Se Jun Park

Background: This study aimed to define the clinical significance of pretreatment serum growth differentiation factor-15 (GDF-15), including its associations with clinical vulnerability, survival, and chemotherapy outcomes in advanced pancreatic ductal adenocarcinoma (PDAC). Methods: Pretreatment serum samples were prospectively collected from 80 patients with locally advanced or metastatic PDAC. GDF-15 was measured using an enzyme-linked immunosorbent assay and analyzed continuously and according to the cohort median. Associations with clinicopathological characteristics and overall survival (OS) were evaluated in the overall cohort. Treatment effectiveness, delivery, and safety were additionally assessed among 68 patients who received systemic chemotherapy. Results: The median GDF-15 concentration was 362.6 pg/mL. Higher GDF-15 was associated with poor performance status, involvement of multiple metastatic organ sites, an elevated neutrophil-to-lymphocyte ratio, and hypoalbuminemia. Eleven of the 12 patients unable to receive chemotherapy because of clinical deterioration had high GDF-15. The high GDF-15 group had shorter OS than the low GDF-15 group in the overall cohort (median, 6.1 vs. 13.9 months; hazard ratio [HR] = 1.96; 95% CI, 1.23–3.13; p = 0.002). The association between continuous GDF-15 and OS was attenuated and no longer statistically significant after multivariable adjustment (HR per doubling = 1.22; 95% CI, 0.97–1.52; p = 0.085). Among treated patients, progression-free survival and objective response did not differ significantly between groups, whereas high GDF-15 was associated with shorter OS (median, 8.7 vs. 14.2 months; HR = 1.72; 95% CI, 1.02–2.90; p = 0.025) and treatment duration (median, 3.2 vs. 6.3 months; p = 0.007). Relative dose intensity and subsequent treatment rates were similar. Febrile neutropenia occurred exclusively in the high GDF-15 group, which also accounted for four of five treatment-related deaths. Conclusions: Elevated pretreatment GDF-15 was associated with limited treatment fitness and inferior survival in patients with advanced PDAC, without clear evidence of intrinsic chemotherapy resistance. GDF-15 may represent a potential marker of systemic vulnerability in advanced PDAC, although its clinical utility requires external validation.

Biliary tract cancers (BTCs) are associated with poor outcomes despite recent incorporation of immune checkpoint inhibitors into first-line chemotherapy. Human epidermal growth factor receptor 2 (HER2) overexpression or amplification defines a therapeutically targetable subset of BTC but its integration into first-line chemoimmunotherapy has not been prospectively evaluated. This multi-institutional, open-label, phase 1b/2 HERBOT study (KCSG-HB23-05) aimed to evaluate first-line HER2-targeted quadruplet regimen consisting of trastuzumab, nivolumab, gemcitabine and cisplatin in participants with HER2-positive advanced BTC. Here the primary endpoint was met with an objective response rate of 55% (95% confidence interval (CI) 38.5–70.7; one complete response and 21 partial responses among 40 participants) and a disease control rate of 95% (95% CI 83.5–99.4); the median duration of response was 12.6 months (95% CI 5.7–not reached). With a median follow-up of 17.0 months, the median progression-free survival was 10.6 months (95% CI 7.8–17.4) and median overall survival was not reached. Two participants (5.0%) underwent curative-intent conversion surgery. Common grade ≥3 treatment-related adverse events included neutropenia (57.5%), anemia (30.0%) and thrombocytopenia (22.5%). Preplanned artificial-intelligence-powered whole-slide image analyses suggested that tumors with higher proportions of HER2 3+ cells were associated with greater clinical benefit. These findings suggest that upfront HER2-targeted therapeutic intensification in BTC may represent a promising direction for future first-line treatment strategies, with relevance to ongoing phase 3 studies. ClinicalTrials.gov identifier: NCT05749900.

Purpose: Targeting aberrant metabolism in tumors with alterations in genes encoding Krebs cycle enzymes, a central component of glucose metabolism, is a promising therapeutic strategy. These tumors rely on aerobic glycolysis and promote VEGF-dependent angiogenesis; furthermore, EGFR signaling enhances aerobic glycolysis. This phase II trial evaluated bevacizumab and erlotinib in patients with solid tumors harboring Krebs cycle gene mutations. Patients and Methods: Eligible patients had solid tumors bearing pathogenic mutations in fumarate hydratase (FH), isocitrate dehydrogenase 1/2, succinate dehydrogenase, or maleate dehydrogenase 2 and measurable disease per RECIST version 1.1 or Response Assessment in Neuro-Oncology 2.0 criteria. Participants received bevacizumab (10 mg/kg IV on day 1) and erlotinib (150 mg orally once daily) every 14 days until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival, and safety. Results: From February to November 2023, 35 participants were enrolled: 19 with biliary tract cancer (54.3%), seven with brain tumors (20.0%), and five with FH-deficient renal cell carcinomas (FH-deficient RCC, 17.1%). ORR was 37.1% (one complete and 12 partial responses). The disease control rate was 85.7%. Subgroup ORR were 80.0% in FH-deficient RCC, 36.8% in biliary tract cancer, and 28.6% in brain tumors. At a median follow-up of 11.7 months, the median PFS was 8.3 months; median overall survival was not reached. No new safety signals were observed. Exploratory transcriptomic analyses revealed VEGF and immune pathway enrichment in patients with favorable PFS, whereas amino acid, fatty acid metabolism, and oxidative phosphorylation–related pathways were enriched in those with poor PFS. Conclusions: Bevacizumab plus erlotinib demonstrated promising efficacy in tumors with Krebs cycle gene mutations, warranting further investigation beyond FH-deficient RCC.

KRAS mutations occur in over 90% of pancreatic ductal adenocarcinomas (PDACs), most commonly at codon 12, but the clinical implications of codon-specific subtypes in advanced disease remain unclear. We retrospectively analyzed 269 patients with advanced PDAC who underwent next-generation sequencing between 2020 and 2024 at a single tertiary cancer center. Clinical features, co-mutations, treatment outcomes, and survival were evaluated. KRAS mutations were detected in 92% of patients, most frequently G12V (36%) and G12D (34%), followed by G12R (10%) and non-G12 variants (9%). TP53 was the most frequent co-mutation (67%) and was significantly enriched in G12D tumors compared with wild type (74.2% vs. 31.8%). Mutations in homologous recombination and DNA damage response genes were more common in non-G12 and wild-type tumors, although not statistically significant. Serum CA 19-9 was elevated in most G12-mutant tumors, whereas approximately 40% of non-G12 and wild-type patients showed normal levels despite advanced disease. No significant survival differences were observed among KRAS subtypes in the overall or treated cohorts. However, patients with G12V mutations achieved significantly longer survival with fluorouracil-based than gemcitabine-based chemotherapy. These findings suggest that, while KRAS subtyping alone lacks prognostic value, the G12V subtype may inform chemotherapy selection and warrants further prospective validation.

Background: Multiple primary cancers (MPCs) often indicate an underlying hereditary predisposition. Current genetic testing guidelines mainly target specific cancer types, potentially missing MPC patients who do not meet these criteria. This study evaluated the utility of MPCs as an independent criterion for germline genetic testing by comparing the pathogenic variant (PV) diagnostic yields of guideline-based and MPC-based testing. Methods: Between June 2022 and June 2023, we prospectively enrolled 62 patients diagnosed with two or more pathologically confirmed primary cancers. Patients were classified into a Guideline group (n = 29), which met NCCN/ACMG testing criteria, and a Non-Guideline group (n = 33) classified solely on the MPC status. Germline testing was performed using a 25-gene hereditary cancer panel and by BRCA1/2 next-generation sequencing. Results: Pathogenic variants were identified in four patients (6.5%): two in the Guideline group (CHEK2, BRCA2) and two in the Non-Guideline group (ATM, TP53). Diagnostic yields were similar in the two groups (6.9% vs. 6.1%, respectively, p = 0.763). Of eight patients with ≥3 primary cancers, one patient (12.5%) had a clinically significant TP53 deletion without meeting Li-Fraumeni syndrome criteria. All PV-positive patients had a family history of cancer. Variants of uncertain significance were identified in 25 (40.3%) of the 62 study subjects. Conclusions: Germline genetic testing based solely on MPC had a diagnostic yield comparable to guideline-based testing. MPC could be considered as an independent criterion for genetic testing to improve the identification of a hereditary cancer predisposition.

Background: Nivolumab plus chemotherapy is a standard first-line treatment for advanced gastric cancer (GC), but reliable early biomarkers for predicting treatment outcomes remain lacking. This study aimed to identify early immunological predictors through dynamic immune profiling. Methods: Fifty patients with advanced or unresectable GC receiving nivolumab plus XELOX or FOLFOX were enrolled. Peripheral blood was collected at baseline, week 1, and week 6. Plasma biomarkers (Granzyme B, Ki-67, CXCL10, IFN-γ, TGF-β1) were measured by ELISA, and immune cell subsets, including cytotoxic T cells, immune checkpoint–positive populations, and memory T-cell subsets, were analyzed by flow cytometry. Cutoffs were defined by medians, established thresholds for NLR and lymphocyte count, and criteria for long-term response (≥9.5 months). Associations with response and progression-free survival (PFS) were evaluated using Kaplan–Meier analysis, Cox regression, and ROC curves. Results: Early responders exhibited significant increases in Granzyme B and CXCL10, with ΔGranzyme B alone and in combination with ΔKi-67 predicting response with high accuracy. A lower week 1 neutrophil-to-lymphocyte ratio was associated with long-term benefit. Elevated week 1 CD8⁺ T-cell proportion and greater decreases in PD1⁺CD69⁺Ki-67⁺CD8⁺ T cells were linked to improved PFS. Higher baseline PD1⁺LAG-3⁺Ki-67⁺CD8⁺ T-cell levels and combined TIM-3⁺/LAG-3⁺ expression enhanced prognostic stratification. Additionally, elevated baseline activated TEMRA cells and declines at week 6 in the same subset correlated with better outcomes. Conclusions: These findings highlight the clinical utility of serial immune monitoring to enable early treatment stratification and guide personalized immunotherapy strategies in advanced GC.

Introduction: The combination of liposomal irinotecan with fluorouracil and leucovorin (Nal-IRI/FL) has shown efficacy in phase II trials for advanced biliary tract cancer (BTC) following gemcitabine-cisplatin (GP) therapy. However, its effectiveness and safety in real-world clinical settings have not been well established. This study aimed to assess the real-world outcomes of Nal-IRI/FL in BTC patients who experienced disease progression after gemcitabine-based treatment.Materials and methods: This retrospective, multicenter study evaluated patients with advanced BTC who received Nal-IRI/FL following progression on GP-based therapy between January 2022 and December 2024. Survival outcomes, radiologic responses, toxicities, and molecular alterations were evaluated, with key findings compared against those reported in prior clinical trials.Results: A total of 93 patients were included. The median progression-free survival (PFS) and overall survival (OS) were 2.1 and 4.2 months, respectively. Among 76 radiologic response evaluable patients, median PFS and OS were 2.5 and 5.0 months. The disease control rate was 40.8%, and objective response rate was 7.5%. Higher disease burden and poor performance status were associated with inferior outcomes. Efficacy did not significantly differ between second- and third-line settings or based on RAS or TP53 mutation status. Hematological toxicities were common, including grade ≥3 neutropenia (38.7%) and febrile neutropenia (7.5%). The median relative dose intensity was 0.69. Treatment-related death occurred in 4 patients (4.3%).Conclusions: Nal-IRI/FL showed modest effectiveness in real-world settings, with outcomes generally less favorable than clinical trials, potentially reflecting patient characteristics. Its efficacy was consistent across treatment lines and mutation subgroups, including patients with RAS or TP53 mutations. Careful patient selection and proactive supportive care are essential. Further studies are warranted to clarify its role across diverse populations.

Background: The predictive value of muscle-related indicators in triple-negative breast cancer (TNBC) patients undergoing neoadjuvant chemotherapy (NAC) remains unclear. This study aimed to evaluate the association between the skeletal muscle density (SMD) and clinical variables related to the physical reserve with respect to its impact on the pathologic complete response (pCR). Methods: We retrospectively analyzed TNBC patients who underwent NAC at Seoul St. Mary’s Hospital, Catholic University of Korea, from March 2021 to March 2024, via receiving paclitaxel/carboplatin followed by doxorubicin/cyclophosphamide, with or without pembrolizumab. Muscle indices were assessed from CT measurements of the entire cross-sectional muscle area at the L3 level using commercial deep learning software (ClariMetabo version 1.03). Results: A total of 144 patients were included, where 102 received chemoimmunotherapy (NACIT) and 42 received chemotherapy alone (NACT). A higher SMD was significantly associated with a younger age, lower BMI, and fewer comorbidities. In the NACIT group, patients in the high-SMD group (n = 68) demonstrated a higher relative dose intensity (p = 0.003) and improved pCR rates (63.2% vs. 44.1%, p = 0.066) compared with the low-SMD group (n = 34). The multivariable regression analysis identified a higher SMD (per 5-unit increment: OR = 1.67, p = 0.003) and increased PD-L1 combined positive score (per 10-unit increment: OR = 1.38, p = 0.019) as independent predictors of a pCR. The event-free survival was significantly longer in the high-SMD group (p = 0.017) and among patients that achieved a pCR (p < 0.001). In the NACT group, the SMD was not associated with a pCR or survival. Conclusions: The CT-measured SMD reflected the physical reserve in the TNBC patients that received NAC. Alongside the CPS, SMD may serve as a predictive marker for NACIT efficacy.

Introduction: The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is widely used to assess patient status but relies on subjective judgment and may not fully reflect their physical reserve. While studies have shown that skeletal muscle quality and quantity are associated with patient prognosis, their role in cancers of unknown primary (CUP) remains unclear. Therefore, this study aimed to investigate whether computed tomography (CT)-based skeletal muscle indicators reflect physical reserve and their prognostic value in patients with CUP. Methods: This study enrolled 184 patients with CUP, comprising both inpatients and outpatients, who were diagnosed at Seoul St. Mary’s Hospital between 1 January 2008, and 30 June 2024. Overall survival (OS) was evaluated using the Kaplan–Meier method and analyzed using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazard models. Statistical significance was defined as p < 0.05. Correlation analyses were conducted to evaluate the relationships between skeletal muscle density (SMD), skeletal muscle index (SMI), and other prognostic factors. Results: SMD was positively correlated with SMI and negatively correlated with age, neutrophil-to-lymphocyte ratio, Charlson Comorbidity Index (CCI), and ECOG-PS. Jonckheere’s trend test revealed that SMD decreased significantly as CCI and ECOG-PS increased (p < 0.001), indicating that a higher comorbidity burden and poorer performance status were associated with lower SMD. Both ECOG-PS and SMD were identified as prognostic factors in the univariate analysis of survival; however, only SMD demonstrated statistical significance regarding prognostic value in the multivariate analysis (p = 0.004) Conclusions: SMD, as a measure of muscle quality, demonstrates superior prognostic value compared to the subjective ECOG-PS and may serve as a reliable objective tool for assessing physical reserve in patients with CUP.

Background/Objectives: Patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy face limited treatment options. While trifluridine–tipiracil (FTD–TPI) and regorafenib have shown modest efficacy in prior clinical trials, recent data from the SUNLIGHT trial demonstrated that combining FTD–TPI with bevacizumab (FTD–TPI+BEV) may improve overall survival compared to FTD–TPI alone. However, supporting evidence from real-world populations remains scarce. Methods: This retrospective study assessed the real-world effectiveness and safety of FTD–TPI+BEV versus FTD–TPI monotherapy in patients with refractory mCRC treated at two institutions from June 2020 to October 2024. Results: A total of 106 patients were included, with 47 treated with FTD–TPI+BEV and 59 with FTD–TPI alone. Median progression-free survival (PFS) was significantly longer with FTD–TPI+BEV compared to FTD–TPI alone (4.1 vs. 2.1 months; HR = 0.56; p = 0.004), while median overall survival showed a non-significant trend favoring FTD–TPI+BEV (8.4 vs. 6.3 months; HR = 0.74; p = 0.189). The disease control rate was also significantly higher with FTD–TPI+BEV (59.6% vs. 25.4%, p = 0.001). Subgroup analyses showed consistent PFS benefits. Grade 3–5 adverse events occurred at comparable rates between groups. Conclusions: FTD–TPI+BEV may represent a preferred salvage treatment option for refractory mCRC.