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Assessing the impact of PCSK9 inhibition in small cell lung cancer with novel DLL3-targeted bispecific T-cell engager therapy.
e20135 Background: B-specific T-cell engagers (BiTEs) such as tarlatamab, have improved upon the efficacy and durability of response in small cell lung cancer (SCLC). However, an unmet need remains due to the known “immune-cold” microenvironment and immune evasion of SCLC. PCSK9 has been shown to enhance tumor immunity by increasing tumor antigen presentation and CD8+ T-cell infiltration. We hypothesized that combining PCSK9 inhibition with tarlatamab would enhance anti-tumor immune responses in SCLC. Methods: Fresh surgically resected SCLC tissue was mechanically minced and enzymatically dissociated using Human Tumor Dissociation (HRA) enzymes (Miltenyi Biotec) to generate single-cell suspensions. Cells were mixed with Matrigel and processed using the MOSgen platform to generate micron-scale Matrigel droplets containing SCLC cells and organoids, forming MicroOrganoSpheres (MOS). SCLC MOS were supplemented with interleukin-2 (IL-2) to preserve immune cells and treated with increasing concentrations of alirocumab (PCSK9 inhibitor) and tarlatamab (DLL3-targeted BiTE), alone and in combination for 72 hours. Cell viability was quantified using CellTiter-Glo (CTG) luminescent ATP assay. Data were normalized to untreated control conditions and expressed as percent viability. Results: To develop a method to predict patient responses to the alirocumab and tarlatamab combination therapy, we leveraged our existing MicroOrganoSphere (MOS) technology. At time of submission, two patient-derived SCLC MOS samples were successfully generated and evaluated. Both samples demonstrated a limited response to alirocumab monotherapy across all tested concentrations. These responses were improved by the addition of tarlatamab. The MOS platform successfully maintained viable tumor architecture and immune cell populations throughout the 72-hour treatment period, enabling functional assessment of immunotherapy combinations. Conclusions: This study establishes the first patient-derived SCLC MOS platform for evaluating PCSK9 inhibition combined with tarlatamab. This proof-of-concept demonstrates technical feasibility for rapid functional drug screening in SCLC. Future studies will expand to additional patient samples with comprehensive immune profiling including T-cell activation markers, cytokine secretion (IFN-γ, TNF-α, granzyme B), and exhaustion markers (PD-1, TIM-3, LAG-3) to identify predictive biomarkers of response. These findings will inform the design of investigator-initiated clinical trials combining PCSK9 inhibitors with tarlatamab ± checkpoint inhibitors in metastatic SCLC patients who have progressed on prior therapy.
PEAK-1: A randomized, double-blind, active-control, multicenter phase 3 trial of casdatifan and cabozantinib versus placebo and cabozantinib in patients with advanced clear cell renal cell carcinoma.
TPS4636 Background: For patients (pts) with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have relapsed post anti-PD-1/PD-L1 treatment, second line treatment options remain limited, consisting primarily of tyrosine kinase inhibitors (TKI) monotherapy. Hypoxia-inducible factor 2 alpha (HIF-2α) inhibition represents a promising target as its mechanism of action has been clinically validated in ccRCC and is distinct from that of TKIs without overlapping toxicities. Casdatifan (cas) is an orally bioavailable, selective HIF-2α inhibitor that has a potentially improved pharmacodynamic profile relative to other members of the therapeutic class (Ghasemi 2025). Combining cas with a TKI (cabozantinib [cabo]) that targets VEGFR, MET, and AXL may yield enhanced antitumor activity beyond the individual agents. Preliminary efficacy data from the Phase 2 ARC-20 Study demonstrated promising antitumor activity with the combination (cas + cabo; Choueiri 2025). PEAK-1 is currently the only Phase 3 that examines the efficacy and safety of a HIF-2α inhibitor in combination with a TKI in ccRCC. Methods: PEAK-1 (NCT07011719) is an ongoing Phase 3, randomized, active-control, double-blind, 2-arm, global, multicenter study in adult pts with confirmed advanced or metastatic ccRCC who have experienced progression on or after anti-PD1 or anti-PD-L1 treatment. Approximately 720 pts will be enrolled and randomized 2:1 to treatment with 100 mg QD cas + 60 mg QD cabo (experimental arm) or placebo + 60 mg QD cabo (comparator arm). Crossover is not allowed. Stratification factors include by region (North America vs Western Europe vs rest of world); prior VEGFR-TKI (yes vs no); and International Metastatic RCC Database Consortium risk score (favorable vs intermediate/poor). Key eligibility requirements include adults (≥ 18 years) who have received anti-PD-1 or anti-PD-L1 treatment as part of the most recent regimen (either adjuvant monotherapy or first line in combination with anti-CTLA-4 or VEGFR-TKI), with ≤ 1 prior regimens in the metastatic setting. Pts must have a Karnofsky Performance Status score ≥ 80%, at least 1 target lesion measurable by computed tomography/magnetic resonance imaging per RECIST 1.1, and adequate organ and marrow function. Key exclusion criteria include prior treatment with a HIF-2α inhibitor or cabo, receiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, and uncontrolled or poorly controlled hypertension (sustained blood pressure >140/90 mm Hg on ≥ 3 antihypertensives). The primary endpoint of the study is PFS BICR according to RECIST 1.1. Secondary endpoints include safety, overall survival, overall response rate, duration of response, and disease control rate. Pt reported outcomes using NFKSI-DRS will also be assessed. Enrolment is ongoing as of 1 Oct 2025. Clinical trial information: NCT07011719 .
Association of steroid exposure with overall survival and hypersensitivity reaction risk in paclitaxel-treated patients with gynecologic cancers.
5541 Background: Paclitaxel remains a first-line agent in chemotherapy regimens for gynecologic cancers but is associated with hypersensitivity reactions (HSRs) in up to 40% of patients. Though this risk is largely mitigated by dexamethasone-based premedications, preclinical studies suggest that dexamethasone can induce treatment resistance through enhanced DNA repair capacity, immune suppression, or inhibition of apoptosis, raising concern that pretreatment could compromise paclitaxel efficacy. Furthermore, the effect of cumulative steroid exposure on survival outcomes remains unknown. This study evaluates the impact of cumulative steroid exposure on overall survival (OS) and explores factors associated with HSRs among paclitaxel-treated patients with gynecologic cancers. Methods: This IRB-approved retrospective cohort study included patients with gynecologic malignancies treated with paclitaxel-based chemotherapy at the R.J. Zuckerberg Cancer Center, Northwell Health Cancer Institute, New York, between May 2023 and December 2024. Treatment characteristics and outcomes data were analyzed using univariable and multivariable zero-inflated Poisson regression models for HSRs and Cox regression models for OS. Results: A total of 163 patients who completed at least three cycles of paclitaxel-based chemotherapy were included. The median age (range, 38-87) was 66 years. Patients were 49% White, 18% Asian, 17% Black, 6% Hispanic, and 11% other or unknown. Cancer types included endometrial cancer (53%), ovarian/peritoneal (42%), cervical (4%), and vaginal (1%). At initial diagnosis, 30% of patients had AJCC stage I disease, 31% stage II-III, 9% stage IV, and 30% had insufficient staging data. Most patients (85%) were newly diagnosed. Twenty one percent of patients developed at least one HSR. Body surface area, race, and prior exposure to paclitaxel were not independently associated with HSRs. In contrast, stage IV disease at diagnosis was associated with a higher rate of HSR compared with stage I disease, with a rate ratio of 2.83 (95% CI 1.01-7.93; p=0.048) after adjustment for key confounders. Cumulative dexamethasone exposure did not impact OS in either univariable or multivariable analyses. Conclusions: HSRs occurred in 21% of paclitaxel-treated patients and were independently more common among those with stage IV disease. This suggests that greater disease burden may reflect differences in immune responsiveness that predispose to HSRs. While dexamethasone is commonly used to improve treatment tolerability and reduce the risk of HSRs, cumulative exposure did not impact OS. Further studies are needed to clarify the mechanisms underlying paclitaxel-associated HSR and to define the optimal role of steroid premedication.
Fear of cancer recurrence in oncology follow-up: Prevalence and the role of patient–oncologist communication.
e24101 Background: Fear of cancer recurrence (FCR) is one of the most frequent and least addressed concerns among patients in oncological follow-up. Its impact on quality of life and emotional well-being has been widely documented, but its systematic evaluation and management in clinical practice remain insufficient. Objective: To assess the prevalence of FCR in a cohort of patients in oncological follow-up and to analyze its association with sociodemographic and clinical variables. Additionally, to explore the interaction between patients and oncologists regarding FCR, focusing on doctor–patient communication and support during consultations. Methods: Cross-sectional study using the Cancer Worry Scale and a structured questionnaire that inquired about doctor–patient dialogue, strategies provided, and desired support. A total of 153 patients in cancer follow-up were included, excluding those under active treatment. Bivariate analyses were performed according to age, educational level, sex, stage, tumor site, and time since diagnosis. Results: A total of 153 patients were included (median age 66 years, 53.6% women). According to the CWS, 26.1% showed high FCR, 29.4% moderate, and 44.4% low. High FCR was more frequent in younger patients, those with higher educational level, advanced stage, and shorter time since diagnosis (p < 0.05). Nearly half (48.4%) discussed FCR with their oncologist, and 15.7% did so in more than one consultation; among those who did not address it, the main reason was not considering it a problem (65.8%). High FCR was associated with lack of opportunity during consultation and with medical strategies perceived as not useful. Conclusions: FCR is frequent among patients in oncological follow-up and is more closely related to sociodemographic than clinical factors. Doctor–patient communication plays a central role in its management. These findings highlight the need for systematic evaluation and support strategies tailored to each patient’s profile, in order to provide more equitable and person-centered care.
Tumor-type–stratified causal machine learning to identify heterogeneous benefit of PD-(L)1+CTLA-4 versus PD-(L)1 monotherapy: A hypothesis-generating analysis from the MSK pan-cancer cohort.
e14505 Background: Combination immune checkpoint inhibition (ICI) can improve survival but increases immune-related adverse events; the incremental benefit varies across tumors and patients, and traditional subgroup analyses are underpowered and multiplicity-prone. Methods: Using the publicly available MSK pan-cancer ICI cohort (Samstein et al., Nat Genet 2019), we compared PD-(L)1+CTLA-4 versus PD-(L)1 monotherapy for 12-month overall survival, defining time zero as first ICI to mitigate immortal time bias. Primary analyses were tumor-type–stratified. We estimated conditional and average treatment effects with a doubly robust learner (DRLearner) using 3-fold cross-fitted propensity and outcome models, evaluated overlap, and trimmed propensity scores to 0.05–0.95. We computed tumor-specific 12-month survival differences with 1,000 bootstrap samples for 95% CIs and bootstrap z-test p-values. We learned an interpretable treatment-selection rule via decision trees and estimated counterfactual policy value with inverse-probability weighting; sensitivity analyses included E-values and inverse probability of censoring weighting. Results: Among 1,285 eligible patients (1,066 monotherapy; 219 combination), 848 remained after trimming (34% trimmed). The doubly robust average treatment effect favored combination by +14.1 percentage points (pp) in 12-month survival (95% CI 11.2–17.0; p < 0.001; E-value 1.86). Marked heterogeneity emerged: renal cell carcinoma showed a robust benefit (+21.1pp; 95% CI 10.6–30.5; p < 0.001; 96.4% vs 75.4% 12-month survival), and non–small cell lung cancer showed a large but imprecise benefit (+30.5pp; 95% CI 10.0–48.3; p = 0.002; combination n = 21). Melanoma showed no significant incremental benefit (+6.0pp; 95% CI −4.7 to 17.0; p = 0.28), as did esophagogastric cancer (+6.1pp; 95% CI −16.9 to 28.9; p = 0.62) and bladder cancer (−1.4pp; 95% CI −25.8 to 21.8; p = 0.91). Decision trees highlighted tumor histology and tumor mutational burden as key effect modifiers. The learned policy recommended combination for 66.7% of patients and achieved 84.7% expected 12-month survival versus 83.2% for treat-all combination and 63.4% for treat-all monotherapy, suggesting potential de-escalation in ~10% without compromising survival. Conclusions: Tumor-type–stratified doubly robust causal ML identified heterogeneous 12-month survival benefit of PD-(L)1+CTLA-4 versus PD-(L)1 monotherapy, strongest in RCC and NSCLC and minimal in melanoma. Despite possible residual confounding from unavailable variables (e.g., ECOG, PD-L1, line), the signal persisted after cross-fitting, overlap/trimming, and sensitivity analysis (E-value 1.86), supporting a robust, hypothesis-generating benefit.
A four-marker-protein signature to predict ramucirumab efficacy in combination with TAS-102 in advanced colorectal cancer: Translational analysis of the RAMTAS trial of the German AIO (AIO-KRK-0316/IKF643).
3588 Background: The combination of TAS-102 and bevacizumab is standard in the treatment of advanced colorectal cancer (aCRC). Ramucirumab (Ram) is a mAb that blocks VEGFR2. Ram in combination with Tas-102 did not improve OS compared to Tas-102 alone in the ITT population of the RAMTAS trial. Subgroups such as female patients (pts) and pts with left-sided tumors appeared to benefit from the combination (DOI:10.1016/j.annonc.2024.08.2264). Here we aimed at identifying angiogenesis-related, soluble, predictive biomarkers defining a RAMTAS subpopulation benefitting from the addition of Ram to Tas-102. Methods: Serum samples were available from 194 of 428 pts from the RAMTAS study (96 pts randomized to TAS-102, 98 pts to TAS-102 plus Ram). Serum levels of 85 angiogenesis-related proteins obtained prior to treatment with Tas-102 +/- Ram (baseline, BL) and at cycle 2 day 1 prior to the start of the next cycle (treatment, TR) were quantified via multiplex-ELISA by Myriad-RBM. Multivariate Cox regression models were developed within the combination arm using stepwise selection and ridge regularization. Model performance was assessed via C-index and validated using 10 x 5-fold cross-validation (CV) as well as full quality control for multicollinearity and proportional hazard assumptions. To distinguish predictive from general prognostic effects, the identified signatures were applied to the monotherapy control arm. Results: A TR model incorporating just 4 serum proteins demonstrated robust discrimination in the combination arm (Training C-index: 0.712; CV C-index: 0.708 ± 0.063). This model successfully stratified patients into a “Ram benefit” and a “no Ram benefit” group with a corresponding median PFS of 7.0 mo and 1.9 mo, respectively (HR 6.97, p < 0.001). A Baseline (BL) model yielded a C-index of 0.699, also utilizing just 4 serum proteins. Application of both models to the TAS-102 mono arm resulted in poor discrimination (C-index ~0.60) indicating that the signatures are specific predictors for the combination. In a comparative survival analysis, "Ram-benefit" TR model patients achieved a significantly longer PFS with the combination compared to monotherapy (7.00 vs. 2.14 mo; HR 0.558, p=0.0078). Conversely, "no-Ram-benefit" patients derived no significant benefit from the addition of Ram (PFS 1.91 vs. 1.91 mo; HR 0.946, p=0.4204). Conclusions: Oligo-marker serum signatures, when incorporating early on-treatment dynamics after one cycle of Tas-102/Ram, may effectively predict a survival benefit for aCRC-pts receiving TAS-102 in combination with Ram. We propose that a two-stage “Screen & Monitor” (BL+TR) strategy will help to identify primary refractory patients who gain no benefit from the addition of Ram. Such an approach could maximize therapeutic utility while reducing potential toxicity. Clinical trial information: NCT03520946 .
Global burden of disease analysis of acute lymphoblastic leukemia in children in Africa: Incidence, prevalence, and DALYs (1990–2023).
e18620 Background: Hematological malignancies, including leukemia, lymphoma, and multiple myeloma, contribute significantly to the global cancer burden and are 5th most common cause of cancer related mortality . In Africa, infection-related risks, poor surveillance, and delayed care cause higher mortality than in high-income regions. However, mortality patterns by age, time, and region remain poorly characterized due to under-representation of African communities in cancer registries. This study examines mortality trends from Acute Lymphoblastic leukemia (ALL) among children aged 1–14 years in Africa. Methods: Data from the 2023 Global Burden of Disease (GBD) database was analyzed to evaluate ALL related Disability-Adjusted Life Years (DALYs), Age-Standardized Death Rate (ASDRs), Incidence Rate (ASIR) and Prevalence Rates (ASPR), among children aged 1-14 years in African regions. Trends from 1990 to 2023 were assessed using Annual Average Percentage Change (AAPC), Annual Percentage Change (APC) was also calculated for specific time intervals to identify periods of significant mortality shifts from the overall trend. Results: DALYs attributed to ALL showed statistically significant downward trend across all regions of Africa, with the recorded overall AAPC of -1.24% (95% CI -1.39 to -1.10, p value < 0.00001). Regionally, the Eastern region showed the steepest decline with recorded AAPC of -1.57%, followed by Northern (AAPC = -1.50%). The overall ASIR was also consistent with the DALY trend, with recorded AAPC of -0.86% (95% CI -1.00 to -0.71, p value < 0.00001). Region based analysis showed the Eastern region leading the way with AAPC of -1.49%, followed by Western region (AAPC = -1.18%). Overall ASPR was negative with AAPC of -0.46% (95% CI -0.60 to -0.35, p value < 0.00001). Based on regions, marked decline in ASPR were seen in the Southern region with AAPC of -1.05%, followed by Eastern (AAPC = -0.91%), however the northern region showed an inclining trend with AAPC of 1.33%. Conclusions: In conclusion, our study shows that the burden due to ALL among children aged 1-14 years in Africa has reduced significantly over the past three decades, reflected by both DALYs and other parameters. While some fluctuations exist, the overall trajectory suggests improved outcomes, but further research is required to identify risk factors and systemic flaws contributing to these diverse trends.
Characteristics of cancer drug-indication pairs recommended for funding on the Australian Pharmaceutical Benefits Scheme (PBS), 2005-2025.
e23039 Background: The cost of cancer drugs is substantial and increasing, intensifying scrutiny of regulatory and health technology assessment (HTA) processes to ensure that reimbursement decisions align with meaningful clinical benefit and value. Australia has a universal healthcare system in which medicines are assessed for federal funding on the Pharmaceutical Benefits Scheme following evaluation by the Pharmaceutical Benefits Advisory Committee (PBAC). No prior study has described HTA outcomes for cancer medicines in Australia. Methods: We conducted a retrospective cohort study of solid cancer drug–indication pairs submitted to the PBAC between July 2005 and July 2025. Submission characteristics, supporting clinical evidence, efficacy outcomes (overall survival (OS) and progression-free or disease-free survival (PFS)), and economic analyses were extracted. Hazard ratios for OS and PFS were meta-analysed. Multivariable logistic regression was used to assess factors associated with a funding recommendation. Results: Of 410 solid cancer drug–indication pairs submitted to the PBAC, 184 (44.9%) were recommended for funding. Recommended drugs were commonly supported by randomised (96.2%), phase III (87.5%), and unblinded (57.4%) trials, with overall survival (OS) as the most frequent (co-)primary endpoint (48.9%). Across recommended drugs, pooled hazard ratios indicated a 24% relative reduction in the hazard of death and a 36% reduction in the hazard of progression, corresponding to gains in mOS of 3.2 months (IQR 0.0–6.9) and mPFS of 4.1 months (IQR 1.8–9.6). Recommended drugs were more likely to be resubmissions (46.7% v 35.6%, p = 0.03), involve curative-intent (20.1% v 11.9%, p = 0.03) or first-line therapy (57.6% v 44.7%, p = 0.03), and present a comparator deemed appropriate by the PBAC (94.3% vs 85.9%, p = 0.01). mOS gains were modestly greater among recommended drugs (3.2 vs 2.3 months, p = 0.04). Recommended drugs were more frequently supported by cost-minimisation analyses (33.2% v 11.9%, p < 0.01) and lower ICER ranges ( p < 0.01). In multivariable logistic regression, no single clinical or economic variable independently predicted funding recommendations. Conclusions: Cancer drugs recommended for federal funding in Australia typically demonstrate statistically significant but modest survival benefits and are supported by late-phase randomised evidence. PBAC recommendations appear to reflect a deliberative HTA process incorporating comparative credibility, economic framing, and contextual considerations beyond efficacy or cost-effectiveness thresholds.
Clinical impact of GLP-1 receptor agonist use on lung cancer incidence in high-risk patients: A real-world analysis.
10559 Background: Lung cancer (LC) is the leading cause of cancer-related mortality in the United States. Lifetime risk is ~7% in the general population but substantially higher among high-risk groups with tobacco use, environmental exposures, or family/genetic predisposition. Despite screening recommendations for select high-risk populations, no pharmacologic prevention is established. Emerging evidence suggests that Glucagon-like peptide-1 receptor agonists (GLP-1RA) may influence cancer risk through antiproliferative, anti-inflammatory, and immunomodulatory effects, but data on LC remain limited. This study evaluated the association between GLP-1RA use and LC incidence in high-risk patients. Methods: This multicenter retrospective study used de-identified electronic health data from TriNetX, a global federated research network. Adults ≥18 with high-risk features of tobacco use, environmental or occupational exposure, chronic lung disease, personal/family cancer history, or radiation were included. Participants were stratified by GLP-1RA use. Propensity score matching (1:1) adjusted for demographics, comorbidities, and medications. The primary endpoint was LC incidence. Participants with LC before the study entry were excluded. Multivariate logistic regression and Cox models assessed associations; results reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Before matching, 2,715,963 participants were identified. After matching, 68,374 were analyzed (34,187 per cohort) with similar demographics (mean age 58, 54% female, 46% male; 75% White, 17% Black, 1.5% Asian). Median follow-up was 2,324 days. LC incidence was 2% (688/33,784) in the GLP-1RA cohort vs 2.4% (797/33,369) in controls, yielding an absolute risk reduction of 0.4% and a number needed to treat (NNT) of 250. GLP-1RA use was associated with a 31% reduction in LC incidence [HR 0.687 (0.621–0.761)]. Conclusions: In this large retrospective cohort of high-risk individuals, GLP-1RA use was associated with lower LC incidence compared with matched controls. Despite modest absolute risk reduction, relative risk reduction and favorable number needed to treat suggest potential population-level impact in a disease with limited preventive options. Findings are biologically plausible given the anti-inflammatory, metabolic, and immunomodulatory effects of GLP-1RAs. While causal inference is limited by observational design, this study supports further prospective investigation of GLP-1RAs as a pharmacologic strategy for LC prevention in high-risk populations.
Clinicopathological spectrum and HER2/MSI biomarker status in gastric adenocarcinoma: A tertiary care retrospective cohort from Pakistan.
e16084 Background: Gastric cancer (GC) is a leading cause of cancer mortality in Pakistan, where delayed diagnosis, limited endoscopic access, and fragmented referral systems result in mostly advanced-stage presentations. Data on histopathological subtypes and actionable biomarkers, particularly HER2 overexpression and mismatch repair (MMR) deficiency, remain scarce. Understanding these patterns is crucial for guiding targeted therapies in tertiary care centers managing complex cases. Objective: To describe the clinicopathological spectrum and determine the prevalence of HER2 overexpression and MMR deficiency in gastric adenocarcinoma, with implications for personalized treatment strategies in Pakistan. Methods: We retrospectively reviewed 82 patients with primary gastric adenocarcinoma diagnosed between 2019 and 2024. Patients with prior chemotherapy, incomplete pathology, or non-adenocarcinoma histology were excluded. Tumors were classified according to WHO 2020 criteria. HER2 immunohistochemistry (IHC) was interpreted by two independent pathologists; equivocal cases were confirmed by FISH. MMR protein expression (MLH1, PMS2, MSH2, MSH6) was assessed to identify MSI-high tumors. Descriptive statistics summarized clinical and pathological features. Associations between categorical variables were analyzed using chi-square or Fisher’s exact tests, with p < 0.05 considered significant. Ethical approval was obtained (IRB-2023-0750). Results: The cohort (n = 82) had a median age of 58 years (IQR 50–65) and a male-to-female ratio of 1.6:1. The pyloric antrum was the most common tumor site (73.2%). Tubular adenocarcinoma predominated (75.6%), followed by signet ring cell carcinoma (SRCC, 12.2%). Most patients presented with advanced disease (stage III: 41.5%, stage IV: 26.8%). HER2 overexpression was observed in 14.6% (12/82), while MMR deficiency occurred in 8.5% (7/82). SRCC showed a significant inverse association with HER2 positivity (p = 0.02). All dMMR tumors were intestinal type. No associations were found between biomarkers and age or stage. Conclusions: Gastric adenocarcinoma in this Pakistani cohort predominantly affects the distal stomach and presents at advanced stages. HER2 overexpression and MMR deficiency occur at rates comparable to global reports, supporting biomarker-guided personalized therapy. Routine HER2 and MMR testing in tertiary centers is feasible and can inform targeted treatment strategies.
Trends and disparities in procedure-related mortality among older U.S. adults with digestive system malignancies: A 24-year analysis of the CDC WONDER database.
e15717 Background: Older adults with digestive system malignancies (DSM) frequently undergo diagnostic and therapeuticprocedures and are vulnerable to procedure-related complications. Understanding national mortalitytrends and disparities can inform risk stratification and peri-procedural care. Methods: Using CDC WONDER (1999-2023), we conducted a retrospective population-based analysis ofprocedure-related mortality (Y83-Y84) among U.S. adults ≥65 years with DSM (C15-C26).Crude mortality rates (CMR) and age-adjusted mortality rates (AAMR) per 100,000 were calculated andstratified by year, sex, race, census region, state, and metropolitan status. Temporal trends wereevaluated using Joinpoint regression to estimate annual percent change (APC) with 95% confidenceintervals; statistical significance was defined as P < 0.05. Results: From 1999 to 2023, 22,624 procedure-related deaths occurred among older adults with DSM(58.9% male). The overall AAMR declined from 3.42 in 1999 to 1.05 in 2023. Trend analysisrevealed three distinct phases: a decrease through 2015 (APC −6.42%; 95% CI −7.35 to −5.47),a marked increase from 2015–2021 (APC 18.81%; 95% CI 12.24 to 25.76), and a sharp declinefrom 2021–2023 (APC −45.64%; 95% CI −58.82 to −28.23). The cumulative APC was −5.06%(95% CI −7.49 to −2.56; P < 0.001).Mortality increased with age, peaking in patients ≥85 years(CMR 3.92) compared to those 65–74 years (CMR 1.33). Men had a significantly higher AAMRthan women (2.60 vs 1.28). While the White population accounted for the majority of deaths(86.87%; AAMR 2.13), Asian/Pacific Islanders had the highest mortality rate (AAMR 2.32)despite representing the smallest share of deaths (0.55%).Geographically, the West reportedthe highest mortality (CMR 2.60; AAMR 2.67), followed by the Midwest, South, and Northeast.At the state level, Nebraska (3.82) and Vermont (3.70) reported the highest AAMR, withMassachusetts lowest (1.18). Non-metropolitan areas showed higher AAMR than metropolitancenters (2.46 vs 2.06) despite significantly fewer total deaths. Conclusions: Procedure-related mortality among older adults with DSM declined overall but showed a markedrise during 2015–2021 followed by a sharp decline. Persistent disparities by age, sex, race,geography, and metropolitan status highlight the need for improved peri-procedural riskstratification and targeted interventions.
Treatment outcomes and unmet needs in patients with acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy (IC): A systematic literature review (SLR).
e18517 Background: AML is an aggressive cancer that accounts for around one third of all leukemias. Approximately 42% of patients with AML are ineligible for first-line (1L) IC, representing a vulnerable population with limited treatment options and poor outcomes. This SLR aimed to synthesize current evidence on clinical, economic, and patient-reported outcomes of available interventions. Methods: An SLR was conducted (PROSPERO: CRD420251034510) in accordance with NICE, Cochrane, and PRISMA guidelines. Databases and key congress presentations were searched for studies published from 2015-25 and 2023-25, respectively. Ineligibility for IC was defined as age ≥75, receipt of AML 1L treatments other than IC, or explicit statement of IC ineligibility. Clinical outcomes (e.g., efficacy/safety), economic burden, and patient experiences and patient-reported outcomes were assessed. Data were synthesized narratively due to heterogeneity of the study types and patient populations. Results: The clinical outcome analysis identified 55 trials reporting efficacy/safety. Of the 32 randomized controlled trials (RCTs), most studies (n=27) evaluated treatments involving hypomethylating agents (HMAs; azacitidine [n=14] or decitabine [n=5]) and low-dose cytarabine (LDAC; n=8). Efficacy/safety outcomes were generally improved across studies for combinations vs monotherapies. Among RCT studies included in the safety analysis, only 2 studies reported hematological treatment-related adverse events (AEs). The 38 studies included in the economic burden analysis showed that the main drivers of direct costs included costs of drug administration, hospitalization, transfusion, and AE management. As expected, oral therapies (eg, venetoclax and hydroxycarbamide) had lower costs associated with drug administration than intravenous therapies (eg, LDAC). Indirect costs and productivity losses were substantial but less frequently studied. Analysis of patient-reported outcomes showed that fatigue, anxiety, and depression were present at baseline and generally improved or did not worsen following non-IC treatment. None of the included studies reported quantitative data on caregiver burden, highlighting a gap in the literature. Conclusions: Patients with AML who are ineligible for IC face significant clinical, economic, and disease burden challenges. Further research and novel oral regimens that can provide optimal, patient-centered, and economically sustainable care are essential for this high-need population.
Emerging demographic and geographic disparities in cerebrovascular mortality among U.S. patients with colorectal cancer: A CDC WONDER analysis, 1999–2023.
e15730 Background: Colorectal cancer (CRC) is the third most common malignancy globally, with rising incidence in adults under 50. Stroke, a leading cause of death, frequently co-occurs with CRC due to hypercoagulability, elevated D-dimer, genetic predisposition, and cancer therapies. CRC-related ischemic stroke (CRCIS) is associated with worse prognosis, underscoring the need to understand mortality trends. We evaluated national trends in cerebrovascular mortality among CRC patients in the U.S. from 1999–2023, focusing on demographic and geographic disparities. Methods: We conducted a population-based cohort study using the CDC WONDER database (1999–2023) to identify adults ≥45 years with CRC (ICD-10: C18–C20) and cerebrovascular disease (ICD-10: C160–C169) as underlying or contributing causes of death. Age-adjusted mortality rates (AAMRs) per 100,000 and annual percent changes (APCs) were calculated via Joinpoint Regression. Analyses were stratified by year, age, sex, race/ethnicity, U.S. census region, and urbanization. Results: Among 48,527 decedents, overall AAMR declined from 1999–2015 (APC: -5.59%; 95% CI: -5.93 to -5.25; P < 0.0001), followed by a modest increase from 2015–2023 (APC: 1.77%; 95% CI: 0.58–2.98; P = 0.006). Females showed a faster increase (2016–2023; APC: 3.12%; 95% CI: 0.79–5.50; P = 0.01) than males (2017–2023; APC: 2.20%; 95% CI: 0.33–4.10; P = 0.02). Adults aged 45–64 experienced the steepest rise (2016–2023; APC: 9.48%; 95% CI: 6.52–12.51; P < 0.0001), whereas trends in those ≥65 remained stable. Racial disparities emerged with significant increases among Black (2018–2023; APC: 6.79%; 95% CI: 2.04–11.76; P = 0.007) and Hispanic populations (2018–2023; APC: 7.87%; 95% CI: 0.83–15.41; P = 0.03). Geographically, the Midwest exhibited the most pronounced rise (2016–2023; APC: 2.32%; 95% CI: 0.82–3.85; P = 0.004), and non-metropolitan areas showed significant increases (APC: 4.15%; 95% CI: 1.85–6.50; P = 0.002), while metropolitan trends were stable. Conclusions: After long-term declines, cerebrovascular mortality among CRC patients has risen since 2015, disproportionately affecting middle-aged adults, women, Black and Hispanic populations, and residents of rural and Midwestern areas. These emerging disparities warrant targeted research and interventions to improve outcomes in high-risk subgroups.
PhaseX as a phase 0.9 translational platform to de-risk BiTE immunotherapy through mechanistic patient explant profiling.
2615 Background: Bispecific T-cell engagers (BiTEs) redirect cytotoxic T cells to tumor cells, but responses in solid tumors remain heterogeneous due to antigen variability, T-cell exclusion, stromal barriers, and immunosuppressive cues within the tumor microenvironment (TME). PhaseX (patient-derived hydrogel-assisted explants) preserves native tissue architecture and endogenous immune composition ex vivo, enabling mechanistic, patient-specific interrogation of immunotherapies in a physiologically relevant context. We used PhaseX to define BiTE mechanism of action (MoA) and resolve response phenotypes in head and neck squamous cell carcinoma (HNSCC). Methods: Tumor explants from ~25 HNSCC patients were ex-vivo cultured in PhaseX and treated for 6 days with CD3×B7-H3 or CD3×EpCAM BiTEs with matched controls. Supernatants were collected longitudinally for multiplex secretome profiling. At endpoint, explants were dissociated and subjected to flow cytometry, while some explants were fixed and processed to FFPE sections for multiplex immunofluorescence (mIF). Cancer cells were quantified using epithelial markers (PanCK and p60). Tumor response states were classified as tumoricidal (increased tumor-cell CC3 [cleaved caspase-3] with reduced PanCK + /p60 + cancer cell burden) versus tumorostatic (preserved PanCK + /p60 + cancer cell burden with reduced Ki-67 in PanCK + /p60 + cancer cells). Results: Across both CD3×B7-H3 and CD3×EpCAM BiTE-treated explants, PhaseX captured core BiTE MoA: (i) TCR-driven activation with expansion of activated CD8 + T cells (CD137 + ) and enrichment of tumor-reactive CD8 + subsets (CD137 + CD103 + CD39 + ); (ii) immune trafficking and inflammatory programming consistent with IFNγ signaling, evidenced by increased CXCL9/10/11 and coordinated effector cytokine signatures; and (iii) effector execution in tissue, integrating increased cytotoxic mediators (perforin, granulysin) with spatial mIF evidence of enhanced intratumoral CD8+ infiltration. Tumoricidal responders showed elevated tumor-cell CC3 with concomitant loss of PanCK + /p60 + tumor area, whereas tumorostatic responders showed decreased tumor-cell Ki-67 expression with comparatively limited CC3 induction, supporting biologically distinct on-treatment states. Conclusions: PhaseX serves as a “Phase 0.9” translational platform that preserves the TME and resolves BiTE MoA from activation to trafficking to effector execution, while distinguishing tumoricidal and tumorostatic response phenotypes. This framework supports mechanistic deconvolution, biomarker discovery, and patient stratification to de-risk bispecific antibody development.
Real-world impact of atrial fibrillation (AFib) on cardiovascular (CV) outcomes and healthcare resource utilization (HCRU) in patients with chronic lymphocytic leukemia (CLL).
7042 Background: While the association between AFib and CLL has been reported, real-world evidence on its clinical and economic impact is limited. This study evaluated impact of AFib on CV outcomes (stroke, bleeding, heart failure) and HCRU in patients (pts) with CLL overall, by age, and by Bruton tyrosine kinase inhibitor (BTKi) therapy. Methods: This retrospective observational study used the US Symphony database to identify adults newly diagnosed with CLL (2014-2024). Pts were followed for 1 year after CLL diagnosis to assess incidence of AFib. Subsequent CV outcomes (stroke, bleeding, heart failure) and HCRU (inpt, outpt, other services) were compared in CLL pts with and without AFib. Multivariate regression analyses assessed associations between AFib and outcomes. Subgroup analyses were conducted in elderly pts aged ≥65 years. Exploratory analyses compared first-line (1L) BTKi use (ibrutinib, acalabrutinib, or zanubrutinib). Results: In 233,362 newly diagnosed CLL pts, 13.1% had AFib within 1 year of CLL diagnosis. A significantly greater proportion of CLL pts with AFib had ≥1 inpt visit within 1 year of CLL diagnosis than those without AFib (54.9% vs 23.2%, P <.0001), as well as a higher likelihood to incur inpt service (OR: 2.28, 95%CI [2.21, 2.35], P <.0001). Significantly higher proportions of CLL pts with AFib had subsequent stroke (14.3% vs 8.9%), bleeding (27.9% vs 19.1%), and heart failure (54.5% vs 18.9%) than those without AFib ( P <.0001). Age ≥65, male, non-white, and AFib were associated with subsequent stroke, bleeding, or heart failure ( P <.01). Results were consistent in pts aged ≥65 years. In pts initiating 1L BTKi, AFib rate within 1 year of treatment for 1L zanubrutinib vs acalabrutinib vs ibrutinib was 11% vs 13% vs 16%, respectively; P <.0001. Compared to 1L ibrutinib and 1L acalabrutinib, a lower proportion of CLL pts with AFib treated with 1L zanubrutinib had subsequent stroke (12.2% vs 9.4% vs 4.8%, respectively), bleeding (27.4% vs 21.5% vs 17.4%), and heart failure (50.9% vs 45.6% vs 39.6%) ( P <.002). CLL pts with AFib treated with 1L zanubrutinib had less inpt services than 1L ibrutinib and 1L acalabrutinib within 1 year of BTKi treatment (46.4% vs 51.5% vs 60.4%; P <.0001). In multivariate regression, 1L acalabrutinib pts had 29% higher odds than 1L zanubrutinib pts (OR: 1.29, 95% CI [1.12, 1.50], P =.0005); 1L ibrutinib pts had 69% higher odds than 1L zanubrutinib pts (OR: 1.69, 95% CI [1.48, 1.93], P <.0001) to incur inpt service within 1 year after initiating BTKi treatment. Conclusions: Findings highlight significant real-world CV and HCRU burden incurred by CLL pts with AFib. Exploratory analyses suggested 1L zanubrutinib may offer potentially favorable outcomes over other BTKi in lessening AFib and related clinical and HCRU complications. Future studies with longer follow-up are warranted to confirm these findings.
Molecular classification of neuroendocrine carcinoma of the bladder.
4628 Background: Neuroendocrine carcinoma (NEC) of the bladder is a rare and aggressive cancer with limited treatment options. Recent studies reported molecular subtypes resembling small cell lung cancer (SCLC), specifically those associated with transcription factors (TFs) ASCL1, NEUROD1, and POU2F3. A subset of bladder NEC remains unclassified. ATOH1 was recently identified as a TF associated with a minority of SCLC tumors. Methods: The Tempus Lens Platform (Tempus AI, Inc., Chicago, IL) was used to query the multimodal de-identified database and establish a cohort of 121 patients with bladder NEC. We analyzed the genomic and transcriptomic profiles using tempusverse and custom code. K-means consensus clustering of gene expression was used to identify molecular subtypes; subsequently, tumor genetic alterations (single-nucleotide variants [SNVs], indels, and copy number alterations [CNAs]) and gene expression profiles were compared across these subtypes. Fisher’s exact test was used to compare the frequency of events across categorical groups. limma-trend and empirical Bayes statistics were used for differential gene expression analysis. The Cox proportional hazards model and the Kaplan-Meier method were used for survival analysis. consensusMIBC was used for the consensus molecular classification. Results: Within the cohort, 103 were classified as neuroendocrine (NE)-like using consensusMIBC and were further analyzed in this study. The median age at diagnosis was 71 years (interquartile range, 63–76), with a male predominance (77%). Using the four SCLC TFs (ASCL1, NEUROD1, POU2F3, and ATOH1; YAP1 was excluded as it was recently found to be expressed in the non-NE components of mixed bladder NECs), we identified a five-type system that classifies most samples: ASCL1+/NEUROD1- (n=37; 36%), ASCL1-/NEUROD1+ (n=23; 22%), ASCL1+/NEUROD1+ (n=16; 16%), POU2F3+ (n=23; 22%), and ATOH1+ (n=4; 4%). Each subtype was associated with a distinct gene expression profile with representative markers: ASCL1 , SOX2 , and DLL3 (ASCL1+/NEUROD1-); NEUROD1 , NEUROD4 , and SSTR2 (ASCL1-/NEUROD1+); ETV1 , NKX2-1 , and NKX2-2 (ASCL1+/NEUROD1+); POU2F3 , GFI1B , and POU2AF2 (POU2F3+); ATOH1 , POU4F3 , and USH2A (ATOH1+). POU2F3+ tumors expressed low NE markers and high PLCG2 and ERBB3 ; ATOH1+ tumors often expressed NE markers and tended to overexpress ALK . No statistically significant tumor SNVs, indels, or CNAs were differentially observed across the subtypes; TP53 (92%), TERT (82%), and RB1 (62%) were the most frequently altered genes in the entire cohort. Univariate analysis showed a worse real-time overall survival of ASCL1+/NEUROD1+ (hazard ratio [HR]=3.1, p=0.01), POU2F3+ (HR=3.4, p=0.001), and ATOH1+ (HR=8.4, p=0.0003), compared with ASCL1+/NEUROD1- tumors. Conclusions: We report an effective, clinically relevant molecular classification system for bladder NECs, including the newly described ATOH1+ subtype.
Real-world risk-assessment using the Mirai breast cancer risk prediction model: A preliminary analysis of patients from a comprehensive cancer screening clinic.
e22560 Background: The current standard of care for breast cancer risk assessments is the Tyrer-Cuzick (TC) model, which requires clinical variables including family history, hormone exposure and breast density. Mirai, a validated artificial intelligence program designed to determine breast cancer risk based solely on mammographic images, requires less clinical data and predicts the probability that a woman will develop breast cancer over the next five years. Our study aims to describe Mirai performance on mammograms from a sample of women that were seen for a breast cancer risk assessment in a comprehensive cancer screening clinic within a large health system. Methods: This preliminary descriptive analysis includes 84 identified women with mammograms available for Mirai analysis and an available TC lifetime risk estimate of developing breast cancer. All patients were seen between 12/2021 and 6/2023. Women with known pathogenic variants or hereditary cancer syndromes and those with prior breast cancer diagnoses, including DCIS, were excluded. Probabilities from the Mirai model were categorized as low risk ( < 1.8%), and then intermediate or high-risk based on the median cut-point of probabilities > 1.8%. TC lifetime risk estimates were categorized as low ( < 20%), intermediate (20% - < 40%), or high ( > 40%). Mirai results were compared to TC model results and the percentage of patients who would have a change in risk level based on using Mirai instead of TC was assessed. Results: Patients had an average age of 47 years (range: 29-72 years) and 64% were White, 13% were Asian, 7% were Black/African-American, and 15% were of unknown or another race. Lifetime breast cancer risk estimated from the TC model ranged from 6.4%-56.0% with 19.0% of patients categorized as low-risk (n = 16), 71.4% as intermediate risk (n = 60), and 9.5% as high-risk (n = 8). Comparatively, 5-year risk prediction estimates from Mirai ranged from 0.97%-5.3% with 67.9% (n = 57), 17.9% (n = 15), and 14.3% (n = 12) categorized as low, intermediate, and high-risk, respectively. Overall, 29.8% of patients (n = 25) were concordant in the assigned risk category from the TC and Mirai models. Of the 59 (70.2%) patients that had a discordant risk assessment category, 47 (79.7%) were found to be at a lower risk by the Mirai model compared to their TC score. Twelve (20.3%) patients undergoing Mirai had a higher risk compared to their TC score. Conclusions: These preliminary results from patients seen for a breast cancer risk assessment suggest an overall modest concordance in assigned risk assessment categories. The Mirai model demonstrates its potential in deescalating short-term breast cancer screening in a majority of patients seen in a high-risk clinic by using a shorter-interval, more accurate risk estimate that does not rely on historical data. Larger trials are needed to prospectively validate these findings.
Urinary tumor DNA as a biomarker of pathologic response and molecular residual disease in muscle-invasive bladder cancer: A systematic review.
e15055 Background: Despite advances in multimodal therapy, recurrence after curative-intent treatment for muscle-invasive bladder cancer (MIBC) remains common. Urine-derived tumor DNA (utDNA)represents a non-invasive biomarker that may refine risk stratification, predict treatmentresponse, and detect molecular residual disease (MRD). We systematically reviewed the clinicalutility of utDNA in non-metastatic MIBC. Methods: Following PRISMA guidelines and a pre-registered protocol (PROSPERO: CRD420251147550),PubMed, Embase, Scopus, and clinicaltrials.gov were searched through October 2025 withoutlanguage restriction. Eligible studies enrolled adults with non-metastatic MIBC undergoingdiagnostic evaluation, radical cystectomy (RC), or bladder-preserving therapy, evaluatingutDNA. Screening, data extraction, and quality appraisal were performed independently induplicate using the Newcastle–Ottawa Scale (NOS), QUADAS-2, and GRADE frameworks. Results: Of 245 screened records, eight studies comprising 306 patients met inclusion criteria. Overallmethodological quality was moderate, with all studies observational and heterogeneous inassay platforms, urine fractions analyzed, timing of sample collection, and outcome definitions.Urinary tumor DNA was consistently detectable across cohorts, with detection rates generallyhigher than matched plasma ctDNA. Across studies, utDNA positivity—particularly afterneoadjuvant therapy or prior to definitive treatment—was associated with residual pathologicdisease, absence of pathologic complete response, and lower rates of pathologic downstaging.Longitudinal analyses further demonstrated that persistence or rising utDNA levels correlatedwith worse oncologic outcomes, while declining utDNA burden paralleled treatment response.Despite heterogeneity and limited sample sizes, the direction of association between utDNApositivity and adverse pathologic or prognostic outcomes was consistent across studies. Conclusions: Urinary tumor DNA demonstrates feasibility and promising diagnostic,predictive, and prognostic value in MIBC. Standardization of assay platforms and multicentervalidation are needed before integration into MRD-guided clinical decision-making.
Hepatic artery infusion chemotherapy plus adebrelimab and bevacizumab as first-line treatment for advanced hepatocellular carcinoma with portal vein tumor thrombus.
e16165 Background: Advanced-stage hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is usually associated with poor survival outcomes. There are currently few clinical therapy options available for individuals with PVTT, who frequently have rapid disease progression, reduced hepatic reserve, and very low overall survival. This study aimed to evaluate the effectiveness of bevacizumab and PD-L1 inhibitors (adebrelimab) in conjunction with hepatic arterial infusion chemotherapy (HAIC) as a first-line treatment for HCC patients with PVTT. Methods: This single-arm, prospective study plans to enroll 35 patients with HCC who have not been systematically treated. Patients was treated with HAIC (every 3 weeks for up to 6 treatments) combined with adebrelimab (20mg/kg,d1, iv, Q3W) and bevacizumab (15 mg/kg, iv, Q3W). Tumor response was assessed using both RECIST 1.1 and mRECIST criteria. Survival outcomes were analyzed using Kaplan-Meier methods. The primary endpoint is progression-free survival (PFS), while secondary endpoints comprised objective response rate (ORR), overall survival disease (OS), control rate (DCR), time to progression (TTP) and Duration of response (DoR). Results: 29 patients were enrolled from February 17, 2025, to January 12, 2026. The median age was 54 years (range: 34-70), the majority were male (89.3%). In all the patients, 96.6% (28/29) had HBV infection, 58.6% (17/29) and 41.1% (12/29) had PVTT classified as Vp3 and Vp4. The median PFS and OS were not reached. According to mRECIST, among the 17 patients evaluated for tumor response, 1 (5.9%) achieved complete remission (CR), 4 (23.5%) achieved partial remission (PR), 9 (52.9%) had stable disease (SD), and 3 (23.5%) experienced disease progression (PD). The ORR was 29.4% (5/17) and the DCR was 82.4% (14/17) . 11 patients (37.9%) experienced graded 1/2 adverse events. 1 patient (3.4%) suffered a grade 3/4 adverse event. The most common grade 1/2 adverse events were fatigue (3/29, 10.3%), fever (2/29, 6.9%), proteinuria (1/29, 3.4%), decreased platelet count (1/29, 3.4%), and gastrointestinal reactions (1/29, 3.4%). The single grade 3 adverse reaction was hepatic impairment. No treatment related death was observed. Conclusions: The combination of hepatic artery infusion chemotherapy, adebrelimab and bevacizumab, showed promising efficacy and manageable toxicity for the first line treatment of locally advanced hepatocellular carcinoma with portal vein tumor thrombus. Clinical trial information: ChiCTR2400094431.
Experimental and quantitative observational research in fencing and wheelchair fencing: A scoping review
Background Fencing and wheelchair fencing are Olympic and Paralympic sports with growing global participation and increasing scientific interest. However, the overall structure, methodological profile, and thematic distribution of experimental and quantitative observational research in both has not been systematically characterized. Objective To map the scope, methodological characteristics, and thematic focus of experimental and quantitative observational studies involving fencing and wheelchair fencing athletes. Methods A scoping review was conducted in accordance with PRISMA-ScR guidelines. PubMed, Scopus, and EBSCOhost were searched for studies containing the terms “fencing,” “fencer,” or “fencers” in the title or abstract. Eligible studies employed experimental or quantitative observational designs and included fencing athletes as participants. Data were extracted using a structured framework and summarized descriptively across study design, research domain, participant characteristics, sample size, weapon discipline, and geographic distribution. Results A total of 445 studies met inclusion criteria. Publication volume increased substantially after 2015. Laboratory-based (35.7%) and cross-sectional (30.3%) designs predominated, whereas prospective cohort studies (5.4%) and randomized controlled trials (4.3%) were comparatively uncommon. Performance and skill analysis constituted the largest research domain (41.1%), while injury/epidemiology (7.9%), recovery/rehabilitation (4.3%), and training load/fatigue (1.6%) research were limited. Most studies involved small sample sizes with fewer than 50 participants and focused on able-bodied athletes; wheelchair fencing was markedly underrepresented. Sex was not specified in 24.3% of studies, and weapon discipline was not reported in 44.9%. Research output was geographically concentrated in Europe and select North American and East Asian countries. Conclusions Although fencing research has expanded rapidly in recent years, it remains methodologically and thematically uneven. Greater emphasis on longitudinal and interventional designs, injury surveillance, rehabilitation research, improved reporting practices, and inclusive representation across sex, weapon discipline, geographic regions, and wheelchair athletes are necessary to strengthen the translational relevance and evidence-based development of fencing sport science.