its Modulating Factors in Anaplastic Thyroid Carcinoma
Shipra Agarwal, Chan Kwon Jung, Pranitha Gaddam, Mitsuyoshi Hirokawa, Takuya Higashiyama, Jen-Fan Hang, Wei-An Lai, Somboon Keelawat, Zhiyan Liu, Hee Young Na, So Yeon Park, Junya Fukuoka, Shinya Satoh, Zhanna Mussazhanova, Masahiro Nakashima, Kennichi Ka
American Journal of Surgical Pathology.2024; 48(10): 1233. CrossRef

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Comparison of the Predictive Power of a Combination versus Individual Biomarker Testing in Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: Hyojin Kim, Hyun Jung Kwon, Eun Sun Kim, Soohyeon Kwon, Kyoung Jin Suh, Se Hyun Kim, Yu Jung Kim, Jong Seok Lee, Jin-Haeng Chung; Cancer Res Treat. 2022;54(2):424-433. Published online July 7, 2021; DOI: https://doi.org/10.4143/crt.2021.583

Abstract PDF Supplementary Material PubReader ePub

Purpose
Since tumor mutational burden (TMB) and gene expression profiling (GEP) have complementary effects, they may have improved predictive power when used in combination. Here, we investigated the ability of TMB and GEP to predict the immunotherapy response in patients with non–small cell lung cancer (NSCLC) and assessed if this combination can improve predictive power compared to that when used individually.
Materials and Methods
This retrospective cohort study included 30 patients with NSCLC who received immune checkpoint inhibitors (ICI) therapy at the Seoul National University Bundang Hospital. programmed cell death-ligand-1 (PD-L1) protein expression was assessed using immunohistochemistry, and TMB was measured by targeted deep sequencing. Gene expression was determined using NanoString nCounter analysis for the PanCancer IO360 panel, and enrichment analysis were performed.
Results
Eleven patients (36.7%) showed a durable clinical benefit (DCB), whereas 19 (63.3%) showed no durable benefit (NDB). TMB and enrichment scores (ES) showed significant differences between the DCB and NDB groups (p=0.044 and p=0.017, respectively); however, no significant correlations were observed among TMB, ES, and PD-L1. ES was the best single biomarker for predicting DCB (area under the curve [AUC], 0.794), followed by TMB (AUC, 0.679) and PD-L1 (AUC, 0.622). TMB and ES showed the highest AUC (0.837) among other combinations (AUC [TMB and PD-L1], 0.777; AUC [PD-L1 and ES], 0.763) and was similar to that of all biomarkers used together (0.832).
Conclusion
The combination of TMB and ES may be an effective predictive tool to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

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Microdroplet-enhanced chip platform for high-throughput immunotherapy marker screening from extracellular vesicle RNAs and membrane proteins
Chuanhao Tang, Zaizai Dong, Shi Yan, Bing Liu, Zhiying Wang, Long Cheng, Feng Liu, Hong Sun, Yimeng Du, Lu Pan, Yuhao Zhou, Zhiyuan Jin, Libo Zhao, Nan Wu, Lingqian Chang, Xiaojie Xu
Biosensors and Bioelectronics.2025; 267: 116748. CrossRef
Exploring the ferroptosis-related gene lipocalin 2 as a potential biomarker for sepsis-induced acute respiratory distress syndrome based on machine learning
Jiayi Zhan, Junming Chen, Liyan Deng, Yining Lu, Lianxiang Luo
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.2024; 1870(4): 167101. CrossRef
Evaluation of Blood Tumor Mutation Burden for the Efficacy of Second-Line Atezolizumab Treatment in Non-Small Cell Lung Cancer: BUDDY Trial
Cheol-Kyu Park, Ha Ra Jun, Hyung-Joo Oh, Ji-Young Lee, Hyun-Ju Cho, Young-Chul Kim, Jeong Eun Lee, Seong Hoon Yoon, Chang Min Choi, Jae Cheol Lee, Sung Yong Lee, Shin Yup Lee, Sung-Min Chun, In-Jae Oh
Cells.2023; 12(9): 1246. CrossRef
Unveiling the role of regulatory T cells in the tumor microenvironment of pancreatic cancer through single-cell transcriptomics and in vitro experiments
Wei Xu, Wenjia Zhang, Dongxu Zhao, Qi Wang, Man Zhang, Qiang Li, Wenxin Zhu, Chunfang Xu
Frontiers in Immunology.2023;[Epub] CrossRef
Facilitating “Omics” for Phenotype Classification Using a User-Friendly AI-Driven Platform: Application in Cancer Prognostics
Uraquitan Lima Filho, Tiago Alexandre Pais, Ricardo Jorge Pais
BioMedInformatics.2023; 3(4): 1071. CrossRef
Current state and challenges of emerging biomarkers for immunotherapy in hepatocellular carcinoma (Review)
Mo Cheng, Xiufeng Zheng, Jing Wei, Ming Liu
Experimental and Therapeutic Medicine.2023;[Epub] CrossRef

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Lung cancer

Genetic Alterations in Preinvasive Lung Synchronous Lesions: Soyeon Ahn, Jisun Lim, Soo Young Park, Hyojin Kim, Hyun Jung Kwon, Yeon Bi Han, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung; Cancer Res Treat. 2020;52(4):1120-1134. Published online June 5, 2020; DOI: https://doi.org/10.4143/crt.2020.307

Abstract PDF Supplementary Material PubReader ePub

Purpose
Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD)
Materials and Methods
We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing.
Results
Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions.
Conclusion
Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

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Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma
Jisun Lim, Yeon Bi Han, Soo Young Park, Soyeon Ahn, Hyojin Kim, Hyun Jung Kwon, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung
Cells.2021; 10(12): 3484. CrossRef

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Clinical Significance of Pleural Attachment and Indentation of Subsolid Nodule Lung Cancer: Hyung-Jun Kim, Jun Yeun Cho, Yeon Joo Lee, Jong Sun Park, Young-Jae Cho, Ho Il Yoon, Jin-Haeng Chung, Sukki Cho, Kwhanmien Kim, Kyung Won Lee, Jae Ho Lee, Choon-Taek Lee; Cancer Res Treat. 2019;51(4):1540-1548. Published online March 25, 2019; DOI: https://doi.org/10.4143/crt.2019.057

Abstract PDF Supplementary Material PubReader ePub

Purpose
Lung cancers presenting as subsolid nodule commonly have peripheral location, making the cancer-pleura relationship noteworthy. We aimed to evaluate the effect of pleural attachment and/or indentation on visceral pleural invasion (VPI) and recurrence-free survival.
Materials and Methods
Patients who underwent curative resection of lung cancer as subsolid nodules from April 2007 to January 2016 were retrospectively evaluated. They were divided into four groups according to their relationship with the pleura. Clinical, radiographical, and pathological findings were analyzed.
Results
Among 404 patients with malignant subsolid nodule, 120 (29.7%) had neither pleural attachment nor indentation, 26 (6.4%) had attachment only, 117 (29.0%) had indentation only, and 141 (34.9%) had both. VPI was observed in nodules of 36 patients (8.9%), but absent in nonsolid nodules and in those without pleural attachment and/or indentation. Compared to subsolid nodules with concurrent pleural attachment and indentation, those with attachment only (odds ratio, 0.12; 95% confidence interval [CI], 0.02 to 0.98) and indentation only (odds ratio, 0.10; 95% CI, 0.03 to 0.31) revealed lower odds of VPI. On subgroup analysis, the size of the solid portion was associated with VPI among those with pleural attachment and indentation (p=0.021). Such high-risk features for VPI were associated with earlier lung cancer recurrence (adjusted hazard ratio, 3.31; 95% CI, 1.58 to 6.91).
Conclusion
Concurrent pleural attachment and indentation are risk factors for VPI, and the odds increase with larger solid portion in subsolid nodules. Considering the risk of recurrence, early surgical resection could be encouraged in these patients.

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Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non-small Cell Lung Cancer: Junghoon Shin, Jin-Haeng Chung, Se Hyun Kim, Kyu Sang Lee, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Jeong-Ok Lee, Jin-Won Kim, Yu-Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Jong-Seok Lee; Cancer Res Treat. 2019;51(3):1086-1097. Published online November 5, 2018; DOI: https://doi.org/10.4143/crt.2018.537

Abstract PDF PubReader ePub

Purpose
Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum-based chemotherapy on tumor PD-L1 expression and its clinical implications.
Materials and Methods
We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival.
Results
The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1‒negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar’s test, p < 0.001). Increase in PD-L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival.
Conclusion
Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome.

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Curative Resection for Metachronous Pulmonary Metastases from Colorectal Cancer: Analysis of Survival Rates and Prognostic Factors: Myong Hoon Ihn, Duck-Woo Kim, Sukki Cho, Heung-Kwon Oh, Sanghoon Jheon, Kwhanmien Kim, Eun Shin, Hye Seung Lee, Jin-Haeng Chung, Sung-Bum Kang; Cancer Res Treat. 2017;49(1):104-115. Published online May 9, 2016; DOI: https://doi.org/10.4143/crt.2015.367

Abstract PDF PubReader ePub

Purpose
Prognostic factors in patients with pulmonary metastases (PM) from colorectal cancer (CRC) are still controversial. This study assessed oncologic outcomes and prognostic factors in patients with metachronous PM from CRC.
Materials and Methods
Between June 2003 and December 2011, 122 patients with CRC underwent curative resection of PM detected at least 4 months after CRC resection. Clinico-pathological factors selected from the prospectively maintained database were analyzed retrospectively.
Results
The median disease-free interval (DFI) between resection of the primary tumor and detection of PM was 22.0 months (range, 4 to 85 months). Solitary PM were detected in 77 patients (63.1%), with a median maximal tumor diameter of 12.0 mm (range, 2 to 70 mm). Of 52 patients who underwent mediastinal lymph node (LN) dissection, eight patients had LN involvement. Five-year overall survival and disease-free survival (DFS) rates after initial pulmonary metastasectomy were 66.4% and 50.9%, respectively. DFI, mediastinal LN involvement, and the number and distribution of PM were significantly prognostic factors for DFS. In multivariable analysis DFI ≥ 12 months, solitary lesion, and absence of mediastinal LN involvement were independently prognostic for DFS. Of the 122 patients, 48 patients (39.3%) developed recurrent PM a median 13.0 months after initial pulmonary metastasectomy. Recurrent DFI was independently prognostic of DFS in patients who underwent repeated pulmonary metastasectomy.
Conclusion
There is a potential survival benefit for patients with metachronous PM from CRC who undergo pulmonary metastasectomy, even those with recurrent PM. Pulmonary metastasectomy should be considered in selected patients, particularly those with longer DFI, solitary lesions, and absence of mediastinal LN involvement.

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