Cancer Research and Treatment

Original Articles

Second-Line Fluoropyrimidine-Based Chemotherapy in Advanced Biliary Tract Cancer: A Meta-Analysis Based on Individual Patient-Level Data of Randomized Trials: Jaewon Hyung, Minsu Kang, Ilhwan Kim, Kyu-pyo Kim, Baek-Yeol Ryoo, Jaekyung Cheon, Hyewon Ryu, Ji Sung Lee, Ji-Won Kim, In Sil Choi, Jin Hyun Park, Ghassan K. Abou-Alfa, Jin Won Kim, Changhoon Yoo; Received July 16, 2024 Accepted October 15, 2024 Published online October 17, 2024; DOI: https://doi.org/10.4143/crt.2024.652 [Accepted]

Abstract PDF: Purpose
While fluoropyrimidine-based chemotherapy regimens are recommended second-line treatment for patients with advanced biliary tract cancer (BTC), there have been no studies comparing different regimens head-to-head.
Materials and Methods
We performed individual patient-level meta-analysis based on data from the intention-to-treat population of the phase 2b NIFTY trial (liposomal irinotecan [nal-IRI] plus fluorouracil and leucovorin [5-FU/LV] vs. 5-FU/LV; NCT03542508) and the phase 2 FIReFOX trial (modified oxaliplatin plus 5-FU/LV [mFOLFOX] vs. modified irinotecan plus 5-FU/LV [mFOLFIRI]; NCT03464968). Pairwise log-rank tests and multivariable analysis using Cox proportional hazards modeling with shared frailty to account for the trial's effect were used to compare overall survival (OS) between regimens.
Results
A total of 277 patients were included. The nal-IRI plus 5-FU/LV group (n=88) showed significantly better OS compared to the mFOLFOX group (n=49, pairwise log-rank, p=0.02), and mFOLFIRI group (n=50, p =0.03). Multivariable analysis showed consistent trends in OS with adjusted hazard ratios of 1.39 (mFOLFOX vs nal-IRI plus 5-FU/LV, 95% CI 0.93-2.07, p=0.11) and 1.36 (mFOLFIRI vs nal-IRI plus 5-FU/LV, 95% CI 0.92-2.03, p=0.13), respectively. Compared to the 5-FU/LV group, the mFOLFOX group and the mFOLFIRI group did not show differences in terms of OS (pairwise log-rank p=0.83 and p=0.58, respectively). The nal-IRI plus 5-FU/LV group experienced more frequent diarrhea, while the mFOLFOX group experienced peripheral neuropathy.
Conclusion
Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should be considered along with efficacy.

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The Role of Direct Oral Anticoagulants in Managing Myeloproliferative Neoplasms Patients: Ji Yun Lee, Ju-Hyun Lee, Woochan Park, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Sang-A Kim, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang; Received August 5, 2024 Accepted September 19, 2024 Published online September 20, 2024; DOI: https://doi.org/10.4143/crt.2024.738 [Accepted]

Abstract PDF: Purpose
Thrombosis and bleeding significantly affect morbidity and mortality in myeloproliferative neoplasms (MPNs). The efficacy and safety of direct oral anticoagulants (DOACs) in MPN patients remain uncertain.
Materials and Methods
We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service database from 2010 to 2021.
Results
Out of the 368 MPN patients included in the final analysis, 62.8% were treated with DOACs for atrial fibrillation (AF), and 37.2% for venous thromboembolism (VTE). The AF group was statistically older with higher CHA2DS2-VASc scores compared to the VTE group. Antiplatelet agents were used in 51.1% of cases, and cytoreductive drugs in 79.3%, with hydroxyurea being the most common (64.9%). The median follow-up was 22.3 months, with one-year cumulative incidence rates of thrombosis and bleeding at 11.1% and 3.7%, respectively. Multivariate analysis identified CHA2DS2-VASc scores ≥ 3 (HR=3.48), concomitant antiplatelet use (HR = 2.57), and cytoreduction (HR=2.20) as significant thrombosis risk factors but found no significant predictors for major bleeding.
Conclusion
Despite the limitations of retrospective data, DOAC treatment in MPN patients seems effective and has an acceptable bleeding risk.

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Association of TP53 Mutation Status and Sex with Clinical Outcome in Non–Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study: Songji Choi, Se Hyun Kim, Sejoon Lee, Jeongmin Seo, Minsu Kang, Eun Hee Jung, Sang-A Kim, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Jin Won Kim, Jeong-Ok Lee, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Jong Seok Lee; Received January 15, 2024 Accepted August 6, 2024 Published online August 7, 2024; DOI: https://doi.org/10.4143/crt.2024.046 [Epub ahead of print]

Abstract PDF Supplementary Material: Purpose
Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non–small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC.
Materials and Methods
Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of The Cancer Genome Atlas and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed.
Results
In SNUBH cohort, no statistically significant difference was observed in the median progression-free survival (PFS) according to TP53 mutation status (p=0.930); however, female patients with TP53 mutations (MT) had a significantly prolonged median PFS compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). Programmed death-ligand 1 (PD-L1) high (≥ 50%) expression was significantly enriched in female patients with TP53 MT (p=0.005). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p < 0.001). In TCGA analysis, expression of immune-related genes, and tumor mutation burden score in TP53 MT females were higher than in males without TP53 MT.
Conclusion
Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

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Gastrointestinal cancer

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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A Phase 1b/2a Study of GC1118 with 5-Fluorouracil, Leucovorin and Irinotecan (FOLFIRI) in Patients with Recurrent or Metastatic Colorectal Cancer: Keun-Wook Lee, Sae-Won Han, Tae Won Kim, Joong Bae Ahn, Ji Yeon Baek, Sang Hee Cho, Howard Lee, Jin Won Kim, Ji-Won Kim, Tae-You Kim, Yong Sang Hong, Seung-Hoon Beom, Yongjun Cha, Yoonjung Choi, Seonhui Kim, Yung-Jue Bang; Cancer Res Treat. 2024;56(2):590-601. Published online December 7, 2023; DOI: https://doi.org/10.4143/crt.2023.1117

Abstract PDF Supplementary Material PubReader ePub

Purpose
GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a).
Materials and Methods
Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m²; leucovorin 400 mg/m²; 5-fluorouracil 400 mg/m² bolus and 2,400 mg/m² infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study.
Results
RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0).
Conclusion
GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

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Drug combinations of camptothecin derivatives promote the antitumor properties
Zhen Liu, Yajie Yuan, Ning Wang, Peng Yu, Yuou Teng
European Journal of Medicinal Chemistry.2024; 279: 116872. CrossRef

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General

Impact of Patient Sex on Adverse Events and Unscheduled Utilization of Medical Services in Cancer Patients Undergoing Adjuvant Chemotherapy: A Multicenter Retrospective Cohort Study: Songji Choi, Seyoung Seo, Ju Hyun Lee, Koung Jin Suh, Ji-Won Kim, Jin Won Kim, Se Hyun Kim, Yu Jung Kim, Keun-Wook Lee, Jwa Hoon Kim, Tae Won Kim, Yong Sang Hong, Sun Young Kim, Jeong Eun Kim, Sang-We Kim, Dae Ho Lee, Jae Cheol Lee, Chang-Min Choi, Shinkyo Yoon, Su-Jin Koh, Young Joo Min, Yongchel Ahn, Hwa Jung Kim, Jin Ho Baek, Sook Ryun Park, Jee Hyun Kim; Cancer Res Treat. 2024;56(2):404-413. Published online November 7, 2023; DOI: https://doi.org/10.4143/crt.2023.784

Abstract PDF Supplementary Material PubReader ePub

Purpose
The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade ≥ 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex.
Materials and Methods
This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea.
Results
A total of 1,170 patients with colorectal, gastric, or non–small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade ≥ 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits.
Conclusion
Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions.

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Toxicidad del esquema FOLFOX-6, asociado o no a bolo de 5-fluorouracilo, en cáncer colorrectal metastásico
María Teresa Garrido Martínez, María Rodríguez Jorge, Ignacio García Giménez, María Isabel Guzmán Ramos, Salvador Grutzmancher Sáiz, Victoria Aviñó Tarazona
Farmacia Hospitalaria.2024;[Epub] CrossRef

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Gastrointestinal cancer

Genomic and Transcriptomic Characterization of Gastric Cancer with Bone Metastasis: Sujin Oh, Soo Kyung Nam, Keun-Wook Lee, Hye Seung Lee, Yujun Park, Yoonjin Kwak, Kyu Sang Lee, Ji-Won Kim, Jin Won Kim, Minsu Kang, Young Suk Park, Sang-Hoon Ahn, Yun-Suhk Suh, Do Joong Park, Hyung Ho Kim; Cancer Res Treat. 2024;56(1):219-237. Published online August 11, 2023; DOI: https://doi.org/10.4143/crt.2023.340

Abstract PDF Supplementary Material PubReader ePub

Purpose
Bone metastasis (BM) adversely affects the prognosis of gastric cancer (GC). We investigated molecular features and immune microenvironment that characterize GC with BM compared to GC without BM.
Materials and Methods
Targeted DNA and whole transcriptome sequencing were performed using formalin-fixed paraffin-embedded primary tumor tissues (gastrectomy specimens) of 50 GC cases with distant metastases (14 with BM and 36 without BM). In addition, immunohistochemistry (IHC) for mucin-12 and multiplex IHC for immune cell markers were performed.
Results
Most GC cases with BM had a histologic type of poorly cohesive carcinoma and showed worse overall survival (OS) than GC without BM (p < 0.05). GC with BM tended to have higher mutation rates in TP53, KDR, APC, KDM5A, and RHOA than GC without BM. Chief cell-enriched genes (PGA3, PGC, and LIPF), MUC12, MFSD4A, TSPAN7, and TRIM50 were upregulated in GC with BM compared to GC without BM, which was correlated with poor OS (p < 0.05). However, the expression of SERPINA6, SLC30A2, PMAIP1, and ITIH2 were downregulated in GC with BM. GC with BM was associated with PIK3/AKT/mTOR pathway activation, whereas GC without BM showed the opposite effect. The densities of helper, cytotoxic, and regulatory T cells did not differ between the two groups, whereas the densities of macrophages were lower in GC with BM (p < 0.05).
Conclusion
GC with BM had different gene mutation and expression profiles than GC without BM, and had more genetic alterations associated with a poor prognosis.

Citations

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Targeted Sequencing in Gastric Cancer: Association with Tumor Molecular Characteristics and FLOT Therapy Effectiveness
Liudmila V. Spirina, Alexandra V. Avgustinovich, Olga V. Bakina, Sergey G. Afanas’ev, Maxim Yu. Volkov, Sergey V. Vtorushin, Irina V. Kovaleva, Tatyana S. Klyushina, Igor O. Munkuev
Current Issues in Molecular Biology.2024; 46(2): 1281. CrossRef
SLC30A2-Mediated Zinc Metabolism Modulates Gastric Cancer Progression via the Wnt/β-Catenin Signaling Pathway
Fan Li, Xiaohong Zhang, Li Feng, Xingxing Zhang
Frontiers in Bioscience-Landmark.2024;[Epub] CrossRef

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Palliative medicine

A Prognostic Model to Facilitate Palliative Care Referral in Oncology Outpatients: Yu Jung Kim, Yusuke Hiratsuka, Sang-Yeon Suh, Beodeul Kang, Si Won Lee, Hong-Yup Ahn, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jin Won Kim, Keun-Wook Lee, Jee Hyun Kim, Jong Seok Lee; Cancer Res Treat. 2022;54(2):621-629. Published online July 12, 2021; DOI: https://doi.org/10.4143/crt.2021.483

Abstract PDF PubReader ePub

Purpose
We aimed to develop a prognostic model to assist palliative care referral at least 3 months before death in advanced cancer patients treated at an outpatient medical oncology clinic.
Materials and Methods
In this prospective cohort study, a total of 200 patients were enrolled at a tertiary cancer center in South Korea. The major eligibility criterion was an expected survival of less than a year as estimated by their oncologists. We analyzed the influences of known prognostic factors along with chemotherapy status, mid-arm circumference, and triceps skinfold thickness on survival time.
Results
The mean age of the patients was 64.5 years, 36% were female, and the median survival time was 7.6 months. In the multivariate analysis, we found 6 significant factors related to poor survival: a poor Eastern Cooperative Oncology Group (ECOG) performance status (≥2), not undergoing chemotherapy, anorexia, a low lymphocyte level (<12%), a high lactate dehydrogenase (LDH) level (≥300 IU/L), and a low mid-arm circumference (<23 cm). We developed a prognostic model (score, 0-8.0) to predict 3-month survival based on the multivariate analysis. Patients who scored ≥4.0 points had a short survival of less than 3 months (p<0.001). The discriminating ability of the prognostic model using the area under the receiver operating characteristic curve (AUC) was 0.88.
Conclusion
The prognostic model using ECOG performance status, chemotherapy status, anorexia, lymphocytes, LDH, and mid-arm circumference can predict 3-month survival in medical oncology outpatients. It can alert oncologists to refer patients to palliative care specialists before it is too late.

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Clinicians’ Prediction of Survival Is Most Useful for Palliative Care Referral
Eun Hee Jung, Yusuke Hiratsuka, Sang-Yeon Suh, Seok-Joon Yoon, Beodeul Kang, Si Won Lee, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jin Won Kim, Keun-Wook Lee, Yu Jung Kim
Palliative Medicine Reports.2024; 5(1): 365. CrossRef

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Gastrointestinal cancer

Adjuvant Chemotherapy in Microsatellite Instability–High Gastric Cancer: Jin Won Kim, Sung-Yup Cho, Jeesoo Chae, Ji-Won Kim, Tae-Yong Kim, Keun-Wook Lee, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im; Cancer Res Treat. 2020;52(4):1178-1187. Published online June 11, 2020; DOI: https://doi.org/10.4143/crt.2020.313

Abstract PDF Supplementary Material PubReader ePub

Purpose
Microsatellite instability (MSI) status may affect the efficacy of adjuvant chemotherapy in gastric cancer. In this study, the clinical characteristics of MSI-high (MSI-H) gastric cancer and the predictive value of MSI-H for adjuvant chemotherapy in large cohorts of gastric cancer patients were evaluated. Material and Methods This study consisted of two cohorts. Cohort 1 included gastric cancer patients who received curative resection with pathologic stage IB-IIIC. Cohort 2 included patients with MSI-H gastric cancer who received curative resection with pathologic stage II/III. MSI was examined using two mononucleotide markers and three dinucleotide markers.
Results
Of 359 patients (cohort 1), 41 patients (11.4%) had MSI-H. MSI-H tumors were more frequently identified in older patients (p < 0.001), other histology than poorly cohesive, signet ring cell type (p=0.005), intestinal type (p=0.028), lower third tumor location (p=0.005), and absent perineural invasion (p=0.027). MSI-H status has a tendency of better disease-free survival (DFS) and overall survival (OS) in multivariable analyses (hazard ratio [HR], 0.4; p=0.059 and HR, 0.4; p=0.063, respectively). In the analysis of 162 MSI-H patients (cohort 2), adjuvant chemotherapy showed a significant benefit with respect to longer DFS and OS (p=0.047 and p=0.043, respectively). In multivariable analysis, adjuvant chemotherapy improved DFS (HR, 0.4; p=0.040).
Conclusion
MSI-H gastric cancer had distinct clinicopathologic findings. Even in MSI-H gastric cancer of retrospective cohort, adjuvant chemotherapy could show a survival benefit, which was in contrast to previous prospective studies and should be investigated in a further prospective trial.

Citations

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Management of Microsatellite Instability High (MSI-H) Gastroesophageal Adenocarcinoma
Katherine I. Zhou, Brent A. Hanks, John H. Strickler
Journal of Gastrointestinal Cancer.2024; 55(2): 483. CrossRef
The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023
Feng‐Hua Wang, Xiao‐Tian Zhang, Lei Tang, Qi Wu, Mu‐Yan Cai, Yuan‐Fang Li, Xiu‐Juan Qu, Hong Qiu, Yu‐Jing Zhang, Jie‐Er Ying, Jun Zhang, Ling‐Yu Sun, Rong‐Bo Lin, Chang Wang, Hao Liu, Miao‐Zhen Qiu, Wen‐Long Guan, Sheng‐Xiang Rao, Jia‐Fu Ji, Yan Xin, Wei‐
Cancer Communications.2024; 44(1): 127. CrossRef
Clinical Significance of Fibrinogen and Platelet to Pre-Albumin Ratio in Predicting the Prognosis of Advanced Gastric Cancer
Huakai Tian, Zitao Liu, Zuo Zhang, Lipeng Zhang, Zhen Zong, Jiang Liu, Houqun Ying, Hui Li
Journal of Inflammation Research.2023; Volume 16: 4373. CrossRef
Fatty acid metabolism is related to the immune microenvironment changes of gastric cancer and RGS2 is a new tumor biomarker
Shifeng Yang, Boshi Sun, Wenjing Li, Hao Yang, Nana Li, Xinyu Zhang
Frontiers in Immunology.2022;[Epub] CrossRef
Chemotherapy in Neuroendocrine Tumors
Satya Das, Taymeyah Al-Toubah, Jonathan Strosberg
Cancers.2021; 13(19): 4872. CrossRef

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A Phase II Study of Avelumab Monotherapy in Patients with Mismatch Repair–Deficient/Microsatellite Instability–High or POLE-Mutated Metastatic or Unresectable Colorectal Cancer: Jwa Hoon Kim, Sun Young Kim, Ji Yeon Baek, Yong Jun Cha, Joong Bae Ahn, Han Sang Kim, Keun-Wook Lee, Ji-Won Kim, Tae-You Kim, Won Jin Chang, Joon Oh Park, Jihun Kim, Jeong Eun Kim, Yong Sang Hong, Yeul Hong Kim, Tae Won Kim; Cancer Res Treat. 2020;52(4):1135-1144. Published online April 24, 2020; DOI: https://doi.org/10.4143/crt.2020.218

Abstract PDF Supplementary Material PubReader ePub

Purpose
We evaluated the efficacy and safety of avelumab, an anti-PD-L1 antibody, in patients with metastatic or unresectable colorectal cancer (mCRC) with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) or POLE mutations.
Materials and Methods
In this prospective, open-label, multicenter phase II study, 33 patients with mCRC harboring dMMR/MSI-H or POLE mutations after failure of ≥1st-line chemotherapy received avelumab 10 mg/kg every 2 weeks. dMMR/MSI-H was confirmed with immunohistochemical staining (IHC) by loss of expression of MMR proteins or polymerase chain reaction (PCR) for microsatellite sequences. POLE mutation was confirmed by next-generation sequencing (NGS). The primary endpoint was the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors ver. 1.1.
Results
The median age was 60 years, and 78.8% were male. Thirty patients were dMMR/MSI-H and three had POLE mutations. The ORR was 24.2%, and all of the responders were dMMR/MSI-H. For 21 patients with MSI-H by PCR or NGS, the ORR was 28.6%. At a median follow-up duration of 16.3 months, median progression-free survival and overall survival were 3.9 and 13.2 months in all patients, and 8.1 months and not reached, respectively, in patients with MSI-H by PCR or NGS. Dose interruption and discontinuation due to treatment-related adverse events occurred in 4 and 2 patients, respectively, with no treatment-related deaths.
Conclusion
Avelumab displayed antitumor activity with manageable toxicity in patients with previously treated mCRC harboring dMMR/MSI-H. Diagnosis of dMMR/MSI-H with PCR or NGS could be complementary to IHC to select patients who would benefit from immunotherapy.

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Molecular subtypes of endometrial cancer: Implications for adjuvant treatment strategies
Ye Yang, Su Fang Wu, Wei Bao
International Journal of Gynecology & Obstetrics.2024; 164(2): 436. CrossRef
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Suying Yan, Wanting Wang, Zhiqiang Feng, Jun Xue, Weizheng Liang, Xueliang Wu, Zhiquan Tan, Xipeng Zhang, Shuai Zhang, Xichuan Li, Chunze Zhang
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Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment?
Jonadab E Olguin, Monica G Mendoza-Rodriguez, C Angel Sanchez-Barrera, Luis I Terrazas
World Journal of Gastrointestinal Oncology.2023; 15(2): 251. CrossRef
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Wattana Leowattana, Pathomthep Leowattana, Tawithep Leowattana
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Wattana Leowattana, Pathomthep Leowattana, Tawithep Leowattana
World Journal of Gastroenterology.2023; 29(10): 1569. CrossRef
Case report: long-term sustained remission in a case of metastatic colon cancer with high microsatellite instability and KRAS exon 2 p.G12D mutation treated with fruquintinib after local radiotherapy: a case report and literature review
Ruiqi Wang, Dan Cong, Yuansong Bai, Wenlong Zhang
Frontiers in Pharmacology.2023;[Epub] CrossRef
Avelumab vs Standard Second-Line Chemotherapy in Patients With Metastatic Colorectal Cancer and Microsatellite Instability
Julien Taïeb, Olivier Bouche, Thierry André, Karine Le Malicot, Pierre Laurent-Puig, Jérémie Bez, Clémence Toullec, Christophe Borg, Violaine Randrian, Ludovic Evesque, Stéphane Corbinais, Hervé Perrier, Bruno Buecher, Frederic Di Fiore, Claire Gallois, J
JAMA Oncology.2023; 9(10): 1356. CrossRef
Circulating Tumor DNA Response and Minimal Residual Disease Assessment in DNA Polymerase Epsilon-Mutated Colorectal Cancer Undergoing Immunotherapy
Areeb Lutfi, Maaz K Afghan, Pashtoon M Kasi
Cureus.2023;[Epub] CrossRef
Next generation immuno-oncology biomarkers in gastrointestinal cancer: what does the future hold?
Hassan Abushukair, Obada Ababneh, Ayah Al-Bzour, Ibrahim Halil Sahin, Anwaar Saeed
Expert Review of Molecular Diagnostics.2023; 23(10): 863. CrossRef
Immunological Assessment of Recent Immunotherapy for Colorectal Cancer
Subhadeep Das, Diptikanta Acharya
Immunological Investigations.2023; 52(8): 1065. CrossRef
Can the tumor-agnostic evaluation of MSI/MMR status be the common denominator for the immunotherapy treatment of patients with several solid tumors?
Daniele Fanale, Lidia Rita Corsini, Raimondo Scalia, Chiara Brando, Alessandra Cucinella, Giorgio Madonia, Alessandra Dimino, Clarissa Filorizzo, Nadia Barraco, Marco Bono, Alessia Fiorino, Luigi Magrin, Roberta Sciacchitano, Alessandro Perez, Tancredi Di
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Immunotherapy for a POLE Mutation Advanced Non-Small-Cell Lung Cancer Patient
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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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Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer: Ah-Rong Nam, Ji-Won Kim, Ji Eun Park, Ju-Hee Bang, Mei Hua Jin, Do-Youn Oh, Yung-Jue Bang; Cancer Res Treat. 2019;51(3):886-900. Published online October 1, 2018; DOI: https://doi.org/10.4143/crt.2018.375

Abstract PDF Supplementary Material PubReader ePub

Purpose
Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied.
Materials and Methods
We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC.
Results
Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and p27 expression.
Conclusion
Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.

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Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma: Sun Min Lim, Sang Hee Cho, In Gyu Hwang, Jae Woo Choi, Hyun Chang, Myung-Ju Ahn, Keon Uk Park, Ji-Won Kim, Yoon Ho Ko, Hee Kyung Ahn, Byoung Chul Cho, Byung-Ho Nam, Sang Hoon Chun, Ji Hyung Hong, Jung Hye Kwon, Jong Gwon Choi, Eun Joo Kang, Tak Yun, Keun-Wook Lee, Joo-Hang Kim, Jin Soo Kim, Hyun Woo Lee, Min Kyoung Kim, Dongmin Jung, Ji Eun Kim, Bhumsuk Keam, Hwan Jung Yun, Sangwoo Kim, Hye Ryun Kim; Cancer Res Treat. 2019;51(1):300-312. Published online May 9, 2018; DOI: https://doi.org/10.4143/crt.2018.012

Abstract PDF Supplementary Material PubReader ePub

Purpose
Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients.
Materials and Methods
Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data.
Results
Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%).
Conclusion
We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

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Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma Kinase‒Positive Anaplastic Large Cell Lymphoma: Wendan Xu, Ji-Won Kim, Woo June Jung, Youngil Koh, Sung-Soo Yoon; Cancer Res Treat. 2018;50(2):599-613. Published online June 19, 2017; DOI: https://doi.org/10.4143/crt.2016.357

Abstract PDF Supplementary Material PubReader ePub

Purpose
Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)‒anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated.
Materials and Methods
We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228.
Results
We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells.
Conclusion
Crizotinib combinedwith everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

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The PI3K signaling pathway; from normal lymphopoiesis to lymphoid malignancies
Bahareh Kashani, Zahra Zandi, Atieh Pourbagheri‑Sigaroodi, Amir-Mohammad Yousefi, Seyed H. Ghaffari, Davood Bashash
Expert Review of Anticancer Therapy.2024; 24(7): 493. CrossRef
Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma
Yuan Wang, Jing He, Manyu Xu, Qingfeng Xue, Cindy Zhu, Juan Liu, Yaping Zhang, Wenyu Shi
Frontiers in Oncology.2022;[Epub] CrossRef
Inhibiting ALK-TOPK signaling pathway promotes cell apoptosis of ALK-positive NSCLC
Juanjuan Xiao, Lu Zhang, Huijun Yi, Ling Zou, Jianmei Mo, Feng Xue, Jinhua Zheng, Yingze Huang, Hui Lu, Hansheng Wu, Peipei Xue, Xin Zhang, Lifei He, Zhaoxin Li, Shigui Pang, Guibin Qiao, Qiuhong Duan, Feng Zhu
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Combined crizotinib and endocrine drugs inhibit proliferation, migration, and colony formation of breast cancer cells via downregulation of MET and estrogen receptor
Nehad M. Ayoub, Amer E. Alkhalifa, Dalia R. Ibrahim, Ahmed Alhusban
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The Dual Role of Autophagy in Crizotinib-Treated ALK+ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise
Estelle Espinos, Raymond Lai, Sylvie Giuriato
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Hexokinases II‐mediated glycolysis governs susceptibility to crizotinib in ALK‐positive non‐small cell lung cancer
Caiyu Lin, Hengyi Chen, Rui Han, Li Li, Conghua Lu, Shuai Hao, Yubo Wang, Yong He
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Clinical Implications of VEGF, TGF-beta1, and IL-1beta in Patients with Advanced Non-small Cell Lung Cancer: Ji-Won Kim, Youngil Koh, Dong-Wan Kim, Yong-Oon Ahn, Tae Min Kim, Sae-Won Han, Do-Youn Oh, Se-Hoon Lee, Seock-Ah Im, Tae-You Kim, Dae Seog Heo, Yung-Jue Bang; Cancer Res Treat. 2013;45(4):325-333. Published online December 31, 2013; DOI: https://doi.org/10.4143/crt.2013.45.4.325

Abstract PDF PubReader ePub

PURPOSE
Vascular endothelial growth factor (VEGF)-A, VEGF165b, interleukin (IL)-1beta, and transforming growth factor (TGF)-beta1 are known to influence tumor angiogenesis. Clinical implications of these cytokines need to be elucidated.
MATERIALS AND METHODS
Using clinical data and baseline serum samples of 140 consecutive patients with advanced non-small cell lung cancer who received platinum-based combination chemotherapy, we investigated the association among serum cytokine levels, treatment outcomes, as well as leukocyte and platelet counts.
RESULTS
The median age of patients was 64 years (range, 26 to 86 years). The male to female ratio was 104:36. High TGF-beta1 and IL-1beta levels were associated with shorter progression-free survival, and high VEGF-A and IL-1beta levels were associated with shorter overall survival in the univariate analysis. VEGF165b was not related to the treatment outcomes. Leukocytosis and thrombocytosis were associated with shorter overall survival. The multivariate analysis demonstrated that VEGF-A, IL-1beta, and leukocytosis were significant prognostic factors (p=0.0497, p=0.047, and p<0.001, respectively). Leukocytosis was not associated with recent pneumonia (p=0.937) and correlated with VEGF-A (p<0.001) and TGF-beta1 (p=0.020) levels.
CONCLUSION
Serum VEGF-A, TGF-1beta, and IL-1beta levels, in addition to leukocyte and platelet counts, are shown to be associated with clinical outcomes. Leukocyte and platelet counts are correlated with serum VEGF-A and TGF-beta1 levels.

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Case Report

A Case of Desmoplastic Small Round Cell Tumor Diagnosed in a Young Female Patient: Ji-Won Kim, Jin Hyun Park, Hyeon Jin Cho, Ji-Hyun Kwon, Youngil Koh, Su-Jung Kim, Se Hyung Kim, Se-Hoon Lee, Seock-Ah Im, Yong-Tae Kim, Woo Ho Kim; Cancer Res Treat. 2009;41(4):233-236. Published online December 31, 2009; DOI: https://doi.org/10.4143/crt.2009.41.4.233

Abstract PDF PubReader ePub

Desmoplastic small round cell tumor is a very rare malignancy. We report the case of a 26-year-old woman who suffered from dyspepsia and abdominal pain for 2 months. We performed an endoscopic biopsy of the duodenal mass and diagnosed her disease as desmoplastic small round cell tumor using immunohistochemical staining, fluorescence in situ hybridization, and reverse transcriptase polymerase chain reaction. Because the mass invaded the pancreas and superior mesenteric vein as well as duodenum and the disease was disseminated to liver and peritoneum, she received palliative chemotherapy using vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. The maximal response to chemotherapy was stable disease. The patient expired 9 months after diagnosis.

Citations

Citations to this article as recorded by

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