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Factors influencing the selection of CheckMate-9LA (nivolumab, ipilimumab, and chemotherapy) regimen in AGA-negative advanced NSCLC.
e20667 Background: The treatment of advanced non-small cell lung cancer (aNSCLC) without actionable genomic alteration (AGA) has seen significant improvement with the introduction of immunecheckpoint inhibitors. However, challenges persist in selecting the optimal first-line (1L) treatment regimen. This study aims to identify clinical, pathological, and non-clinical factors influencing the selection of the CheckMate 9LA (CM9LA) regimen (nivolumab and ipilimumab with chemotherapy) through a retrospective chart review and a brief clinician survey at a Canadian academic centre. Methods: This retrospective observational cohort study included adults with AGA-negative aNSCLC treated with the CM9LA regimen at a tertiary care centre between May 2020 and July 2025. Data were extracted from electronic medical records (EMRs), and a brief clinician survey assessed decision-making regarding CM9LA selection. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods, with exploratory stratified analyses and Univariate Cox regression to evaluate associations with baseline factors. Concordance between survey-derived decision-making themes and observed clinical characteristics was assessed descriptively. Statistical analyses were performed using IBM SPSS Statistics, and p-values < 0.05 were considered statistically significant. Results: Thirty-six patients with AGA-negative aNSCLC received 1L CM9LA. The median age at diagnosis was 66.5 years, with a male predominance (72%). Most patients (89%) had an ECOG status of 0-1, and > 90% had a history of smoking. Almost evenly split between adenocarcinoma (44%) and squamous cell carcinoma (39%), the majority (55.6%) were PD-L1 negative. Most patients (94%) had ≥ 2 visceral metastases, commonly in bone (39%) and brain (25%). Median follow-up was 20.2 months, with median PFS of 12.1 months and OS of 18.1 months. Worse outcomes were observed in patients with brain metastasis (p = 0.01) and squamous histology (p = 0.01), and were associated with lower albumin (p = 0.03), higher LDH (p = 0.03), and greater visceral metastatic burden (p = 0.02). Treatment preference documentation was present in 64% of cases and was not related to differences in survival. Clinician survey responses indicated that CM9LA selection was driven by perceived survival benefit, squamous histology, limited chemotherapy exposure, patient willingness and favourable fitness, with concordance between survey themes and real-world use in patients with good performance status, while PD-L1 expression was less decisive. Conclusions: The selection of CM9LA in real-world practice is influenced by patient fitness, disease burden, practical considerations, and clinician decision-making, with survey responses aligning with observed practice and outcomes, thereby supporting individualized treatment decisions.
Development and evaluation of a novel digital pathology image analysis pipeline for prediction of clinical outcomes with the TROP2-directed antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) in triple-negative breast cancer (TNBC).
1026 Background: Digital pathology (DP), including artificial intelligence (AI)-based image analysis methods, enables IHC biomarker assessment on a continuous scale, potentially improving precision and accuracy versus conventional IHC scoring. DP may also capture features relevant to ADC response that traditional methods miss. As proof of concept, we developed and evaluated an AI-assisted DP image analysis pipeline to explore the association between target antigen expression and clinical outcomes of sac-TMT, a TROP2-directed ADC with a unique bifunctional linker, in TNBC. Methods: We analyzed whole-slide images of IHC-stained tumor samples from participants with TNBC enrolled in the phase 1/2 MK-2870-001 study (NCT04152499) evaluating sac-TMT in pretreated advanced solid tumors. We established a set of prespecified human-interpretable features (HIFs), including IHC signal intensity, subcellular localization, and spatial patterns of cell and signal distribution. To mitigate overfitting, we prioritized a subset of 35 HIFs based on correlation structure and biological hypotheses, and in a blinded fashion, assessed their association with clinical outcomes (BOR; PFS) in a development cohort (DC) (n = 58). After unblinding clinical outcome data, additional HIFs and a multivariate model trained to predict clinical outcomes in the DC were prioritized for validation. Both sets of HIFs (identified from blinded and unblinded analyses) were assessed for their relationship to clinical outcomes in an independent validation cohort (IVC) from the same study (n = 34). In both cohorts, DP HIFs were compared with conventional TROP2 H-scores (on paired slides) for prediction of clinical outcome using the area under the receiver operating characteristic curve (AUROC) and Harrell C-index. Results: The blinded approach identified a HIF that was positively associated with BOR (multiplicity-adjusted P = 0.023), with an AUROC higher than TROP2 H-scores (0.76 vs 0.70). After unblinding, 5 additional HIFs and a multivariate model were selected for their associations with BOR (AUROC, 0.70-0.80). In the IVC, the 6 prioritized HIFs and 1 multivariate model were associated with response to sac-TMT (AUROC, 0.60-0.69); each outperformed TROP2 H-scores with respect to association with BOR (H-score AUROC, 0.57) and demonstrated incrementally better association with PFS than TROP2 H-scores (Harrell C-index, 0.64-0.66 vs 0.62). Conclusions: In this proof-of-concept study, DP-derived HIFs were associated with response to sac-TMT in TNBC and showed incrementally better nominal performance than conventional TROP2 H-scores. While the sample size was small, data from this study suggest that DP-based image analysis can identify novel biomarkers of response to sac-TMT in TNBC.
Spatially organized immune niches in high-grade primary prostate cancer.
5118 Background: Prostate cancer (PC) has historically been considered immunologically “cold” due to low immune infiltration and a predominantly immunosuppressive tumor microenvironment (TME). However, this understanding is largely based on immune profiling studies of metastatic castration-resistant prostate cancer and may not apply in earlier stages of disease. The composition and organization of the immune TME in primary PC remains poorly defined, especially in relation to Gleason score, the gold standard of pathologic PC grading. We hypothesized that the local PC immune TME is more heterogeneous than previously appreciated, with differences in immune composition and spatial organization between High Gleason (HG) and Low Gleason (LG) PC. Methods: We analyzed 29 radical prostatectomy samples (15 LG vs. 14 HG) using a 40-marker multiplex immunofluorescence panel to profile the TME at single-cell resolution. Immune cell phenotypes were defined with respect to the marker panel. Using R, cell composition was computed within tumor, stroma, and tertiary lymphoid structures (TLS, organized aggregates of immune cells that resemble secondary lymphoid organs) and within defined boundary regions at interfaces between each compartment. Results: We discovered that HG PC exhibited higher total immune infiltration (p < 0.05) and specifically TLS (p < 0.05) relative to LG PC. Furthermore, advancing Gleason grade was associated with increased T cell infiltration (p < 0.05) and M2-like macrophage density (p < 0.05). Strikingly, TLS were enriched in exhausted (PD1+) CD4 and CD8 T cells, especially near Tregs (p < 0.001) and demonstrated a higher M2-like to M1-like macrophage ratio compared to surrounding tumor (p < 0.001) and stroma (p < 0.05). We observed paradoxically increased proportions of CD4PD1 cells (p < 0.05) and Tregs (p < 0.05) in HG vs. LG samples at the tumor-TLS interface. In HG samples, CD8PD1 cells (p < 0.01), CD4PD1 cells (p < 0.05), and Tregs (p < 0.05) were enriched in tumor-TLS interface relative to TLS-stroma interface. HG tumors also demonstrated a higher ratio of M2-like to M1-like macrophages at the tumor-TLS interface compared to intra-tumoral regions (p < 0.05). Conclusions: Our findings challenge the notion that primary PC is uniformly immunologically inert. We show that HG PC has increased levels of immune infiltration. We describe a paradoxical TLS phenotype in HG PC, where TLS harbor high levels of exhausted T cells near Tregs and have an unfavorable macrophage composition. Critically, the tumor-TLS interface emerged as a unique niche of suppression in HG PC, demonstrating multiple features of lymphocytic and myeloid-driven immunosuppression. These immunosuppressive features were not seen in LG PC. The spatial organization of immunosuppressive cells in HG PC provides a rationale for novel immunotherapeutic targeting of the TLS-rich suppressive landscape of HG PC to improve clinical outcomes in the neoadjuvant setting.
Disruption of the ATAD3A-VDAC1 complex to enhance anti-tumor immunity and response to immune checkpoint blockade in lung adenocarcinoma.
e20623 Background: Elucidating the role of mitochondrial function in anti-tumor immunity is crucial for improving the efficacy of immunotherapy. ATAD3A is a mitochondrial protein, but its mechanism of action in regulating tumor immunity remains unclear. This study aimed to investigate whether and how ATAD3A affects the response to immunotherapy in lung adenocarcinoma (LUAD). Methods: This study integrated clinical data analysis from multi-center LUAD patient cohorts, in vitro and in vivo gene-editing models, immune cell flow cytometry analysis, co-immunoprecipitation, protein domain mapping, and site-directed mutagenesis. Furthermore, a blocking peptide (0123–A1) was designed based on the structural mechanism, and its effects on anti-tumor immunity and immunotherapy efficacy were evaluated in cell lines and mouse xenograft models. Results: Clinical data analysis revealed that low ATAD3A expression was significantly associated with improved prognosis in LUAD patients following treatment with immune checkpoint inhibitors (ICIs). Mechanistically, the deletion of ATAD3A in cancer cells promoted the infiltration of anti-tumor CD274⁺ macrophages characterized by strong phagocytic capacity and potential for CD8⁺ T cell activation. ATAD3A directly binds to the 100-200 amino acid region of the VDAC1 protein, inhibiting its oligomerization and subsequent release of mitochondrial DNA into the cytosol. A key site mutation (D73A) completely abolished this interaction. The designed blocking peptide 0123–A1, based on this mechanism, effectively disrupted the ATAD3A-VDAC1 complex, significantly enhancing anti-tumor immune responses and improving the efficacy of immunotherapy both in vitro and in vivo. Conclusions: This study identifies ATAD3A as a key mitochondrial immune regulator in LUAD, which impairs anti-tumor immunity by binding to and inhibiting VDAC1 function. Strategies targeting the disruption of the ATAD3A-VDAC1 interaction can effectively reshape the tumor immune microenvironment and enhance the response to immunotherapy. This provides a novel potential therapeutic target and combination strategy for LUAD patients.
Tuning CAR-T cell response with <i>TNFAIP3</i> variants.
e14527 Background: The clinical success of Chimeric Antigen Receptor (CAR)-T cell therapy is frequently limited by two major, interconnected challenges: T cell exhaustion and subsequent tumour-mediated immune escape associated with chronic antigen stimulation, which represent strategic opportunities to improve therapeutic outcomes. Global deletion of TNFAIP3 is embryonically lethal in animal models and haploinsufficiency is poorly tolerated in humans, while selective loss of TNFAIP3 in immune cells confers protection to infections rather than detriment due to a reduction in the immune threshold response boosting immune stimulation. Further to this, we have previously shown that coding gene variants of TNFAIP3 can modify protein enzymic function and hence tune the level of TNFAIP3’s anti-inflammatory effect – contrasting the classical view that TNFAIP3 acts a binary control point. We propose the strategic engineering of CAR-T cells with specific TNFAIP3 variants will enhance CAR-T cell efficacy, overcome exhaustion, and improve therapeutic persistence. Methods: Here we tested the impact of two reduction of function TNFAIP3 variants on CAR-T response. Variant-1 was identified from our ongoing functional genomic screen of super responders to checkpoint inhibition therapy; Variant-2 was reported in a family with hereditary inflammatory disease and validated by us as a reduction of function variant in functional studies. We genetically modified human T cell lines and primary T cells to express variant-1 or variant-2 with an anti-CD19 directed CAR and investigated their impact on CAR-T cell activation and function. For this study, we designed a CAR construct based on 3 rd generation parameters. Results: Modifying CAR-T cells with TNFAIP3 variant-1 and variant-2 led to robust upregulation of NF-κB signalling and increased stimulus dependent levels of NF-κB target genes. Modified cells showed significantly higher levels of activation and migration marker expression with enhanced secretion of key effector cytokines compared to control CAR-T cells. Quantitatively, the tested TNFAIP3 variants enhanced cytotoxic ability above baseline in static assays systems. Current experiments are focused on investigating real-time target cell death kinetics upon engagement with tumour cells (high content imaging). Conclusions: Our data supports the hypothesis that TNFAIP3 variants can successfully tune CAR-T cell response by lowering the CAR-T cell activation threshold for more favourable anti-tumour outcomes.
Impact of diabetes on respiratory infection risk and hospitalization following immune checkpoint inhibitor initiation in non–small cell lung cancer: A propensity-matched retrospective cohort analysis.
11187 Background: Immune checkpoint inhibitors (ICIs) are a cornerstone of treatment for non-small cell lung cancer (NSCLC); however, patients with diabetes mellitus may have altered immune responses and higher susceptibility to infections. Data comparing infectious respiratory outcomes, healthcare utilization, and mortality between diabetic and non-diabetic NSCLC patients treated with ICIs is limited. We aimed to evaluate these outcomes in NSCLC patients receiving ICIs, stratified by diabetes status. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Adults (≥18 years) diagnosed with NSCLC who initiated immune checkpoint inhibitor therapy (PD-1/PD-L1 or CTLA-4 inhibitors) within one year of diagnosis were included. Two cohorts were defined: patients with type 2 diabetes mellitus (DM) and patients without diabetes (non-DM). Propensity score matching (1:1) was performed based on demographics, comorbidities, cancer stage surrogates, smoking history, chemotherapy exposure, radiation therapy, and concurrent medications. Outcomes were assessed from 30 days to 3 years after ICI initiation and included bacterial pneumonia, viral pneumonia, severe sepsis with or without shock, ER visit/hospitalization, critical care needs, and overall survival. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. Results: After propensity score matching, 905 patients were included in each cohort. Baseline characteristics were well balanced between groups. Compared with the non-DM cohort, patients with diabetes had a significantly higher risk of severe infectious complications, including bacterial pneumonia (HR 1.44, 95% CI 1.01–2.08), severe sepsis (HR 1.79, 95% CI 1.29–2.49). Rates of viral pneumonia did not significantly differ between groups (HR 0.79, 95% CI 0.45-1.38). Diabetic patients also demonstrated higher incidence of hospitalization (HR 1.17, 95% CI 1.05–1.30) and critical care utilization (HR 1.27, 95% CI 1.02–1.57). However, no statistically significant difference in overall survival between cohorts was detected (HR 1.12, 95% CI 0.98–1.29). Conclusions: Among NSCLC patients treated with immune checkpoint inhibitors, diabetes mellitus is associated with higher risk of respiratory infections and severe sepsis. Hospital visits and critical care utilization were more frequent in the diabetic cohort, without a corresponding difference in overall survival. These findings highlight the importance of heightened infection surveillance and proactive supportive care in diabetic patients undergoing immunotherapy. Prospective studies are warranted to better define underlying mechanisms and to optimize risk mitigation strategies in this vulnerable population.
Variations in ambient airborne carcinogen concentrations (particulate matter; PM <sub>2.5</sub> ) in urban neighborhoods in Rhode Island.
e22514 Background: Fine particulate matter smaller than 2.5 μm in diameter (PM 2.5 ) carries toxic substances including sulfates, hydrocarbons, and heavy metals, penetrating the lungs and bloodstreams. PM 2.5 is associated with increased incidence of lung cancer, and the World Health Organization (WHO) air quality guidelines set acceptable exposure at 5 μg/m 3 annual average and 15 μg/m 3 for the 24-hour limit, not to be exceeded more than 3-4 days yearly. Currently, the United States Environmental Protection Agency defines the standard for PM 2.5 at 9.0 μg/m 3 (annual average) and 35 μg/m 3 (daily limit). Methods: The Breathe Providence Project was created by Brown University researchers to characterize neighborhood-scale air quality. Twenty-five locations across the city of Providence, Rhode Island were selected based on Air Quality Vulnerability Index scores and proximity to high foot traffic public institutions. Environmental Air-Quality and CO2 Network sensor nodes measured local PM 2.5 levels throughout 2023. Data were analyzed as daily, weekly, and monthly averages, and stratified by daytime (5AM to 5PM) and nighttime (5PM to 5AM). Results: In 2023, PM 2.5 daily average values ranged from 1 to 10 μg/m 3 from January to May, with monthly averages of 1 to 3 μg/m 3 . PM 2.5 values peaked during the summer months of June to August, with daily averages as high as 36 μg/m 3 and weekly and monthly averages up to 16 and 9 μg/m 3 , respectively. During these summer months, there were 17 days for which the daily average levels exceeded the WHO daily limit of 15 μg/m 3 . From September to December, daily average values ranged 1 to 16 μg/m 3 , with monthly averages of 4 to 6 μg/m 3 , demonstrating an overall increase in air pollution levels through the year. Nighttime PM 2.5 concentrations were typically 1 to 2 μg/m 3 higher than daytime values. Conclusions: There was seasonal and diurnal variability in PM 2.5 in Providence, with multiple exceedances of WHO guidelines in 2023. Elevated nightly values likely reflect stagnant atmospheric conditions, and the summer peaks may be due to record-breaking 2023 Canadian wildfires, which affected air quality across the eastern United States. The state of Rhode Island has a significantly higher incidence rate of lung cancer of 59 per 100,000, exceeding the national rate of 53. Our study highlights the higher PM 2.5 averages during summer months and the evening, which may be contributing to the higher lung cancer incidence in Rhode Island. Larger studies are needed to investigate this correlation. We propose geospatial mapping of PM 2.5 exposure across different regions in the state, with careful regional quantification of long-term PM 2.5 levels and correlating with lung cancer incidence. These studies could inform us of the spatial patterns of lung cancer risk and help formulate mitigation strategies and actionable maps for health systems and policymakers.
A translational approach for in vitro monitoring of patient-derived tumor organoid responses to anti-cancer treatments.
e15610 Background: Patient-derived organoids are often considered the 3D in vitro models that accurately recapitulate the architectural, biochemical, and biophysical features of human cancers compared to conventional cultures. Colorectal cancer (CRC) is a major global health burden, underscoring the urgent need for more predictive preclinical and patient-related models. Yet, the increased physiological relevance of 3D models introduces critical challenges for monitoring therapeutic responses, including limited optical accessibility, pronounced spatial heterogeneity, and the incompatibility of conventional endpoint assays originally designed for monolayer cultures. These limitations impede real-time, very low invasive, and functionally relevant assessments of drug efficacy, thereby reducing the predictive value of in vitro models in CRC research and clinical development. Methods: We developed an innovative in vitro platform that integrates CRC organoids with sensory neurons functioning under a “Neuron-as-a-Sensor” (NaaS) paradigm. In this approach, living neurons act as biological transducers, detecting and integrating tumour-derived biochemical and functional signals, and translating them into quantifiable electrophysiological signatures. The platform comprises a compartmentalized microfluidic device incorporating a customized microelectrode array (MEA), designed to spatially organize co-cultures of patient-derived CRC organoids embedded in a neuro-conductive hydrogel alongside sensory neurons. Results: CRC organoids were derived from a moderately differentiated metastatic adenocarcinoma (left colon, wild-type RAS/RAF, MSS), partially responsive to neoadjuvant treatment (ypT4 N1 M+). We observed robust, spatially organized interactions between neuronal projections and CRC organoids, consistent with an innervated tumour structure. Next, clinically relevant anti-CRC mono and combination therapies were applied, while the therapeutic efficacy was monitored by neuronal activity. MEA recordings revealed statistically significant treatment-dependent alterations in neuronal network activity compared to untreated controls. Notably, robust discrimination between treatment effects required the integration of multiple electrophysiological metrics, enabling the generation of multidimensional response maps that captured distinct therapeutic signatures. Conclusions: This work demonstrates the feasibility and value of a neuron-as-a-sensor strategy for label-free, real-time monitoring of therapeutic responses in complex 3D tumour models. By coupling patient-derived CRC organoids with neuronal biosensors in a microfluidic MEA platform, we provide a scalable, functionally rich approach with strong potential to enhance preclinical drug evaluation and improve the translational relevance of advanced in vitro CRC models.
Real-world inpatient outcomes in Hispanic patients with primary HCC/biliary tract cancer: A retrospective cohort study of admission MELD-Na and hospital mortality, ICU use, and length of stay (2019–2025).
e16303 Background: Hepatic reserve is a key determinant of outcomes in hospitalized hepatocellular carcinoma (HCC) and biliary tract cancers (BTC), yet inpatient risk stratification in Hispanic-majority settings is not well described. We evaluated whether liver function scores obtained at presentation predict in-hospital outcomes and resource utilization. Methods: We conducted a retrospective cohort study of adults admitted with primary HCC or BTC in Hispanic patients from January 2019 through December 2025. We excluded patients < 18 years, those with non-primary liver/biliary malignancy, emergency department visits with discharge, and patients who left against medical advice. For individuals with multiple admissions, only the earliest eligible hospitalization was included. Baseline laboratories were defined as the first values at presentation. MELD-Na and ALBI were calculated from admission data. The primary endpoint was in-hospital mortality; secondary endpoints included ICU admission and length of stay (LOS). Outcomes were compared across MELD-Na categories (< 15, 15–24, ≥25). Logistic regression evaluated the association between MELD-Na and in-hospital mortality with limited adjustment (age and sepsis). Predictive performance was assessed using ROC/AUC. Results: We included 125 patients (100% Hispanic; mean age 63.9 years; 36.8% female): 90 (72%) with HCC and 35 (28%) with BTC. ICU admission occurred in 37 (29.6%) and in-hospital mortality in 10 (8.0%); median LOS was 2 days. Mortality increased with MELD-Na: 0/66 (0%) for < 15, 2/36 (5.6%) for 15–24, and 8/23 (34.8%) for ≥25 (p < 0.001). ICU admission also increased across categories (15.2%, 38.9%, 56.5%; p < 0.001), with longer LOS (median 1, 3, and 4 days). In adjusted analysis, each 5-point increase in MELD-Na was associated with higher odds of in-hospital mortality (OR 2.47, 95% CI 1.58–3.86; p < 0.001). ROC analysis yielded AUC 0.947. As a secondary finding, ALBI grade 3 was associated with higher in-hospital mortality than grade 2 (19.1% vs 1.4%; p≈0.002). Conclusions: In this Hispanic patient cohort admitted with primary HCC/BTC, admission MELD-Na was associated with in-hospital mortality, ICU utilization, and LOS, and showed strong predictive performance for in-hospital mortality. Because MELD-Na is derived from routinely available admission laboratories, it may be useful for early inpatient risk stratification, resource planning, and timely goals-of-care discussions during hospitalization. These findings also support the applicability of MELD-Na–based risk assessment in Hispanic patients with hepatobiliary malignancies.
Relationship between GLP-1 receptor agonists on cancer recurrence and survival of patients with stage I-III colorectal cancer: A retrospective cohort study using the TriNetX database.
3636 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, and obesity is a known risk factor. Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly used for obesity and diabetes management, making it critical to understand their long-term implications. Preclinical studies suggest a protective effect of GLP-1RA in risk for developing obesity-related malignancies, including CRC, but their long-term influence on recurrence and survival among those with CRC is not well characterized. Methods: A retrospective cohort study was conducted using TriNetX, a federated health research network of real-world data. Data were queried on January 22, 2026, from the Global Collaborative Network, encompassing over 190 million de-identified electronic medical records. Adult patients (> 18 years) with a diagnosis of stage I-III CRC between April 1, 2005, and April 1, 2025, were identified. The exposure group was defined as patients prescribed GLP-1RA following their CRC diagnosis. The control group was GLP-1RA nonusers. Propensity score matching (PSM) was employed, achieving balance across demographics, comorbidities, and confounding variables. The primary outcome was recurrence free survival (RFS), and the secondary outcome was overall survival (OS). Kaplan–Meier survival analysis, log-rank test, hazard ratios (HR) with 95% confidence intervals (CI), and risk ratios (RR) were used to estimate outcomes over 5-years of follow-up. Results: Among 20,383 patients with CRC across 19 HCOs, 839 patients per group with mean age 63.0 years remained after 1:1 PSM and exclusions, with comparable median follow-up times (710 vs 1160 days). GLP-1RA use was significantly associated with a lower risk of recurrence compared with nonusers (RR, 0.33; 95% CI, 0.25-0.45; p < 0.001) and improved RFS probabilities (89.0% vs 72.8%; [HR, 0.37; 95% CI, 0.27-0.50; p < 0.001]) at the 5-year follow-up. A significant improvement in OS was also observed in GLP-1RA users compared with nonusers (82.5% vs 71.4%; [HR 0.45; 95% CI, 0.34-0.60; p < 0.001]), and reduced mortality risk (RR, 0.35; 95% CI, 0.27-0.46; p < 0.001) compared with nonuse. Secondary analysis with 15-year median follow-up period demonstrated that these survival and recurrence benefits were sustained long term with median OS of 4,382 and 3,931 days in GLP-1RA users vs nonusers respectively. Conclusions: In this real-world analysis, GLP-1RA use in patients with stage I-III CRC was associated with improved RFS and OS compared to nonusers. These findings were consistent across both 5-year and 15-year follow-up periods, demonstrating a sustained association with improved outcomes in CRC. Prospective trials are needed to strengthen the evidence base for GLP-1RA use in patients with CRC and to define the underlying biological mechanisms.
CCL3 <sup>+</sup> neutrophil signature as a predictor of response to neoadjuvant toripalimab plus chemotherapy in hypopharyngeal squamous cell carcinoma: A phase II trial.
6116 Background: Hypopharyngeal squamous cell carcinoma (HPSCC) has a poor prognosis. Although neoadjuvant chemoimmunotherapy (nCIT) is promising, responses are heterogeneous and PD-L1 combined positive score (CPS) inadequately stratifies benefit. We sought biomarkers to guide patient selection. Methods: In this prospective, single-center, single-arm phase II trial, patients with resectable locally advanced HPSCC received two cycles of neoadjuvant toripalimab, albumin-bound paclitaxel, and nedaplatin. The primary endpoint was the pathological complete response (pCR) rate. Pre-treatment tumor biopsies from a subset of patients (n=13) were analyzed by single-cell RNA sequencing (scRNA-seq) to identify determinants of response. Findings were validated in a larger cohort (n=60) using bulk RNA sequencing and immunohistochemistry. Results: Among 70 evaluable patients, the objective response rate was 82.7%. Of the 64 patients who underwent surgery, the pCR rate was 29.7% (95% CI, 18.9%–42.7%). Baseline PD-L1 CPS was not associated with pathological response (P=0.313). Single-cell analysis revealed that the pre-treatment tumor microenvironment of responders was significantly enriched with a pro-inflammatory neutrophil subset characterized by high expression of CCL3 (Neu_CCL3). A gene signature score derived from this subset was a strong and independent predictor of pCR (AUC = 0.788), significantly outperforming PD-L1 CPS (AUC = 0.621). Conclusions: The efficacy of nCIT in HPSCC is predetermined by a baseline immune architecture orchestrated by a CCL3+ neutrophil subset. The Neu_CCL3 gene signature is a promising, clinically translatable biomarker that can fill a critical gap in precision immunotherapy for HPSCC. Clinical trial information: ChiCTR2400081826.
The role of adjuvant chemotherapy in high-risk stage II colon cancer with microsatellite instability-high or DNA mismatch repair deficiencies: A multicenter pooled analysis (KCSG-CO24-03).
3622 Background: The benefit of adjuvant chemotherapy (CTx) for high-risk stage II MSI-H/dMMR colon cancer remains controversial, with discordant international guidelines. This study evaluated clinical outcomes comparing adjuvant CTx vs. observation in this population. Methods: This multicenter retrospective analysis included 192 patients with high-risk stage II MSI-H/dMMR colon cancer who underwent curative resection (2010-2020). High-risk features included pT4, grade 3-4, lymphovascular invasion, bowel obstruction/perforation, perineural invasion (PNI), inadequate lymph node sampling (<12), or close margins. Primary endpoint was 5-year relapse-free survival (RFS). Secondary endpoints included 5-year overall survival (OS). A propensity score-matched (PSM) analysis was performed. Results: Of 192 patients, 128 (66.6%) received adjuvant CTx (FOLFOX n=66, capecitabine n=40, FL n=17, others n=5) and 64 (33.3%) underwent observation. Median follow-up was 60.5 months. During follow-up, 24 RFS events and 15 OS events occurred. The 5-year RFS was significantly higher with adjuvant CTx versus observation (94.0% vs. 83.7%; P=.001), as was 5-year OS (98.3% vs. 89.0%; P=.001). Multivariate analysis confirmed adjuvant CTx as an independent prognostic factor for both RFS (HR 0.278, 95%CI 0.117-0.660; P=.003) and OS (HR 0.176, 95%CI 0.052-0.594; P=.005). PNI independently predicted worse RFS (HR 4.053; P=.002) and OS (HR 7.490; P=.001). Subgroup analysis demonstrated pronounced benefit in pT4 patients (OS HR 0.094, P=.031; RFS HR 0.230, P=.038) and significant benefit in T3 patients (RFS HR 0.326, P=.031). No survival differences were observed between oxaliplatin-containing vs. non-oxaliplatin regimens (5-year RFS P=.636; OS P=.757). PSM analysis (n=56 pairs) confirmed the survival benefit (matched OS HR 0.344, P=.036). Conclusions: Adjuvant CTx significantly improves RFS and OS in high-risk stage II MSI-H/dMMR colon cancer, particularly in pT4 and PNI patients. The absence of regimen-specific survival differences suggests that treatment administration itself, rather than specific agents, determines outcomes. These findings provide evidence to bridge NCCN and ESMO guideline discrepancies, supporting risk-stratified adjuvant CTx in this population. Multivariate analysis for survival. Relapse free survival Hazard Ratio 95% CI P value Adjuvant chemotherapy No 1 0.117-0.660 0.003 Yes 0.278 Pathologic T stage T3 1 0.955-5.577 0.063 T4 2.308 Perineural invasion No 1 1.627-10.100 0.002 Yes 4.053 Overall survival Hazard Ratio 95% CI P value Adjuvant chemotherapy No 1 0.052-0.594 0.005 Yes 0.176 Age < 60 1 0.607-13.000 0.186 ≥ 60 2.810 Pathologic T stage T3 1 1.223-12.820 0.021 T4 3.959 Perineural invasion No 1 2.184-25.690 0.001 Yes 7.490 Bowel perforation or obstruction No 1 0.933-9.078 0.065 Yes 2.911
Real-world clinical utility of comprehensive genomic and transcriptomic profiling in metastatic breast cancer (mBC).
e13080 Background: Integrated DNA/RNA comprehensive genomic profiling (CGP) may expand therapeutic opportunities and support decision-making in metastatic breast cancer (mBC), yet real-world evidence for its clinical utility remains limited. We evaluated the impact of CGP-guided care on treatment decisions and outcomes in a heterogeneous mBC cohort. Methods: A retrospective, single-center analysis of 207 patients with mBC who underwent BostonGene’s Tumor Portrait test. Actionable alterations were defined per NCCN/FDA guidelines or clinical trial eligibility. Clinical utility is defined as CGP-driven treatment initiation or identification of guideline-supported future options was assessed in patients with ≥60 days of follow-up (n = 160). Subgroup analyses evaluated outcomes with trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), or immune checkpoint inhibitors using RNA-seq-based ADC biomarker thresholds, breast cancer classifier (BCC/PAM50), and tumor microenvironment subtypes. Progression-free survival (PFS) was analyzed using Kaplan–Meier methods and Cox regression. Results: The cohort included HR+/HER2− (58%), TNBC (35%), and HER2+ (7%) mBC, with a median of 2 prior therapy (range: 1–11). Overall, 65.5% of patients had actionable molecular alterations, of which 33.9% were supported by NCCN/FDA-approved indications, while the remaining alterations were potentially targetable within clinical trial settings. CGP directly informed treatment initiation in 10% of patients and identified potential future targeted therapy options in an additional 15%. Luminal B and Basal BCC subtypes were consistently associated with inferior PFS outcomes across the cohort. Among patients treated with T-DXd (n = 45), higher HER2 RNA expression was associated with reduced progression risk, whereas Basal and Luminal B subtypes demonstrated worse PFS (p = 0.006). Among patients receiving SG (n = 55), those with TNBC had longer PFS than those with HR-positive mBC, whereas TROP2 RNA expression was uniformly high and not predictive of outcome. Among patients treated with immunotherapy (n = 25), PD-L1 expression was not significantly associated with PFS. Conclusions: Integrated DNA and RNA CGP identified actionable alterations in most patients in our study cohort. It also either directly informed treatment decisions or identified new guideline-supported treatment options in 25% (total) of cases. Transcriptomic subtyping provided further prognostic insights, particularly among patients receiving T-DXd, that contextualize treatment selection and sequence when multiple therapeutic options are available, including scenarios in which more potent ADC-based regimens may be favored over alternative targeted approaches.
Association of thymic epithelial tumors (TETs) with Lynch syndrome (LS) per germline genetic testing and molecular tumor analysis.
10615 Background: LS is a hereditary cancer syndrome that increases risk for gastrointestinal, gynecologic, genitourinary, and other cancers, and is typically characterized by microsatellite instability (MSI-H), mismatch repair-deficiency (MMR-D), and high tumor mutational burden (TMB). TETs, including thymomas and thymic carcinomas, are rare neoplasms not known to be associated with LS and usually show low TMB and microsatellite-stable (MSS) biology. We sought to describe the clinical, pathologic, and molecular characteristics of TETs diagnosed in individuals with LS seen at our institution. Methods: We conducted a retrospective, single-institution study to identify TETs among individuals with LS. We queried all LS patients seen in the DFCI Cancer Genetics and Prevention program from 1990 (n = 1,386) and identified those with a TET. We also reviewed TET cases that had paired tumor–germline sequencing between July 2023 and September 2025 (n = 12) to identify additional cases with LS pathogenic germline variants (PGVs). Clinical and molecular data, including MMR immunohistochemistry (IHC), and tumor and germline sequencing reports, were abstracted from the medical record. Results: Of the 1,398 cases reviewed, 4 females were identified with TETs (1 thymoma and 3 thymic carcinomas) diagnosed at a median age of 54.0 years (range 23-70 years), all with a confirmed PGV in an MMR gene [Table 1]. All four cases had tumor characteristics consistent with MMR-D. Two TETs were MMR-D by IHC, and one TET had biallelic MLH1 variants on somatic testing, so MMR-D is inferred. Three TET cases were MSI-H by next generation sequencing, and one was MSS, despite being MMR-D by IHC. Three cases had high TMB and one did not have TMB assessment. One patient received neoadjuvant chemotherapy for two cycles, with the addition of pembrolizumab after discovering the tumor’s MSI-H status; this patient had a pathological complete response at surgery. One patient received neoadjuvant chemotherapy, surgery, and adjuvant proton beam radiation; another received neoadjuvant chemoradiotherapy followed by surgery. The fourth underwent resection and plans adjuvant therapy. All four are alive at a median of 34.8 months post-surgery (range 3.6-60.7 months). Conclusions: Our data show that TETs in patients with LS frequently demonstrate molecular biology (MMR-D, MSI-H, TMB-H) like other classic LS-associated cancers, suggesting that these may be rare manifestations of LS. Further clarifying the link between LS and TETs may have important implications for treatments. Age at diagnosis Sex Histologic subgroup TMB (mut/Mb) Microsatellite status MMR status PGV 53 F Thymoma 30.4 MSI-H MMR-D MLH1 c.116+2T>G 70 F Thymic squamous cell carcinoma 18.25 MSI-H NA MSH6 5’UTR_EX6del 23 F Poorly differentiated carcinoma, favor thymic origin 14.48 MSI-H MMR-D MSH2 c.1906G>C 55 F Thymic carcinoma NA MSS MMR-D PMS2 c.2137C>T
Overall survival and treatment-related outcomes with FOLFIRINOX compared with gemcitabine/nab-paclitaxel in metastatic pancreatic cancer.
e16436 Background: FOLFIRINOX and gemcitabine plus nab-paclitaxel are commonly used first-line regimens for metastatic pancreatic ductal adenocarcinoma (mPDAC). While randomized trials have demonstrated survival advantages with FOLFIRINOX, real-world comparative effectiveness and toxicity data remain limited. We compared survival and clinically relevant outcomes between these regimens in routine clinical practice. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network, including adults with mPDAC treated with FOLFIRINOX (cohort 1) or gemcitabine/nab-paclitaxel (cohort 2). The index date was first treatment administration. Outcomes were assessed from 1 to 365 days. Propensity score matching (1:1) was performed to balance demographics, comorbidities, and baseline laboratory values. The primary outcome was overall survival (OS). Secondary outcomes included hospitalization, emergency department (ED) visits, neutropenia, ERCP utilization, transaminitis, venous thromboembolism (DVT/PE), granulocyte colony-stimulating factor (G-CSF) use, and neuropathy. Time-to-event analyses used Kaplan–Meier methods with log-rank testing and Cox proportional hazards models. Results: After propensity score matching, 2,364 patients were included (1,182 per cohort) with well-balanced baseline characteristics. Median OS was significantly longer with FOLFIRINOX compared with gemcitabine/nab-paclitaxel (239 vs 164 days). Kaplan–Meier analysis demonstrated superior survival with FOLFIRINOX (log-rank p < 0.001), corresponding to a 25% reduction in mortality (HR 0.75, 95% CI 0.67–0.84). No significant differences were observed in hospitalization (log-rank p = 0.867; HR 1.01, 95% CI 0.91–1.12), ED visits (log-rank p = 0.754; HR 1.02, 95% CI 0.90–1.16), ERCP utilization (log-rank p = 0.606; HR 1.08, 95% CI 0.81–1.43), transaminitis (log-rank p = 0.305; HR 1.30, 95% CI 0.79–2.16), DVT/PE (log-rank p = 0.457; HR 0.93, 95% CI 0.78–1.12), or neuropathy (log-rank p = 0.464; HR 1.08, 95% CI 0.89–1.30). G-CSF use was significantly higher with FOLFIRINOX (log-rank p < 0.001; HR 2.50, 95% CI 2.10–2.99). Conclusions: In this large real-world analysis, FOLFIRINOX was associated with significantly improved overall survival compared with gemcitabine/nab-paclitaxel in metastatic pancreatic cancer, without increased hospitalization or most toxicity-related outcomes, though with greater hematologic support requirements. These findings provide real-world confirmation of clinical trial data and inform treatment selection in routine practice.
Clinical decision impact of 18F-PSMA-1007 PET/CT for prostate cancer staging: Avoiding over- and under-treatment versus bone scintigraphy.
e15088 Background: For medical oncologists and multidisciplinary teams, staging is not descriptive - it determines treatment intent, intensity, and eligibility for metastasis-directed strategies. Bone scintigraphy can misclassify metastatic status, driving both unnecessary systemic therapy and delayed intensification when occult disease is missed. We assessed whether 18F-PSMA-1007 PET/CT meaningfully changes staging and, consequently, oncology management compared with bone scintigraphy in real-world practice. Methods: We conducted a single-center observational study at European Medical Center (Moscow) from 2018 to 2025 to assess the clinical impact of adding 18F-PSMA-1007 PET/CT to conventional staging in prostate cancer. Bone scintigraphy was performed according to the institutional staging/follow-up pathway, and 18F-PSMA-1007 PET/CT was additionally performed under a predefined research protocol to enable within-patient comparison. Overall, 604 patients underwent PSMA PET/CT during the study period (a total of 976 scans); the comparative cohort comprised 107 patients who underwent both bone scintigraphy and 18F-PSMA-1007 PET/CT. The primary endpoint was metastatic stage reclassification after PSMA PET/CT versus bone scintigraphy (M0→M1 or M1→M0). A prespecified analysis was performed in the high-risk subgroup. Proportions are reported with 95% confidence intervals. Results: PSMA PET/CT altered staging in 44/107 patients (41.1%; 95% CI 32.3-50.6). Upstaging occurred in 34/107 (31.8%) due to previously unrecognized metastatic lesions, while downstaging occurred in 10/107 (9.3%) by excluding false-positive findings on bone scintigraphy. The effect was most pronounced in high-risk patients (n = 51) where restaging was observed in 32/51 (62.7%; 95% CI 49.0-74.7). Among patients with suspected metastatic bone disease on bone scintigraphy (n = 30), PSMA PET/CT excluded systemic involvement in 10/30 (33.3%), supporting avoidance of unnecessary systemic therapy and preserving curative-intent local treatment options. Conclusions: 18F-PSMA-1007 PET/CT produced clinically meaningful stage migration versus bone scintigraphy in routine prostate cancer care, with the largest impact in high-risk disease. By both revealing previously unrecognized metastases and excluding false-positive bone scan findings, PSMA PET/CT can reduce over- and under-treatment and improve selection for curative-intent local therapy versus systemic/combined strategies. Given cost and resource implications, PSMA PET/CT should be applied in a risk-adapted manner, with prioritization of high-risk patients where the decision impact appears greatest. Larger prospective studies are needed to define optimal selection criteria and to validate clinical and outcomes benefits of this approach.
Expression of CXCR4 in gastric NENs.
e16312 Background: Gastric neuroendocrine neoplasms (gNENs) are a rare and heterogeneous group of tumors that include well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs). Treatment selection and prognosis largely depend on tumor type, which is primarily determined by morphological assessment. Among currently investigated diagnostic and prognostic biomarkers, CXCR4 have attracted increasing interest; however, data regarding their expression in gNENs are scarce. Methods: Immunohistochemical evaluation of CXCR4 expression was performed on tumor specimens from 60 patients with histologically confirmed gNENs who underwent surgical treatment at the N.N. Blokhin National Medical Research Center of Oncology. The cohort included 21 patients with type 1 gastric NETs, 13 with type 3 gastric NETs, 14 with large-cell NECs, 8 with small-cell NECs, and 4 with MiNENs. According to tumor grade based on Ki-67 index, cases were classified as Grade 1 (n = 11), Grade 2 (n = 25), and Grade 3 (n = 24). CXCR4 expression levels were semi-quantitatively assessed (0/1+ vs 2+/3+). Results: In type 1 gastric NETs, the majority of cases (62%) demonstrated absent or low CXCR4 expression (0/1+). In type 3 gastric NETs, the proportion of cases with low or absent CXCR4 expression decreased to 46%, while 54% showed moderate to high expression (2+/3+). A further increase in CXCR4 expression was observed in more aggressive gNENs, with NECs exhibiting the highest frequency of 2+/3+ expression (82%). In Grade 3 NETs and MiNENs, high CXCR4 expression was not predominant, accounting for 50% and 25% of cases, respectively. Conclusions: High expression of CXCR4 appears to be a useful diagnostic tool for distinguishing well-differentiated gastric NETs from high-grade gNENs. In addition, these marker may help identify a subgroup of patients with an unfavorable prognosis in terms of survival. Further studies are warranted to clarify their prognostic significance and potential clinical utility.
Stage-specific survival trends in small cell lung cancer in the United States: A population-based analysis.
e20129 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with historically poor survival outcomes. While advances in radiation therapy, diagnostics, and supportive care have led to gradual gains, core systemic treatment options remained largely unchanged for decades, particularly for extensive-stage (ES) disease. The introduction of immune checkpoint inhibitors (ICIs) into first-line therapy in 2018 represented the most significant therapeutic advancement in SCLC in over 30 years. Whether this paradigm shift has translated into population-level survival improvements across all disease stages remains unclear. Methods: We conducted a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Adults aged ≥18 years with histologically confirmed SCLC diagnosed between 2000 and 2021 were included. Diagnostic years were grouped into four treatment eras: 2000–2006, 2007–2011, 2012–2016, and 2017–2021. Stage at diagnosis was defined using SEER Summary Stage. Localized and regional disease were categorized as limited-stage SCLC, while distant disease was classified as extensive-stage SCLC. Overall survival (OS) was calculated from diagnosis to death from any cause or last follow-up. Kaplan–Meier methods were used to estimate survival trends across eras. Results: A total of 76,472 patients with SCLC were identified, including 18,522 (24.2%) with limited-stage and 57,950 (75.8%) with extensive-stage disease at diagnosis. Among patients with limited-stage SCLC, five-year OS improved steadily over time, increasing from 10.2% (95% CI, 9.3–11.3) in 2000–2006 to 12.5% (95% CI, 11.6–13.4) in 2007–2011, 15.5% (95% CI, 14.5–16.5) in 2012–2016, and 18.1% (95% CI, 16.7–19.6) in 2017–2021.In extensive-stage SCLC, 5 year OS remained low but demonstrated improvement over time: 2.0% (95% CI: 1.7%-2.2%) in 2000-2006, 2.0% (95% CI: 1.8%-2.2%) in 2007-2011, 2.3% (95% CI: 2.1%-2.5%) in 2011-2016, 3.6% (95% CI: 3.2%-4.1%) in 2017-2021 with the largest increase seen after 2017. Conclusions: In this large national analysis, long-term survival among patients with SCLC improved modestly over the past two decades. Incremental gains likely reflect advances in staging accuracy with PET–CT imaging, refinements in radiation delivery, and improvements in supportive care that enhance treatment tolerance. The most pronounced survival improvement was observed in extensive-stage disease after 2017, potentially corresponding with the incorporation of immune checkpoint inhibitors into frontline therapy—the first systemic treatment in more than 30 years to demonstrate a meaningful overall survival benefit in SCLC. Despite these advances, five-year survival remains poor across all stages, highlighting the need for more effective therapeutic strategies and improved implementation of emerging treatments at the population level.
Tumor shrinkage and depth of response with fruquintinib in patients with metastatic colorectal cancer: Results from FRESCO and FRESCO-2.
3555 Background: In metastatic colorectal cancer (mCRC), early tumor shrinkage (ETS) and depth of response (DpR) are predictors of overall survival (OS) and progression-free survival (PFS). Durable stable disease (SD) also reflects disease control and can contextualize PFS and OS improvements. The phase 3 FRESCO (F) and FRESCO-2 (F2) trials of fruquintinib vs placebo in patients (pts) with mCRC showed significantly longer OS (F median: 9.3 vs 6.6 months [mo], HR 0.65, P<0.001; F2 median: 7.4 vs 4.8 mo, HR 0.66, P<0.001) and PFS (F median: 3.7 vs 1.8 mo, HR 0.26, P<0.001; F2 median: 3.7 vs 1.8 mo, HR 0.32, P<0.001) with fruquintinib. We report a post-hoc analysis of tumor shrinkage (TS), ETS, and DpR, and the correlation with OS and PFS in F and F2. Methods: Pts were randomized to receive fruquintinib + best supportive care (BSC; F n=278; F2 n=461) or placebo + BSC (F n=138; F2 n=230). Tumors were assessed at screening and every 8 weeks until progressive disease (PD). TS was defined as a decrease from baseline in the sum of the longest diameters of target lesions; ETS was TS by the first post-treatment assessment; duration of TS (DTS) was time from first TS to first tumor size increase, PD, or death; in pts with best overall response of SD, duration of SD was assessed as the time from first occurrence of SD to PD/death; and DpR was the maximum percentage change from baseline in the sum of the longest diameters of target lesions. OS and PFS were assessed in pts who received fruquintinib and had TS/ETS. Results: In F, 129 (46%) fruquintinib-treated pts had TS, of which 124 (45%) achieved ETS; with placebo, 5 pts (4%) had TS and ETS. In F2, similarly, 178 (39%) fruquintinib-treated pts had TS, of which 154 (33%) achieved ETS; with placebo, 15 pts (7%) had TS and 13 pts (6%) had ETS. In pts with TS in F and F2, median DTS with fruquintinib was 1.9 and 2.0 mo, respectively. Median duration of SD was longer with fruquintinib vs placebo in both F (5.5 vs 3.7 mo) and F2 (5.6 vs 3.7 mo). Magnitude of DpR was greater with fruquintinib vs placebo in both trials. In F and F2, median OS and PFS in pts who received fruquintinib were longer in those who achieved TS and ETS vs the ITT fruquintinib arm (Table). Conclusions: ETS was observed in most fruquintinib-treated pts with TS in both F and F2 (F: 96% [124/129 pts]; F2: 87% [154/178 pts]); pts with both TS and ETS showed longer median OS and PFS compared with the fruquintinib ITT population. These data indicate that TS and ETS appear to be predictors of OS and PFS outcomes, and support the prognostic relevance of TS, ETS, and DpR in pts with mCRC. Clinical trial information: NCT02314819 and NCT04322539 . OS and PFS in pts who received fruquintinib with TS/ETS vs the ITT fruquintinib arm in F and F2. Months (95% CI) With TS With ETS ITT Fruquintinib arm F n = 129 n = 124 N = 278 OS 12.1 (10.8–14.9) 11.6 (10.7–14.9) 9.3 (8.2–10.5) PFS 5.5 (5.5–7.3) 5.5 (5.5–6.6) 3.7 (3.7–4.6) F2 n = 178 n = 154 N = 461 OS 10.9 (9.9–12.5) 10.8 (8.9–12.7) 7.4 (6.7–8.2) PFS 5.6 (5.4–6.2) 5.6 (5.1–5.8) 3.7 (3.5–3.8)
Racial and geographic disparities in Hodgkin lymphoma mortality among adolescents and young adults in the United States, 1999-2023.
e13738 Background: Hodgkin lymphoma (HL) in adolescents and young adults (AYAs) is highly curable, and population-level mortality is low. In a highly curable condition, mortality gaps by race/ethnicity may reflect inequities in access to timely diagnosis and curative therapy. We hypothesized that HL mortality would differ by race/ethnicity and vary geographically over time. Prior studies have demonstrated racial and socioeconomic disparities in AYA HL survival, but national and state-level patterns in AYA HL mortality using death certificate-based data remain less well characterized. Methods: We used the CDC WONDER Multiple Cause of Death databases (1999-2020 and 2018-2023) to identify deaths from HL as the underlying cause (ICD-10 C81) among individuals aged 15-44 years, combining 1999-2020 with 2021-2023 to avoid duplicate years. Using CDC WONDER race/ethnicity categories, we report non-Hispanic (NH) White, NH Black, and Hispanic AYAs. We extracted age-adjusted mortality rates (AARs) per 100,000 with 95% confidence intervals (CIs) for 1999-2005, 2006-2012, 2013-2020, and 2021-2023 and summarized regional/state patterns descriptively. Results: HL mortality declined from 1999 to 2023 across all groups, with a larger decline among NH White AYAs (≈80%) than NH Black AYAs (≈56%). In 1999-2005, AAR was 0.399 (CI 0.361-0.436) for NH Black AYAs, 0.337 (CI 0.321-0.352) for NH White AYAs, and 0.168 (CI 0.145-0.192) for Hispanic AYAs. In 2021-2023, AAR was 0.174 (CI 0.138-0.216), 0.068 (CI 0.058-0.079), and 0.068 (CI 0.050-0.091), respectively. Across periods, NH Black AYAs consistently had higher mortality than NH White AYAs, with the largest absolute difference in 2021-2023 (0.106 per 100,000). State-level estimates varied. In states with adequate deaths to estimate stable rates, NH Black AARs exceeded NH White in TN, GA, MS, MD, IL, TX, VA, and MI, with smaller differences in CA, NY, FL, NC, SC, PA, AL, and LA. Conclusions: HL mortality among US AYAs has declined substantially from 1999-2023, yet race/ethnicity differences persist and vary geographically. In a highly curable malignancy, these gaps underscore the need to strengthen equitable access to timely diagnosis and guideline-concordant curative therapy. National age-adjusted HL mortality among AYAs (15-44 years) by period and race/ethnicity. Era Non-Hispanic Black AAR (95% CI) Non-Hispanic White AAR (95% CI) Hispanic AAR (95% CI) Absolute Difference (Non-Hispanic Black - Non-Hispanic White) 1999-2005 0.399 (0.361-0.436) 0.337 (0.321-0.352) 0.168 (0.145-0.192) 0.062 2006-2012 0.305 (0.272-0.338) 0.237 (0.224-0.249) 0.168 (0.148-0.188) 0.068 2013-2020 0.168 (0.147-0.190) 0.100 (0.092-0.108) 0.168 (0.148-0.188) 0.068 2021-2023 0.174 (0.138-0.216) 0.068 (0.058-0.079) 0.068 (0.050-0.091) 0.106 AAR = age-adjusted mortality rate per 100,000; CI = confidence interval.