Jung Yong Hong

Background: Deletion of the MTAP gene at chromosome 9p21.3 defines a therapeutically actionable molecular subset of cancers due to synthetic lethal vulnerability to PRMT5 and MAT2A inhibition. The real-world prevalence and genomic context of MTAP deletion in diverse solid tumors remain incompletely characterized. Methods: We retrospectively analyzed 579 solid tumor specimens subjected to next-generation sequencing-based copy-number profiling. The prevalence of MTAP deletion and its co-occurrence with CDKN2A and CDKN2B were evaluated, and genomic deletion patterns across chromosome 9 were systematically assessed. Results: MTAP deletion was detected in 14 cases (2.4%, 95% confidence interval [CI], 1.45–4.02%), with enrichment in sarcoma, pancreatic cancer, and urothelial carcinoma. Concurrent CDKN2A loss was observed in 92.9% of MTAP-deleted tumors, and 64.3% showed additional CDKN2B loss, indicating a coordinated focal deletion event at 9p21.3. Statistical analyses confirmed strong genomic associations between MTAP and neighboring tumor suppressor genes. Across the full cohort, deletion frequency peaked at the 9p21 locus, and among MTAP-deleted tumors, co-deletion frequency decreased with increasing genomic distance. All MTAP-deleted tumors were microsatellite stable and low tumor mutational burden (TMB-low). Conclusions: Our findings demonstrate that MTAP deletion is an infrequent but genomically coherent event in solid tumors, characterized by a canonical 9p21 co-deletion pattern. This real-world analysis underscores the importance of comprehensive genomic profiling to identify patients who may benefit from emerging MTAP-directed therapies.

Lenvatinib and sorafenib remain viable first-line (1L) options for patients ineligible for newer therapies. This study uses real-world data (RWD) to compare the effectiveness and safety of lenvatinib and sorafenib, addressing gaps between clinical trials and real-world practice. This retrospective, multi-center study utilized the Liver Cancer IN Korea (LINK) database, including HCC patients diagnosed between January 2015 and June 2022 who received 1L lenvatinib or sorafenib. Effectiveness and safety were assessed with real-world overall survival (rwOS), time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and incidence of adverse events of special interest (AESI). Propensity score matching was employed to adjust for potential bias. Post-matching, lenvatinib demonstrated a longer median rwOS of 9.56 months (95% CI: 8.25–10.78) compared to 7.13 months (95% CI: 6.44–7.82) of sorafenib, and longer medians for rwTTD (3.65 months, 95% CI: 3.09–4.07 vs 2.04 months, 95% CI: 1.87–2.30) and rwTTNT (6.51 months, 95% CI: 5.62–7.62 vs 3.71 months, 95% CI: 3.45–4.34). Regarding AESI, lenvatinib was significantly associated with lower rates of hand-foot syndrome (incidence rate ratio, IRR 0.55, 95% CI: 0.33–0.88, p = 0.013) and most hepatotoxicity-related events, but a higher rate of proteinuria (IRR 2.40, 95% CI: 1.49–3.98, p < 0.001). Leveraging RWD, our study demonstrated that 1L lenvatinib may offer a survival advantage over 1L sorafenib in HCC patients, with both treatments exhibiting safety profiles consistent with clinical trials. RWD complements clinical trials by validating long-term outcomes and addressing patient populations excluded from pivotal studies, guiding therapeutic decisions in clinical practice.

Purpose: Neuroendocrine carcinomas (NECs) are aggressive tumors treated with cisplatin-based chemotherapy, though responses vary. As DNA damage response (DDR) pathways influence cisplatin sensitivity, this single-center retrospective study evaluates the efficacy of first-line cisplatin in recurrent or metastatic NEC based on DDR mutation status. Materials and Methods: This study analyzed patients with grade 3 recurrent or metastatic NEC treated with first-line etoposide plus cisplatin at Samsung Medical Center between January 2019 and September 2023. All patients underwent next-generation sequencing to determine DDR mutation status, defined by pathogenic alterations in major DNA repair pathways. Clinical outcomes were assessed per RECIST v1.1. Survival analyses were conducted using Kaplan–Meier methods and Cox regression models, with significance set at p ≤ 0.05. Results: A total of 40 patients with NEC were included in this study. There were 16 patients with DDR wild-type (WT) and 24 patients with DDR mutant type (MT). The most common primary tumor sites were the pancreas (25.0%), stomach (20.0%), and gallbladder/duct (12.5%). Among 40 patients, those with DDR mutations (n = 24) showed significantly higher objective response (58.3% vs. 12.5%) and disease control rates (91.7% vs. 50.0%) compared to patients with DDR WT (n = 16). The median progression-free survival (PFS) showed the favorable trend in the DDR mutant group (8.0 vs. 4.3 months; p = 0.15), with similar trends observed across homologous recombination repair (HRR), Fanconi anemia (FA), and mismatch repair (MMR) subgroups. Conclusions: This study revealed that patients with DDR mutations had significantly higher response to first-line etoposide–cisplatin, suggesting DDR mutation status as a potential predictive marker to guide treatment and improve outcomes in recurrent or metastatic NEC.

Purpose: Therapeutic targeting of RAF1 is a promising cancer treatment, but the relationship between clinical features and RAF1 aberrations in terms of the MAPK signaling pathway is poorly understood in various solid tumors. Methods: Between October 2019 and June 2023 at Samsung Medical Center, 3895 patients with metastatic solid cancers underwent next-generation sequencing (NGS) using TruSight Oncology 500 (TSO500) assays as routine clinical practice. We surveyed the incidence of RAF1 aberrations including mutations (single-nucleotide variants [SNVs]), amplifications (copy number variation), and fusions. Results: Among the 3895 metastatic cancer patients, 77 (2.0%) exhibited RAF1 aberrations. Of these 77 patients, 44 (1.1%) had RAF1 mutations (SNV), 25 (0.6%) had RAF1 amplifications, and 10 (0.3%) had RAF1 fusions. Among the 10 patients with RAF1 fusions, concurrent RAF1 amplifications and RAF1 mutations were detected in one patient each. The most common tumor types were bladder cancer (11.5%), followed by ampulla of Vater (AoV) cancer (5.3%), melanoma (3.0%), gallbladder (GB) cancer (2.6%), and gastric (2.3%) cancer. Microsatellite instability high (MSI-H) tumors were observed in five of 76 patients (6.6%) with RAF1 aberrations, while MSI-H tumors were found in only 2.1% of patients with wild-type RAF1 cancers (p < 0.0001). Conclusion: We demonstrated that approximately 2.0% of patients with metastatic solid cancers have RAF1 aberrations according to NGS of tumor specimens.

Purpose: Antibiotic use preceding immune checkpoint inhibitor (ICI) treatment has been associated with a decreased efficacy of ICI in solid tumors. In this study, we evaluated the effect of antibiotic use before ICI therapy on oncological outcomes. Methods: We examined patients with recurrent gynecologic malignancies at two academic institutions. The clinical data, including antibiotic use within 60 days of ICI initiation, type of antibiotics, reasons for antibiotic use, body mass index, tumor site, chemotherapy-free interval, prior history of radiotherapy, disease control rate (DCR), and overall survival (OS), were assessed. Results: Of 215 patients, 22.9% (n = 47) received antibiotics before ICI treatment. The most common cancer was ovarian (52.1%, n = 112), followed by cervical (24.7%, n = 53) and endometrial (16.7%, n = 36). When we divided the cohort based on antibiotic use before ICIs, there were no significant differences in the DCR and baseline characteristics between the two groups. On multivariate analyses, the variables associated with poor OS were previous use of antibiotics for a cumulative duration of >14 days (HR 2.286, 95% CI 1.210–4.318; p = 0.011); Eastern Cooperative Oncology Group 2 or 3 (HR 4.677, 95% CI 2.497–8.762; p < 0.001); and chemotherapy-free interval of 14 days was associated with reduced survival in recurrent gynecologic malignancies.

Purpose: Therapeutic targeting of RAF1 is promising, but it requires further investigation for the relation between clinical features and RAF1 aberrations regarding the MAPK signaling pathway in various solid tumors to realize the precision medicine. Methods: Between October 2019 and June 2023, Samsung Medical Center, 3,895 patients with metastatic cancer patients received a next-generation sequencing (NGS) using TruSight Oncology 500 (TSO500) assay as a routine clinical practice. We surveyed the incidence of RAF1 aberration including mutation (single-nucleotide variant [SNV]), amplification (copy-number variation), and fusion. Results: In 3,895 metastatic cancer patients, 77 (2.0%) had RAF1 aberrations in their tumor specimen. Of 77 patients, 44 (1.1%) had RAF1 mutations (SNV), 25 (0.6%) had RAF1 amplification and 10 (0.3%) had RAF1 fusions. Among 10 patients with RAF1 fusion, concurrent RAF1 amplification and RAF1 mutation were detected in one patient each. The most common tumor types were bladder cancer (11.5%), followed by ampulla of Vater (AoV) cancer (5.3%), melanoma (3.0%), gallbladder (GB) cancer (2.6%), and gastric cancer (2.3%). Microsatellite instability high (MSI-H) tumors were found in 5 out of 76 patients (6.6%) with RAF1 aberration, while MSI-H tumors were found only in 2.1% of patients with wild-type RAF1 cancer (p < 0.0001). Conclusion: We showed that when patients with metastatic solid cancer receive NGS test, approximately 2.0% have RAF1 aberrations in their tumor specimen.

Introduction: We assessed the performance of F-18 fluorodeoxyglucose positron emission tomography (FDG PET)-based radiomics for the prediction of tumor mutational burden (TMB) and prognosis using a machine learning (ML) approach in patients with stage IV colorectal cancer (CRC). Methods: Ninety-one CRC patients who underwent pretreatment FDG PET/computed tomography (CT) and palliative chemotherapy were retrospectively included. PET-based radiomics were extracted from the primary tumor on PET imaging using the software LIFEx. For feature selection, PET-based radiomics associated with TMB were selected by logistic regression analysis. The performances of seven ML algorithms to predict high TMB were compared by the area under the receiver’s operating characteristic curves (AUCs) and validated by five-fold cross-validation. A PET radiomic score was calculated by averaging the z-score of each radiomic feature. The prognostic power of the PET radiomic score was assessed using Cox proportional hazards regression analysis. Results: Ten significant radiomic features associated with TMB were selected: surface-to-volume ratio, total lesion glycolysis, tumor volume, area, compacity, complexity, entropy, correlation, coarseness, and zone size non-uniformity. The k-nearest neighbors model obtained the good performance for prediction of high TMB (AUC: 0.791, accuracy: 0.814, sensitivity: 0.619, specificity: 0.871). On multivariable Cox regression analysis, the PET radiomic score (Hazard ratio = 4.498, 95% confidential interval = 1.024–19.759; p = 0.046) was a significant independent prognostic factor for OS. Conclusions: This study demonstrates that PET-based radiomics are useful image biomarkers for the prediction of TMB status in stage IV CRC. PET radiomic score, which integrates significant radiomic features, has the potential to predict survival in stage IV CRC patients.

The purpose of the present study was to investigate the clinical significance of preoperative hematological parameters in patients with advanced stomach cancer, and to explore who might benefit from adjuvant concurrent chemoradiotherapy (CCRT) compared to chemotherapy alone. Among 1032 patients with node-positive stomach cancer who had a confirmed diagnosis after complete D2 resection, and who received adjuvant chemotherapy alone or CCRT, a total of 692 patients was selected using propensity score matching. Among absolute neutrophil count, absolute lymphocyte count (ALC), absolute monocyte count (AMC), platelet count, neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and platelet-to-lymphocyte ratio, AMC was the most relevant prognostic factor for overall survival and recurrence-free survival (hazard ratio (HR) 1.674, 95% confidence interval (CI) 1.180–2.376; HR 1.908, 95% CI 1.650–2.695, respectively). In a subgroup with a high ALC, patients treated with adjuvant CCRT had a favorable recurrence-free survival (HR 0.620, 95% CI 0.393–0.980) compared to those treated with chemotherapy alone. Further study is needed to confirm our findings and to develop tailored adjuvant treatment.

ALK gene rearrangement is clinically significant due to the ALK tyrosine kinase inhibitor, important in several types of ALK-rearranged malignancies, most prominently in non–small cell lung cancers. ALK fusion in the gastrointestinal tract is rare. Herein, we report 2 cases of gastric cancer, in which ALK is fused with two uncommon partners, SLMAP and STRN. Two cases of ALK fusion were identified by comprehensive panel sequencing of 231 clinical gastric cancer samples. The results were confirmed using the Ventana ALK (D5F3) CDx assay. Both were advanced stage and were signet ring cell carcinomas with histological features comparable to those of ALK-rearranged non–small cell lung cancers. The patients were treated with conventional chemotherapy ALK fusion, one of the druggable targets in other solid tumors, is rare in gastric cancers and can be detected by comprehensive panel sequencing. Clinical studies are warranted to investigate the therapeutic response of ALK inhibitors in gastric cancers with ALK fusion.

Objectives: To report the long-term follow-up data including computed tomography (CT) findings of oxaliplatin-induced liver damage in patients with colorectal cancer. Methods: Three hundred and fifty-six patients who underwent surgery followed by oxaliplatin-based chemotherapy (OBC) for colorectal cancer between January 2013 and December 2014 were included. Abdominal CT images and laboratory results (serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total bilirubin, and platelet counts) were reviewed immediately before (as baseline), during, and after adjuvant OBC. Abdominal CT images were reviewed to assess the heterogeneous liver parenchyma, increase in size of the spleen, development of acute portosystemic shunts during OBC, and imaging findings of chronic portal hypertension. Results: During OBC, 90.2% (321/356) of the patients developed parenchymal heterogeneity. Increase in the spleen size during the OBC period was seen in 62.4% (225/356) of patients. The overall rate of development of acute portosystemic shunts during OBC was 23.9% (85/356). These findings were resolved after cessation of OBC except in 1.4% (5/356) of the patients in whom chronic portal hypertension persisted even after completion of OBC. Serum AST, ALT, and total bilirubin levels increased and platelet counts decreased during OBC and returned to normal after completion of OBC; however, they did not reach the pre-OBC levels. Conclusion: Although most changes associated with liver damage reversed to normal range after completion of OBC, some parameters did not reverse to the pretreatment level, and chronic portal hypertension developed in a small number of patients. Advances in knowledge: Chronic, persistent oxaliplatin-induced liver damage was not an infrequent complication after oxaliplatin-based chemotherapy for patients with colorectal cancer. It may cause non-cirrhotic portal hypertension and associated complications such as variceal bleeding.