Cancer Research and Treatment

Recent Advances in Genomic Approaches for the Detection of Homologous Recombination Deficiency: Yoo-Na Kim, Doga C. Gulhan, Hu Jin, Dominik Glodzik, Peter J. Park; Cancer Res Treat. 2024;56(4):975-990. Published online July 17, 2024; DOI: https://doi.org/10.4143/crt.2024.154

Abstract PDF PubReader ePub: Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

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Precision Oncology Clinical Trials: A Systematic Review of Phase II Clinical Trials with Biomarker-Driven, Adaptive Design: Hyerim Ha, Hee Yeon Lee, Jee Hyun Kim, Do Yeun Kim, Ho Jung An, SeungJin Bae, Hye-sung Park, Jin Hyoung Kang; Cancer Res Treat. 2024;56(4):991-1013. Published online May 7, 2024; DOI: https://doi.org/10.4143/crt.2024.128

Abstract PDF Supplementary Material PubReader ePub: Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration’s marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs’ efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.

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Data Resource Profile: The Cancer Public Library Database in South Korea: Dong-Woo Choi, Min Yeong Guk, Hye Ri Kim, Kwang Sun Ryu, Hyun-Joo Kong, Hyo Soung Cha, Hyun-Jin Kim, Heejung Chae, Young Sang Jeon, Hwanhee Kim, Jipmin Jung, Jeong-Soo Im, Kui Son Choi; Cancer Res Treat. 2024;56(4):1014-1026. Published online April 30, 2024; DOI: https://doi.org/10.4143/crt.2024.207

Abstract PDF Supplementary Material PubReader ePub

This paper provides a comprehensive overview of the Cancer Public Library Database (CPLD), established under the Korean Clinical Data Utilization for Research Excellence project (K-CURE). The CPLD links data from four major population-based public sources: the Korea National Cancer Incidence Database in the Korea Central Cancer Registry, cause-of-death data in Statistics Korea, the National Health Information Database in the National Health Insurance Service, and the National Health Insurance Research Database in the Health Insurance Review & Assessment Service. These databases are linked using an encrypted resident registration number. The CPLD, established in 2022 and updated annually, comprises 1,983,499 men and women newly diagnosed with cancer between 2012 and 2019. It contains data on cancer registration and death, demographics, medical claims, general health checkups, and national cancer screening. The most common cancers among men in the CPLD were stomach (16.1%), lung (14.0%), colorectal (13.3%), prostate (9.6%), and liver (9.3%) cancers. The most common cancers among women were thyroid (20.4%), breast (16.6%), colorectal (9.0%), stomach (7.8%), and lung (6.2%) cancers. Among them, 571,285 died between 2012 and 2020 owing to cancer (89.2%) or other causes (10.8%). Upon approval, the CPLD is accessible to researchers through the K-CURE portal. The CPLD is a unique resource for diverse cancer research to investigate medical use before a cancer diagnosis, during initial diagnosis and treatment, and long-term follow-up. This offers expanded insight into healthcare delivery across the cancer continuum, from screening to end-of-life care.

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Risk Factors and Prevention of Stomach Cancer, Excluding Helicobacter pylori
Seung-Woo Lee
The Korean Journal of Helicobacter and Upper Gastrointestinal Research.2024; 24(3): 243. CrossRef
Prediction model for survival of younger patients with breast cancer using the breast cancer public staging database
Ha Ye Jin Kang, Minsam Ko, Kwang Sun Ryu
Scientific Reports.2024;[Epub] CrossRef

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General

Safe Utilization and Sharing of Genomic Data: Amendment to the Health and Medical Data Utilization Guidelines of South Korea: Hyojeong Park, Jongkeun Park, Hyun Goo Woo, Hongseok Yun, Minho Lee, Dongwan Hong; Cancer Res Treat. 2024;56(4):1027-1039. Published online June 7, 2024; DOI: https://doi.org/10.4143/crt.2024.146

Abstract PDF Supplementary Material PubReader ePub: Purpose
In 2024, medical researchers in the Republic of Korea were invited to amend the health and medical data utilization guidelines (Government Publications Registration Number: 11-1352000-0052828-14). This study aimed to show the overall impact of the guideline revision, with a focus on clinical genomic data.
Materials and Methods
This study amended the pseudonymization of genomic data defined in the previous version through a joint study led by the Ministry of Health and Welfare, the Korea Health Information Service, and the Korea Genome Organization. To develop the previous version, we held three conferences with four main medical research institutes and seven academic societies. We conducted two surveys targeting special genome experts in academia, industry, and institutes.
Results
We found that cases of pseudonymization in the application of genome data were rare and that there was ambiguity in the terminology used in the previous version of the guidelines. Most experts (>~90%) agreed that the ‘reserved’ condition should be eliminated to make genomic data available after pseudonymization. In this study, the scope of genomic data was defined as clinical next-generation sequencing data, including FASTQ, BAM/SAM, VCF, and medical records. Pseudonymization targets genomic sequences and metadata, embedding specific elements, such as germline mutations, short tandem repeats, single-nucleotide polymorphisms, and identifiable data (for example, ID or environmental values). Expression data generated from multi-omics can be used without pseudonymization.
Conclusion
This amendment will not only enhance the safe use of healthcare data but also promote advancements in disease prevention, diagnosis, and treatment.

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Development and Feasibility Evaluation of Smart Cancer Care 2.0 Based on Patient-Reported Outcomes for Post-Discharge Management of Patients with Cancer: Jin Ah Kwon, Songsoo Yang, Su-Jin Koh, Young Ju Noh, Dong Yoon Kang, Sol Bin Yang, Eun Ji Kwon, Jeong-Wook Seo, Jin sung Kim, Minsu Ock; Cancer Res Treat. 2024;56(4):1040-1049. Published online April 9, 2024; DOI: https://doi.org/10.4143/crt.2024.003

Abstract PDF Supplementary Material PubReader ePub: Purpose
A “Smart Cancer Care” platform that integrates patient-reported outcomes (PROs) with management has been established in Korea. This study focused on improving health behaviors and connecting patients to welfare services by introducing and assessing the feasibility of “Smart Cancer Care 2.0,” an enhanced version designed for monitoring complications post-cancer treatment.
Materials and Methods
Smart Cancer Care 2.0 was developed by conducting a literature review and consulting with expert panels to identify symptoms or variables requiring monitoring and management guidelines based on the treatment type. Qualitative and quantitative surveys were conducted to assess the feasibility of the app and web system based on the experiences of patients with cancer and healthcare workers.
Results
A total of 81 symptoms or variables (chemotherapy-, surgery-, radiotherapy-, rehabilitation-, and health management-related) were selected for management in Smart Cancer Care 2.0. PROs for these symptoms were basically categorized into three severity grades: preventive management, self-treatment, and consultation with a healthcare worker or visit to a healthcare institution. The overall mean scores in the feasibility evaluation by patients and healthcare workers were 3.83 and 3.90 points, respectively, indicating high usefulness.
Conclusion
Smart Cancer Care 2.0 leverages the existing information and communication technologies–based platform, Smart Cancer Care, and further includes health behaviors and welfare services. Smart Cancer Care 2.0 may play a crucial role in establishing a comprehensive post-discharge management system for patients with cancer as it provides suitable interventions based on patients’ responses and allows the regularly collected PROs to be easily viewed for streamlined care.

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Therapeutic Effect of Anti-inflammatory Tripeptide Cream in Hand-Foot Syndrome/Skin Reaction Related to Anticancer Drugs: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial: Yaewon Yang, Jang-Hee Hahn, Min Seo Kim, Minkwan Jo, Yong-Pyo Lee, Hongsik Kim, Hee Kyung Kim, Jihyun Kwon, Ki Hyeong Lee, Hye Sook Han; Cancer Res Treat. 2024;56(4):1050-1057. Published online June 5, 2024; DOI: https://doi.org/10.4143/crt.2024.080

Abstract PDF Supplementary Material PubReader ePub: Purpose
Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are relatively common toxicities that interfere with the quality of life (QoL) of patients with cancer. Anti-inflammatory tripeptide cream (ATPC) is a complex formulation of anti-inflammatory tripeptides, the CD99-agonist Binterin and the Wnt-antagonist Winhibin. The present study aimed to assess the therapeutic effects of ATPC in HFS/HFSR associated with anticancer drugs.
Materials and Methods
This was a single-center, randomized, double-blind, placebo-controlled trial. Patients who developed grade 1 HFS/HFSR after systemic anticancer treatments were enrolled, and randomly assigned to receive either ATPC or placebo cream (PC) and followed up at 3-week intervals for up to 9 weeks. Primary endpoint was the development of grade ≥ 2 HFS/HFSR.
Results
Between April 2019 and July 2022, 60 patients (31 in the ATPC and 29 in the PC group) completed the study. The incidence of grade ≥ 2 HFS/HFSR was significantly lower in the ATPC than in the PC group (25.8% vs. 51.7%, p=0.039). The ATPC showed trends towards a better QoL score, assessed by a HFSR and QoL questionnaire at 9 weeks (26.0 vs. 29.9, p=0.574), and a lower frequency of discontinuation, interruption, or dose reduction of anticancer drugs (51.6% vs. 58.6%, p=0.586) than the PC group over 9 weeks, though without statistical significance.
Conclusion
Our results showed that ATPC significantly decreased the development of grade ≥ 2 HFS/HFSR in patients already with HFS/HFSR. Therefore, ATPC may be an effective treatment for HFS/HFSR associated with anticancer drugs.

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Head and Neck cancer

Metronomic S-1 Adjuvant Chemotherapy Improves Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma: Yi-Feng Yu, Peng Wu, Rui Zhuo, San-Gang Wu; Cancer Res Treat. 2024;56(4):1058-1067. Published online February 19, 2024; DOI: https://doi.org/10.4143/crt.2023.1343

Abstract PDF PubReader ePub

Purpose
This study aimed to investigate the efficacy and safety of using metronomic S-1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC).
Materials and Methods
We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. All patients were treated with induction chemotherapy and concurrent chemoradiotherapy with or without metronomic chemotherapy (MC). Toxicities during MC were recorded. The chi-square test, Kaplan-Meier methods, propensity score matching (PSM), and Cox proportional hazards model were used for statistical analyses.
Results
A total of 474 patients were identified, including 64 (13.5%) and 410 (83.5%) patients with or without receiving MC, respectively. Patients who received metronomic S-1 had significantly better 3-year locoregional recurrence-free survival (LRFS) (100% vs. 90.9%, p=0.038), distant metastasis-free survival (DMFS) (98.5% vs. 84.1%, p=0.002), disease-free survival (DFS) (98.4% vs. 77.5%, p < 0.001), and overall survival (OS) (98.0% vs. 87.7%, p=0.008) compared to those without metronomic S-1. The multivariate prognostic analysis revealed that metronomic S-1 was identified as an independent prognostic factor associated with better DMFS (hazard ratio [HR], 0.074; p=0.010), DFS (HR, 0.103; p=0.002) and OS (HR, 0.127; p=0.042), but not in LRFS (p=0.071). Similar results were found using PSM. Common adverse events observed in the metronomic S-1 group included leukopenia, neutropenia, increased total bilirubin, anorexia, rash/desquamation, and hyperpigmentation. All patients with adverse events were grade 1-2.
Conclusion
It is worth conducting a randomized controlled trial to assess the effect of metronomic S-1 on survival outcomes and toxicities of LANPC.

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Short-term versus long-term metronomic adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma: A propensity score-matched real-world study
Shuhui Dong, Weixin Bei, Lanfeng Lin, Yaofei Jiang, Nian Lu, Guoying Liu, Yanqun Xiang, Weixiong Xia
Oral Oncology.2024; 156: 106908. CrossRef

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Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials: Youjin Kim, Bhumsuk Keam, Eun Joo Kang, Jin-Soo Kim, Hye Ryun Kim, Keun-Wook Lee, Jung Hye Kwon, Kyoung Eun Lee, Yaewon Yang, Yoon Hee Choi, Min Kyoung Kim, Jun Ho Ji, Tak Yun, Moon Young Choi, Ki Hyeong Lee, Sung-Bae Kim, Myung-Ju Ahn; Cancer Res Treat. 2024;56(4):1068-1076. Published online April 15, 2024; DOI: https://doi.org/10.4143/crt.2024.008

Abstract PDF Supplementary Material PubReader ePub: Purpose
In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs).
Materials and Methods
We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed.
Results
In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and three patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6%, 12.4%, and 18.1% months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor.
Conclusion
Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.

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The Impact of Infectious Mononucleosis History on the Risk of Developing Lymphoma and Nasopharyngeal Carcinoma: A Retrospective Large-Scale Cohort Study Using National Health Insurance Data in South Korea: So Hee Kang, Yun-Hee Lee, Jun-Pyo Myong, Minsu Kwon; Cancer Res Treat. 2024;56(4):1077-1083. Published online April 23, 2024; DOI: https://doi.org/10.4143/crt.2023.1356

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aimed to assess the long-term risks associated with a history of infectious mononucleosis (IM), primarily caused by the Epstein-Barr virus (EBV). Specifically analyzing the potential increase in developing nasopharyngeal cancer (NPC) and lymphoma in patients with a history of IM and exploring the prevalence of other EBV-associated conditions.
Materials and Methods
The Korean National Health Insurance Service (NHIS) database was utilized for a retrospective analysis, covering data from 2002 to 2021. A total of 25,582 IM patients and controls were included, with 1:1 propensity score matching. The study monitored outcomes, including lymphoma, NPC, gastric cancer, multiple sclerosis, and all-cause mortality.
Results
Patients with a history of IM demonstrated a significantly higher incidence of lymphoma (hazard ratio [HR], 5.320; 95% confidence interval [CI], 3.208 to 8.820; p < 0.001) and NPC (HR, 7.116; 95% CI, 1.617 to 31.314; p=0.009) during the follow-up period compared with the control group. Additionally, the IM group showed an increased rate of all-cause mortality (HR, 2.225; 95% CI, 1.858 to 2.663; p < 0.001).
Conclusion
This study suggests that individuals with a history of IM have an elevated risk of developing lymphoma and NPC in South Korea, emphasizing the importance of vigilant follow-up and monitoring. The results advocate for heightened awareness and potential national monitoring policies to address the long-term health implications of EBV infection and to implement preventive measures.

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Lung and Thoracic cancer

Adjuvant Pembrolizumab in Patients with Stage IIIA/N2 Non–Small Cell Lung Cancer Completely Resected after Neoadjuvant Concurrent Chemoradiation: A Prospective, Open-Label, Single-Arm, Phase 2 Trial: Junghoon Shin, Sehhoon Park, Kyung Hwan Kim, Eui-Cheol Shin, Hyun Ae Jung, Jong Ho Cho, Jong-Mu Sun, Se-Hoon Lee, Yong Soo Choi, Jin Seok Ahn, Jhingook Kim, Keunchil Park, Young Mog Shim, Hong Kwan Kim, Jae Myoung Noh, Yong Chan Ahn, Hongryull Pyo, Myung-Ju Ahn; Cancer Res Treat. 2024;56(4):1084-1095. Published online April 30, 2024; DOI: https://doi.org/10.4143/crt.2024.084

Abstract PDF Supplementary Material PubReader ePub: Purpose
Optimal treatment for stage IIIA/N2 non–small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT).
Materials and Methods
In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to 2 years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39⁺PD-1⁺CD8⁺ T cells using fold changes in the percentage of proliferating Ki-67⁺ cells from days 1 to 7 of cycle 1 (Ki-67_D7/D1).
Results
Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), nine (26%), and four (12%) had a tumor proportion score of < 1%, 1%-50%, and ≥ 50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a 5-year DFS rate of 29%. The OS rate was 86% at 2 years and 76% at 5 years. Patients with tumor recurrence within 6 months had a significantly lower Ki-67D7/D1 among CD39⁺PD-1⁺CD8⁺ T cells than those without (p=0.036). No new safety signals were identified.
Conclusion
Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.

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Breast cancer

A Nationwide Study on HER2-Low Breast Cancer in South Korea: Its Incidence of 2022 Real World Data and the Importance of Immunohistochemical Staining Protocols: Min Chong Kim, Eun Yoon Cho, So Yeon Park, Hee Jin Lee, Ji Shin Lee, Jee Yeon Kim, Ho-chang Lee, Jin Ye Yoo, Hee Sung Kim, Bomi Kim, Wan Seop Kim, Nari Shin, Young Hee Maeng, Hun Soo Kim, Sun Young Kwon, Chungyeul Kim, Sun-Young Jun, Gui Young Kwon, Hye Jeong Choi, So Mang Lee, Ji Eun Choi, Ae Ri An, Hyun Joo Choi, EunKyung Kim, Ahrong Kim, Ji-Young Kim, Jeong Yun Shim, Gyungyub Gong, Young Kyung Bae; Cancer Res Treat. 2024;56(4):1096-1104. Published online March 6, 2024; DOI: https://doi.org/10.4143/crt.2024.092

Abstract PDF Supplementary Material PubReader ePub

Purpose
Notable effectiveness of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)–low advanced breast cancer (BC) has focused pathologists’ attention. We studied the incidence and clinicopathologic characteristics of HER2-low BC, and the effects of immunohistochemistry (IHC) associated factors on HER2 IHC results.
Materials and Methods
The Breast Pathology Study Group of the Korean Society of Pathologists conducted a nationwide study using real-world data on HER2 status generated between January 2022 and December 2022. Information on HER2 IHC protocols at each participating institution was also collected.
Results
Total 11,416 patients from 25 institutions included in this study. Of these patients, 40.7% (range, 6.0% to 76.3%) were classified as HER2-zero, 41.7% (range, 10.5% to 69.1%) as HER2-low, and 17.5% (range, 6.7% to 34.0%) as HER2-positive. HER2-low tumors were associated with positive estrogen receptor and progesterone receptor statuses (p < 0.001 and p < 0.001, respectively). Antigen retrieval times (≥ 36 minutes vs. < 36 minutes) and antibody incubation times (≥ 12 minutes vs. < 12 minutes) affected on the frequency of HER2 IHC 1+ BC at institutions using the PATHWAY HER2 (4B5) IHC assay and BenchMark XT or Ultra staining instruments. Furthermore, discordant results between core needle biopsy and subsequent resection specimen HER2 statuses were observed in 24.1% (787/3,259) of the patients.
Conclusion
The overall incidence of HER2-low BC in South Korea concurs with those reported in previously published studies. Significant inter-institutional differences in HER2 IHC protocols were observed, and it may have impact on HER2-low status. Thus, we recommend standardizing HER2 IHC conditions to ensure precise patient selection for targeted therapy.

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Impact of immunohistochemistry staining conditions on the incidence of human epidermal growth factor receptor 2 (HER2)-low breast cancer
Min Chong Kim, Sun Young Kwon, Hye Ra Jung, Young Kyung Bae
Virchows Archiv.2024;[Epub] CrossRef
Breast Cancer: Extracellular Matrix and Microbiome Interactions
Lourdes Herrera-Quintana, Héctor Vázquez-Lorente, Julio Plaza-Diaz
International Journal of Molecular Sciences.2024; 25(13): 7226. CrossRef

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Dural Metastasis in Breast Cancer: MRI-Based Morphological Subtypes and Their Clinical Implications: Sung Jun Ahn, Bio Joo, Mina Park, Hun Ho Park, Sang Hyun Suh, Sung Gwe Ahn, Jihwan Yoo; Cancer Res Treat. 2024;56(4):1105-1112. Published online March 19, 2024; DOI: https://doi.org/10.4143/crt.2024.138

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to investigate the clinical factors associated with breast cancer (BRCA) dural metastases (DMs), their impact on prognosis compared to brain parenchymal metastases (BPMs) alone, and differences between DM subtypes, aiming to inform clinical decisions.
Materials and Methods
We retrospectively analyzed 119 patients with BRCA with brain metastasis, including 91 patients with BPM alone and 28 patients with DM. Univariate and multivariate analyses were performed to compare the clinical characteristics between the two groups and within subtypes of DM. Overall survival after DM (OSDM) and the interval from DM to leptomeningeal carcinomatosis (LMC) were compared using Kaplan-Meier analysis.
Results
DM was notably linked with extracranial metastasis, luminal-like BRCA subtype (p=0.033), and skull metastases (p < 0.001). Multiple logistic regression revealed a strong association of DM with extracranial and skull metastases, but not with subtype or hormone receptor status. Patients with DM did not show survival differences compared with patients with BPM alone. In the subgroup analysis, nodular-type DM correlated with human epidermal growth factor receptor 2 status (p=0.044), whereas diffuse-type DM was significantly associated with a higher prevalence of the luminal-like subtype (p=0.048) and the presence of skull metastasis (p=0.002). Patients with diffuse DM did not exhibit a significant difference in OSDM but had a notably shorter interval from DM to LMC compared to those with nodular DM (p=0.049).
Conclusion
While the impact of DM on the overall prognosis of patients with BRCA is minimal, our findings underscore distinct characteristics and prognostic outcomes within DM subgroups.

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Small-cell neuroendocrine carcinoma of the cervix with leptomeningeal spread: A rare coincidence report and literature review
Mohammed A. Azab, Oday Atallah, Nour El-Gohary, Ahmed Hazim, Hamed Abdelma’aboud Mostafa
Surgical Neurology International.2024; 15: 310. CrossRef
Left homonymous hemianopia as an atypical manifestation of isolated pachymeningeal metastasis secondary to breast cancer: Case report and review of the literature
Aziz Ahizoune, Moad Belouad, Houda Alloussi, Mohamed Allaoui, Mohamed Hamid, Ahmed Bourazza
Radiology Case Reports.2024; 19(11): 5459. CrossRef

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A 10-Gene Signature to Predict the Prognosis of Early-Stage Triple-Negative Breast Cancer: Chang Min Kim, Kyong Hwa Park, Yun Suk Yu, Ju Won Kim, Jin Young Park, Kyunghee Park, Jong-Han Yu, Jeong Eon Lee, Sung Hoon Sim, Bo Kyoung Seo, Jin Kyeoung Kim, Eun Sook Lee, Yeon Hee Park, Sun-Young Kong; Cancer Res Treat. 2024;56(4):1113-1125. Published online May 10, 2024; DOI: https://doi.org/10.4143/crt.2024.100

Abstract PDF Supplementary Material PubReader ePub

Purpose
Triple-negative breast cancer (TNBC) is a particularly challenging subtype of breast cancer, with a poorer prognosis compared to other subtypes. Unfortunately, unlike luminal-type cancers, there is no validated biomarker to predict the prognosis of patients with early-stage TNBC. Accurate biomarkers are needed to establish effective therapeutic strategies.
Materials and Methods
In this study, we analyzed gene expression profiles of tumor samples from 184 TNBC patients (training cohort, n=76; validation cohort, n=108) using RNA sequencing.
Results
By combining weighted gene expression, we identified a 10-gene signature (DGKH, GADD45B, KLF7, LYST, NR6A1, PYCARD, ROBO1, SLC22A20P, SLC24A3, and SLC45A4) that stratified patients by risk score with high sensitivity (92.31%), specificity (92.06%), and accuracy (92.11%) for invasive disease-free survival. The 10-gene signature was validated in a separate institution cohort and supported by meta-analysis for biological relevance to well-known driving pathways in TNBC. Furthermore, the 10-gene signature was the only independent factor for invasive disease-free survival in multivariate analysis when compared to other potential biomarkers of TNBC molecular subtypes and T-cell receptor β diversity. 10-gene signature also further categorized patients classified as molecular subtypes according to risk scores.
Conclusion
Our novel findings may help address the prognostic challenges in TNBC and the 10-gene signature could serve as a novel biomarker for risk-based patient care.

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Significance of Multi-Cancer Genome Profiling Testing for Breast Cancer: A Retrospective Analysis of 3326 Cases from Japan’s National Database
Kyoka Kawabata, Hinano Nishikubo, Saki Kanei, Rika Aoyama, Yuki Tsukada, Tomoya Sano, Daiki Imanishi, Takashi Sakuma, Koji Maruo, Yurie Yamamoto, Qiang Wang, Zhonglin Zhu, Canfeng Fan, Masakazu Yashiro
Genes.2024; 15(6): 792. CrossRef

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Gastrointestinal cancer

Identification of New Pathogenic Variants of Hereditary Diffuse Gastric Cancer: Seung-Young Oh, Giyong Jang, Jaeryuk Kim, Kyoung-Yun Jeong, Hyun Myong Kim, Yoon Jin Kwak, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Sung-Yup Cho, Jong-Il Kim, Han-Kwang Yang; Cancer Res Treat. 2024;56(4):1126-1135. Published online April 11, 2024; DOI: https://doi.org/10.4143/crt.2024.328

Abstract PDF PubReader ePub

Purpose
Hereditary diffuse gastric cancer (HDGC) presents a significant genetic predisposition, notably linked to mutations in the CDH1 and CTNNA1. However, the genetic basis for over half of HDGC cases remains unidentified. The aim of this study is to identify novel pathogenic variants in HDGC and evaluate their protein expression.
Materials and Methods
Among 20 qualifying families, two were selected based on available pedigree and DNA. Whole genome sequencing (WGS) on DNA extracted from blood and whole exome sequencing on DNA from formalin-fixed paraffin-embedded tissues were performed to find potential pathogenic variants in HDGC. After selection of a candidate variant, functional validation, and enrichment analysis were performed.
Results
As a result of WGS, three candidate germline mutations (EPHA5, MCOA2, and RHOA) were identified in one family. After literature review and in-silico analyses, the RHOA mutation (R129W) was selected as a candidate. This mutation was found in two gastric cancer patients within the family. In functional validation, it showed RhoA overexpression and a higher GTP-bound state in the Rhoa^R129W mutant. Decreased phosphorylation at Ser127/397 suggested altered YAP1 regulation in the Rho-ROCK pathway. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses linked Rhoa^R129W overexpression to changed migration/adhesion in MKN1 cell line. However, this RHOA mutation (R129W) was not found in index patients in other families.
Conclusion
The RHOA mutation (R129W) emerges as a potential causative gene for HDGC, but only in one family, indicating a need for further studies to understand its role in HDGC pathogenesis fully.

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Current advances and challenges in Managing Hereditary Diffuse Gastric Cancer (HDGC): a narrative review
L. van der Sluis, J.M. van Dieren, R.S. van der Post, T.M. Bisseling
Hereditary Cancer in Clinical Practice.2024;[Epub] CrossRef

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Varlitinib and Paclitaxel for EGFR/HER2 Co-expressing Advanced Gastric Cancer: A Multicenter Phase Ib/II Study (K-MASTER-13): Dong-Hoe Koo, Minkyu Jung, Yeul Hong Kim, Hei-Cheul Jeung, Dae Young Zang, Woo Kyun Bae, Hyunki Kim, Hyo Song Kim, Choong-kun Lee, Woo Sun Kwon, Hyun Cheol Chung, Sun Young Rha; Cancer Res Treat. 2024;56(4):1136-1145. Published online April 29, 2024; DOI: https://doi.org/10.4143/crt.2023.1324

Abstract PDF Supplementary Material PubReader ePub

Purpose
Varlitinib is a pan-human epidermal growth factor receptor (HER) inhibitor targeting epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4. We present a phase Ib/II study of a combination of varlitinib and weekly paclitaxel as a second-line treatment for patients with EGFR/HER2 co-expressing advanced gastric cancer (AGC).
Materials and Methods
Patients whose tumors with EGFR and HER2 overexpression by immunohistochemistry (≥ 1+) were enrolled. Varlitinib and paclitaxel were investigated every 4 weeks. After determining the recommended phase II dose (RP2D) in phase Ib, a phase II study was conducted to evaluate the antitumor activity.
Results
RP2D was treated with a combination of varlitinib (300 mg twice daily) and paclitaxel. Among 27 patients treated with RP2D, the median progression-free survival and overall survival (OS) were 3.3 months (95% confidence interval [CI], 1.7 to 4.9) and 7.9 months (95% CI, 5.0 to 10.8), respectively, with a median follow-up of 15.7 months. Among 16 patients with measurable disease, the objective response rate (ORR) and disease control rate were 31% and 88%, respectively. Patients with strong HER2 expression (n=8) had a higher ORR and longer OS, whereas those with strong EGFR expression (n=3) had poorer outcomes. The most common adverse events (AEs) of any grade were neutropenia (52%), diarrhea (27%), aspartate aminotransferase/alanine transaminase elevation (22%), and nausea (19%). No treatment-related deaths or unexpected AEs resulting from treatment cessation were observed in patients with RP2D.
Conclusion
A combination of varlitinib and paclitaxel displayed manageable toxicity and modest antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy.

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Unraveling the future: Innovative design strategies and emerging challenges in HER2-targeted tyrosine kinase inhibitors for cancer therapy
Sixiang Zheng, Ruixian Chen, Lele Zhang, Lun Tan, Lintao Li, Fangyi Long, Ting Wang
European Journal of Medicinal Chemistry.2024; 276: 116702. CrossRef

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Effector Function Characteristics of Exhausted CD8+ T-Cell in Microsatellite Stable and Unstable Gastric Cancer: Dong-Seok Han, Yoonjin Kwak, Seungho Lee, Soo Kyung Nam, Seong-Ho Kong, Do Joong Park, Hyuk-Joon Lee, Nak-Jung Kwon, Hye Seung Lee, Han-Kwang Yang; Cancer Res Treat. 2024;56(4):1146-1163. Published online April 12, 2024; DOI: https://doi.org/10.4143/crt.2024.317

Abstract PDF PubReader ePub

Purpose
Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability–high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential.
Materials and Methods
We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis.
Results
In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer.
Conclusion
Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer.

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Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer
Yumei Ning, Shilin Fang, Runan Zhang, Jun Fang, Kun Lin, Yang Ding, Haihang Nie, Jingkai Zhou, Qiu Zhao, Hengning Ke, Haizhou Wang, Fan Wang
International Immunopharmacology.2024; 142: 113244. CrossRef

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Association between Endoscopist Volume and Interval Cancers after Colonoscopy: Results from the National Colorectal Cancer Screening Program in Korea: Dong Jun Kim, Nan-He Yoon, Jae Kwan Jun, Mina Suh, Sunhwa Lee, Seongju Kim, Ji Eun Kim, Hooyeon Lee; Cancer Res Treat. 2024;56(4):1164-1170. Published online April 16, 2024; DOI: https://doi.org/10.4143/crt.2024.009

Abstract PDF Supplementary Material PubReader ePub: Purpose
The rate of interval colorectal cancer (iCRC) is now accepted as a key performance indicator of organized colorectal cancer (CRC) screening programs. We aimed to examine the association between endoscopist volumes and the rate of iCRC among individuals with a positive fecal immunochemical test (FIT) within a nationwide population-based CRC screening program.
Materials and Methods
Individuals aged ≥ 50 years who underwent colonoscopy after a positive FIT from January 1, 2019 until December 31, 2020 in the Korean National Cancer Screening Program (KNCSP) were enrolled. We converted the data into per-endoscopist screening results, calculated the iCRC rates per endoscopist, and compared them to the previous year’s annual volume that was divided into five groups (V1, 1-9; V2, 10-29; V3, 30-59; V4, 60-119; V5, ≥ 120).
Results
A total of 10,412 endoscopists performed 216,907 colonoscopies. Overall, the average rate of iCRC per endoscopist was 8.46 per 1,000 examinations. Compared with the group with the highest volume (V5 group), the rate of iCRC was 2.21 times higher in the V1 group. Similar trends were observed in the other groups (V2: relative risks [RR], 2.15; 95% confidence interval [CI], 1.57 to 2.94; V3: RR, 1.56; 95% CI, 1.15 to 2.13; V4: RR, 1.18; 95% CI, 0.83 to 1.67).
Conclusion
The findings emphasize that endoscopists with lower procedure volumes have higher risks of interval cancer being missed or undetected. To maximize the preventative impact of colonoscopy for CRC, this issue should be addressed by monitoring endoscopist volumes and variations in performances.

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Longitudinal Comparative Analysis of Circulating Tumor DNA and Matched Tumor Tissue DNA in Patients with Metastatic Colorectal Cancer Receiving Palliative First-Line Systemic Anti-Cancer Therapy: Seung-been Lee, Ji-Won Kim, Hong-Geun Kim, Sung-Hyun Hwang, Kui-Jin Kim, Ju Hyun Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Koung Jin Suh, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Nak-Jung Kwon, Keun-Wook Lee; Cancer Res Treat. 2024;56(4):1171-1182. Published online April 29, 2024; DOI: https://doi.org/10.4143/crt.2024.016

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy.
Materials and Methods
We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data.
Results
Among 208 consecutively enrolled patients, we selected 84 (41 males; median age, 59 years; range, 35 to 90 years) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, seven mutations in five patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival.
Conclusion
While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer’s clonal evolution. Additionally, baseline-ctDNA’s VAF values were prognostic after treatment.

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Evaluation of Molecular Residual Disease by a Fixed Panel in Resectable Colorectal Cancer: Jian Yang, Chengqing Yu, Haoran Li, Di Peng, Qiaoxia Zhou, Jun Yao, Juan Lv, Shuai Fang, Jiaochun Shi, Yijun Wei, Guoqiang Wang, Shangli Cai, Zhihong Zhang, Zixiang Zhang, Jian Zhou; Cancer Res Treat. 2024;56(4):1183-1196. Published online May 7, 2024; DOI: https://doi.org/10.4143/crt.2023.1371

Abstract PDF Supplementary Material PubReader ePub: Purpose
Molecular residual disease (MRD) is a promising biomarker in colorectal cancer (CRC) for prognosis and guiding treatment, while the whole-exome sequencing (WES) based tumor-informed assay is standard for evaluating MRD based on circulating tumor DNA (ctDNA). In this study, we assessed the feasibility of a fixed-panel for evaluating MRD in CRC.
Materials and Methods
Seventy-five patients with resectable stage I-III CRC were enrolled. Tumor tissues obtained by surgery, and preoperative and postoperative day 7 blood samples were collected. The ctDNA was evaluated using the tumor-agnostic and tumor-informed fixed assays, as well as the WES-based and panel-based personalized assays in randomly selected patients.
Results
The tumor-informed fixed assay had a higher preoperative positive rate than the tumor-agnostic assay (73.3% vs. 57.3%). The preoperative ctDNA status failed to predict disease-free survival (DFS) in either of the fixed assays, while the tumor-informed fixed assay-determined postoperative ctDNA positivity was significantly associated with worse DFS (hazard ratio [HR], 20.74; 95% confidence interval [CI], 7.19 to 59.83; p < 0.001), which was an independent predictor by multivariable analysis (HR, 28.57; 95% CI, 7.10 to 114.9; p < 0.001). Sub-cohort analysis indicated the WES-based personalized assay had the highest preoperative positive rate (95.1%). The two personalized assays and the tumor-informed fixed assay demonstrated same results in postoperative landmark (HR, 26.34; 95% CI, 6.01 to 115.57; p < 0.001), outperforming the tumor-agnostic fixed panel (HR, 3.04; 95% CI, 0.94 to 9.89; p=0.052).
Conclusion
Our study confirmed the prognostic value of the ctDNA positivity at postoperative day 7 by the tumor-informed fixed panel. The tumor-informed fixed panel may be a cost-effective method to evaluate MRD, which warrants further studies in future.

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Prognostic Significance of Bulky Nodal Disease in Anal Cancer Management: A Multi-institutional Study: Seok-Joo Chun, Eunji Kim, Won Il Jang, Mi-Sook Kim, Hyun-Cheol Kang, Byoung Hyuck Kim, Eui Kyu Chie; Cancer Res Treat. 2024;56(4):1197-1206. Published online April 11, 2024; DOI: https://doi.org/10.4143/crt.2024.258

Abstract PDF Supplementary Material PubReader ePub: Purpose
This study aimed to assess the prognostic significance of bulky nodal involvement in patients with anal squamous cell carcinoma treated with definitive chemoradiotherapy.
Materials and Methods
We retrospectively analyzed medical records of patients diagnosed with anal squamous cell carcinoma who underwent definitive chemoradiotherapy at three medical centers between 2004 and 2021. Exclusion criteria included distant metastasis at diagnosis, 2D radiotherapy, and salvage treatment for local relapse. Bulky N+ was defined as nodes with a long diameter of 2 cm or greater.
Results
A total of 104 patients were included, comprising 51 with N0, 46 with non-bulky N+, and seven with bulky N+. The median follow-up duration was 54.0 months (range, 6.4 to 162.2 months). Estimated 5-year progression-free survival (PFS), loco-regional recurrence-free survival (LRRFS), and overall survival (OS) rates for patients with bulky N+ were 42.9%, 42.9%, and 47.6%, respectively. Bulky N+ was significantly associated with inferior PFS, LRRFS, and OS compared to patients without or with non-bulky N+, even after multivariate analysis. We proposed a new staging system incorporating bulky N+ as N2 category, with estimated 5-year LRRFS, PFS, and OS rates of 81.1%, 80.6%, and 86.2% for stage I, 67.7%, 60.9%, and 93.3% for stage II, and 42.9%, 42.9%, and 47.6% for stage III disease, enhancing the predictability of prognosis.
Conclusion
Patients with bulky nodal disease treated with standard chemoradiotherapy experienced poor survival outcomes, indicating the potential necessity for further treatment intensification.

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Efficacy of Lenvatinib Combined with Anti–PD-1 Antibodies Plus Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Retrospective, Multicenter Study: Xiangye Ou, Junyi Wu, Jiayi Wu, Yangkai Fu, Zhenxin Zeng, Shuqun Li, Yinan Li, Deyi Liu, Han Li, Bin Li, Jianyin Zhou, Shaowu Zhuang, Shuqun Cheng, Zhibo Zhang, Kai Wang, Shuang Qu, Maolin Yan; Cancer Res Treat. 2024;56(4):1207-1218. Published online April 30, 2024; DOI: https://doi.org/10.4143/crt.2023.1165

Abstract PDF Supplementary Material PubReader ePub: Purpose
The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti–programmed cell death-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT.
Materials and Methods
This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child-Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles.
Results
During a median follow-up of 11.23 months (range, 3.07 to 34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The 2-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively.
Conclusion
Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

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Clinical and Radiologic Predictors of Response to Atezolizumab-Bevacizumab in Advanced Hepatocellular Carcinoma: Se Jin Choi, Sung Won Chung, Jonggi Choi, Kang Mo Kim, Hyung-Don Kim, Changhoon Yoo, Baek-Yeol Ryoo, Seung Soo Lee, Won-Mook Choi, Sang Hyun Choi; Cancer Res Treat. 2024;56(4):1219-1230. Published online May 7, 2024; DOI: https://doi.org/10.4143/crt.2024.283

Abstract PDF Supplementary Material PubReader ePub

Purpose
This study aimed to identify clinical and radiologic characteristics that could predict response to atezolizumab-bevacizumab combination therapy in patients with advanced hepatocellular carcinoma (HCC).
Materials and Methods
This single-center retrospective study included 108 advanced HCC patients with intrahepatic lesions who were treated with atezolizumab-bevacizumab. Two radiologists independently analyzed imaging characteristics of the index tumor on pretreatment computed tomography. Predictive factors associated with progressive disease (PD) at the best response based on Response Evaluation Criteria in Solid Tumors, ver. 1.1 were evaluated using logistic regression analysis. Progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared with the log-rank test.
Results
Of 108 patients with a median PFS of 15 weeks, 40 (37.0%) had PD during treatment. Factors associated with PD included the presence of extrahepatic metastases (adjusted odds ratio [aOR], 4.13; 95% confidence interval [CI], 1.19 to 14.35; p=0.03), the infiltrative appearance of the tumor (aOR, 3.07; 95% CI, 1.05 to 8.93; p=0.04), and the absence of arterial-phase hyperenhancement (APHE) (aOR, 6.34; 95% CI, 2.18 to 18.47; p < 0.001). Patients with two or more of these factors had a PD of 66.7% and a median PFS of 8 weeks, indicating a significantly worse outcome compared to the patients with one or no of these factors.
Conclusion
In patients with advanced HCC treated with atezolizumab-bevacizumab treatment, the absence of APHE, infiltrative appearance of the intrahepatic tumor, and presence of extrahepatic metastases were associated with poor response and survival. Evaluation of early response may be necessary in patients with these factors.

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Liver Transplantation for Hepatocarcinoma: Results over Two Decades of a Transplantation Programme and Analysis of Factors Associated with Recurrence
María Martínez Burgos, Rocío González Grande, Susana López Ortega, Inmaculada Santaella Leiva, Jesús de la Cruz Lombardo, Julio Santoyo Santoyo, Miguel Jiménez Pérez
Biomedicines.2024; 12(6): 1302. CrossRef

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Distinct Characteristics and Changes in Liver Function of Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab for More Than 1 Year: Youngun Kim, Jung Sun Kim, Beodeul Kang, Ilhwan Kim, Hyeyeong Kim, Won Suk Lee, Yun Beom Sang, Sanghoon Jung, Chansik An, Chan Kim, Hong Jae Chon; Cancer Res Treat. 2024;56(4):1231-1239. Published online May 27, 2024; DOI: https://doi.org/10.4143/crt.2024.237

Abstract PDF Supplementary Material PubReader ePub: Purpose
Since 2020, atezolizumab plus bevacizumab (Ate/Bev) has been the standard first-line therapy for unresectable hepatocellular carcinoma (HCC), but long-term treatment studies are limited. This study evaluated the clinical characteristics and effects of Ate/Bev for over 1 year.
Materials and Methods
This study included patients with unresectable HCC treated with first-line Ate/Bev between May 2020 and April 2022. Those receiving Ate/Bev for 1 year or more were classified as the long-term treatment group.
Results
Of 246 patients, 69 (28.0%) were in the long-term treatment group, which comprised more proportions of intrahepatic tumor burden < 25%, Eastern Cooperative Oncology Group 0, and a lower proportion of portal vein tumor thrombosis than the short-term treatment group. The long-term treatment group had a higher incidence of atezolizumab-related thyroid dysfunction (31.9% vs. 10.7%, p < 0.001; median time to onset [mTTO], 2.8 months), dermatologic toxicity (29.0% vs. 14.7%, p=0.017; mTTO, 3.3 months), bevacizumab-related hypertension (44.9% vs. 22.0%, p=0.001; mTTO, 4.2 months), and proteinuria (69.6% vs. 38.4%, p < 0.001; mTTO, 6.8 months), compared to the short-term treatment group. Regarding liver function in the long-term treatment group, patients initially classified as Child-Pugh class A decreased from 87.0% to 75.4%, and albumin-bilirubin grade 1 decreased from 68.1% to 50.7% after 1 year of treatment.
Conclusion
The Ate/Bev long-term treatment group had a lower intrahepatic tumor burden, less portal vein tumor thrombosis, and better performance status and liver function at baseline. Atezolizumab-related immunological adverse events emerged relatively early in treatment compared to the bevacizumab-related. Additionally, some patients demonstrated liver function deterioration during long-term Ate/Bev treatment.

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Clinical Outcomes of Surgery after Neoadjuvant Chemotherapy in Locally Advanced Pancreatic Ductal Adenocarcinoma: Yoo Na Lee, Min Kyu Sung, Dae Wook Hwang, Yejong Park, Bong Jun Kwak, Woohyung Lee, Ki Byung Song, Jae Hoon Lee, Changhoon Yoo, Kyu-Pyo Kim, Heung-Moon Chang, Baek-Yeol Ryoo, Song Cheol Kim; Cancer Res Treat. 2024;56(4):1240-1251. Published online June 19, 2024; DOI: https://doi.org/10.4143/crt.2023.977

Abstract PDF PubReader ePub: Purpose
Clinical outcomes of surgery after neoadjuvant chemotherapy have not been investigated for locally advanced pancreatic cancer (LAPC), despite well-established outcomes in borderline resectable pancreatic cancer (BRPC). This study aimed to investigate the clinical outcomes of patients with LAPC who underwent curative resection following neoadjuvant chemotherapy.
Materials and Methods
We retrospectively reviewed the records of patients diagnosed with pancreatic adenocarcinoma between January 2017 and December 2020.
Results
Among 1,358 patients, 260 underwent surgery following neoadjuvant chemotherapy. Among 356 LAPC patients, 98 (27.5%) and 147 (35.1%) of 418 BRPC patients underwent surgery after neoadjuvant chemotherapy. Compared to resectable pancreatic cancer (resectable PC) with upfront surgery, both LAPC and BRPC exhibited higher rates of venous resection (28.6% vs. 49.0% vs. 4.0%), arterial resection (30.6% vs. 6.8% vs. 0.5%) and greater estimated blood loss (260.5 vs. 213.1 vs. 70.4 mL). However, hospital stay, readmission rates, and postoperative pancreatic fistula rates (grade B or C) did not differ significantly between LAPC, BRPC, and resectable PC. Overall and relapse-free survival did not differ significantly between LAPC and BRPC patients. The median overall survival was 37.3 months for LAPC and 37.0 months for BRPC. The median relapse-free survival was 22.7 months for LAPC and 26.0 months for BRPC.
Conclusion
Overall survival time and postoperative complications in LAPC patients who underwent curative resection following neoadjuvant chemotherapy showed similar results to those of BRPC patients. Further research is needed to identify specific sub-populations of LAPC patients who benefit most from conversion surgery and to minimize postoperative complications.

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Pediatric cancer

Stratified Treatment in Pediatric Anaplastic Large Cell Lymphoma: Result of a Prospective Open-Label Multiple-Institution Study: Tingting Chen, Chenggong Zeng, Juan Wang, Feifei Sun, Junting Huang, Jia Zhu, Suying Lu, Ning Liao, Xiaohong Zhang, Zaisheng Chen, Xiuli Yuan, Zhen Yang, Haixia Guo, Liangchun Yang, Chuan Wen, Wenlin Zhang, Yang Li, Xuequn Luo, Zelin Wu, Lihua Yang, Riyang Liu, Mincui Zheng, Xiangling He, Xiaofei Sun, Zijun Zhen; Cancer Res Treat. 2024;56(4):1252-1261. Published online May 28, 2024; DOI: https://doi.org/10.4143/crt.2024.104

Abstract PDF Supplementary Material PubReader ePub: Purpose
The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored.
Materials and Methods
On the basis of the non-Hodgkin’s lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL).
Results
A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse.
Conclusion
This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305).

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Hematologic malignancy

Long-term Psychiatric and Endocrine Complications Following Hematopoietic Stem Cell Transplantation in Hematologic Disease in Korea: A Nation-Wide Cohort Study: Min Ji Jeon, Eunjin Noh, Seok Joo Moon, Eun Sang Yu, Chul Won Choi, Dae Sik Kim, Eun Joo Kang; Cancer Res Treat. 2024;56(4):1262-1269. Published online May 9, 2024; DOI: https://doi.org/10.4143/crt.2024.047

Abstract PDF PubReader ePub: Purpose
Numerous patients experience long-term complications after hematopoietic stem cell transplantation (HSCT). This study aimed to identify the frequency and risk factors for psychiatric and endocrine complications following HSCT through big data analyses.
Materials and Methods
We established a cohort of patients with hematologic disease who underwent HSCT in Korea between 2010 and 2012 using the Health Insurance Review & Assessment Service data. A total of 3,636 patients were identified, and insurance claims were tracked using psychiatric and endocrine diagnostic International Classification of Diseases, 10th Revision codes for the ensuing decade. We identified the incidence rates of long-term complications based on the baseline disease and HSCT type. Prognostic factors for each complication were scrutinized using logistic regression analysis.
Results
A total of 1,879 patients underwent allogeneic HSCT and 1,757 patients received autologous HSCT. Post-HSCT, 506 patients were diagnosed with depression, 465 with anxiety disorders, and 659 with diabetes. The highest incidence of long-term complications occurred within the first year post-HSCT (12.2%), subsequently decreasing over time. Risk factors for depressive disorders after allogeneic HSCT included female sex, a total body irradiation–based conditioning regimen, and cyclosporine. Identified risk factors for diabetes mellitus comprised old age, total body irradiation–based conditioning regimen, and non-antithymocyte globulin protocol. Regarding autologous HSCT, only female sex was identified as a risk factor for depressive disorders, whereas elderly patients and those with multiple myeloma were identified as poor prognostic factors for diabetes mellitus.
Conclusion
The incidence of long-term psychiatric and endocrine complications post-HSCT remains high, and patients with risk factors for these complications require vigilant follow-up.

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Endocrine cancer

Combination of Dabrafenib and Trametinib in Patients with Metastatic BRAF^V600E-Mutated Thyroid Cancer: Youngkyung Jeon, Sehhoon Park, Se-Hoon Lee, Tae Hyuk Kim, Sun Wook Kim, Myung-Ju Ahn, Hyun Ae Jung, Jae Hoon Chung; Cancer Res Treat. 2024;56(4):1270-1276. Published online March 6, 2024; DOI: https://doi.org/10.4143/crt.2023.1278

Abstract PDF Supplementary Material PubReader ePub

Purpose
BRAF mutations are detected in 30%-80% of papillary thyroid cancer (PTC) cases. DaBRAFenib and trametinib showed promising antitumor activity in patients with BRAF^V600E-mutated metastatic melanoma and non–small cell lung cancer. This study aimed to evaluate the efficacy and safety of daBRAFenib and trametinib in patients with metastatic BRAF^V600E-mutated thyroid cancer.
Materials and Methods
This was a retrospective study to evaluate the efficacy of daBRAFenib and trametinib in patients with metastatic BRAF^V600E-mutated PTC. The patients received daBRAFenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of daBRAFenib and trametinib.
Results
Between December 2019 and January 2022, 27 PTC patients including eight patients with poorly differentiated or anaplastic transformation, received daBRAFenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients.
Conclusion
DaBRAFenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAF^V600E-mutated metastatic PTC required a dose reduction.

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Korean Thyroid Association Guidelines on the Management of Differentiated Thyroid Cancers; Part III. Management of Advanced Differentiated Thyroid Cancers - Chapter 4. Systemic Therapy for Progressive Radioiodine-Refractory Differentiated Thyroid Cancer 2
Dong Yeob Shin, Ho-Cheol Kang, Sun Wook Kim, Dong Gyu Na, Young Joo Park, Young Shin Song, Eun Kyung Lee, Dong-Jun Lim, Yun Jae Chung, Won Gu Kim
International Journal of Thyroidology.2024; 17(1): 168. CrossRef
Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN–ALK Fusion In Vitro
Silvia Martina Ferrari, Francesca Ragusa, Giusy Elia, Valeria Mazzi, Eugenia Balestri, Chiara Botrini, Licia Rugani, Armando Patrizio, Simona Piaggi, Concettina La Motta, Salvatore Ulisse, Camilla Virili, Alessandro Antonelli, Poupak Fallahi
International Journal of Molecular Sciences.2024; 25(12): 6734. CrossRef
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Palliative medicine

Development of a Prediction Model for Delirium in Hospitalized Patients with Advanced Cancer: Eun Hee Jung, Shin Hye Yoo, Si Won Lee, Beodeul Kang, Yu Jung Kim; Cancer Res Treat. 2024;56(4):1277-1287. Published online February 26, 2024; DOI: https://doi.org/10.4143/crt.2023.1243

Abstract PDF Supplementary Material PubReader ePub: Purpose
Delirium is a common neurocognitive disorder in patients with advanced cancer and is associated with poor clinical outcomes. As a potentially reversible phenomenon, early recognition of delirium by identifying the risk factors demands attention. We aimed to develop a model to predict the occurrence of delirium in hospitalized patients with advanced cancer.
Materials and Methods
This retrospective study included patients with advanced cancer admitted to the oncology ward of four tertiary cancer centers in Korea for supportive cares and excluded those discharged due to death. The primary endpoint was occurrence of delirium. Sociodemographic characteristics, clinical characteristics, laboratory findings, and concomitant medication were investigated for associating variables. The predictive model developed using multivariate logistic regression was internally validated by bootstrapping.
Results
From January 2019 to December 2020, 2,152 patients were enrolled. The median age of patients was 64 years, and 58.4% were male. A total of 127 patients (5.9%) developed delirium during hospitalization. In multivariate logistic regression, age, body mass index, hearing impairment, previous delirium history, length of hospitalization, chemotherapy during hospitalization, blood urea nitrogen and calcium levels, and concomitant antidepressant use were significantly associated with the occurrence of delirium. The predictive model combining all four categorized variables showed the best performance among the developed models (area under the curve 0.831, sensitivity 80.3%, and specificity 72.0%). The calibration plot showed optimal agreement between predicted and actual probabilities through internal validation of the final model.
Conclusion
We proposed a successful predictive model for the risk of delirium in hospitalized patients with advanced cancer.

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Tables of Contents (Vol. 56, No. 1~4, 2024): Cancer Res Treat. 2024;56(4):1288-1298.

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Acknowledgment of Reviewers (2024): Cancer Res Treat. 2024;56(4):1299-1303.

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