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Trends and disparities in cardiomyopathy-associated mortality among breast cancer adults aged ≥45 years in the United States, 1999–2023: CDC WONDER analysis.
e13141 Background: Breast cancer is the second leading cause of cancer death in the United States (US), with approximately 42,000 deaths annually. Although cardiotoxic therapies have improved survival, they may contribute to long-term cardiovascular mortality. Cardiomyopathy is a clinically important cause of morbidity and mortality among breast cancer survivors; however, national trends and disparities in cardiomyopathy-associated mortality in breast cancer patients amongst various demographic and geographic subgroups is unexplored. Methods: We performed a population-based analysis of US Multiple Cause of Death data from the CDC WONDER database (1999–2023). Deaths listing breast cancer (ICD-10 C50.x) and cardiomyopathy (ICD-10 I42.x) as contributing causes were included. Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated using the 2000 U.S. standard population. Joinpoint regression identified temporal inflection points and estimated annual percent change (APC) and average annual percent change (AAPC). Analyses were stratified by sex, age (45–64 vs ≥65 years), race (non-Hispanic White and non-Hispanic Black), census region, urbanization, state, and place of death. Statistical significance was P < 0.05. Results: From 1999–2023, 9,568 cardiomyopathy-associated deaths occurred among individuals with breast cancer, with overall AAMR per 1,000,000 declining from 4.1 to 2.4 (APC -3.1) from 1999–2017, followed by an increase to 2.72 from 2017–2023 (APC 3.3); females followed a similar trend. Adults aged ≥65 years declined initially and increased from 2017–2023 (APC 3.4; AAMR 5.3-5.96), whereas those aged 45–64 years declined overall (AAMR 1.99-0.88). From 2017–2023, non-Hispanic Whites rose (APC 4.1; AAMR 2.23-2.73), whereas non-Hispanic Black or African Americans declined throughout 1999–2023 (APC 6.75−4.32). Regionally, Midwest and South declined from 1999-2023 (APC -1.9 and -2.1), while the West and Northeast declined initially and then increased after 2016 (APC 3.57 and 2.87). Metropolitan areas declined continuously (APC 4.37-2.86), whereas non-metropolitan areas increased from 2018-2020 (APC 21.2; AAMR 2.24-3.32). At the state level, Maryland had the highest AAMR (5.83) and Nevada the lowest (1.04) from 1999–2020; from 2021–2023, Minnesota had the highest (7.33) and Texas the lowest (2.03). Most deaths occurred in inpatient medical facilities (n = 3,379). Conclusions: Cardiomyopathy-associated mortality among breast cancer patients declined from 1999–2017 but subsequently increased in adults aged ≥65 years, females, non-Hispanic Blacks, non-metropolitan areas, and in the Midwest, Northeast, District of Columbia, and Minnesota. These populations may benefit from targeted cardio-oncology surveillance and proactive long-term cardiovascular risk management.
Encyclopedic tumor analysis–guided therapy in refractory advanced cancers: Clinical and health-economic outcomes.
e23145 Background: Treatment of relapsed/refractory metastatic cancers costs $128k–$293k per patient with minimal efficacy (7–45% ORR in precision-medicine trials). Febrile neutropenia adds $12k–$15k per hospitalization, while end-of-life care costs increase up to eightfold of treatment-phase levels. RESILIENT trial evaluated Encyclopedic Tumor Analysis (ETA), integrating genomic, transcriptomic, and in-vitro chemosensitivity profiling to enable organ-agnostic, combination therapy in refractory populations. Methods: Health-economic analysis of RESILIENT trial was performed (n = 126 evaluable; ≥2 prior therapy lines). All ETA-recommended agents were FDA-approved. Endpoints included ORR, clinical benefit rate (CBR), PFS, toxicity grade distribution, PFS2/PFS1 ratios, metastatic containment, and quality-of-life (QoL) preservation. Results: ORR was 42.9% (95% CI 34.3–51.4%) and CBR 90.5%, exceeding historical precision medicine trials (MyPathway 23%, MOSCATO 11%, WINTHER 13%). Among 62 patients with prior PFS ≤90 days, 75.8% achieved PFS2/PFS1 > 1.3× and 35.5% ≥2.5×. Grade ≥3 adverse events occurred in 39.9%, with dose adjustments required in only 32.9% (vs. 50–60% baseline). No grade 4 events or treatment-related deaths were observed. Neutropenia occurred in 22.4% (any grade) and 11.2% (grade ≥3), lower than reported baselines (30–40% and 15–25%, respectively). Among 12 progressors, 75% showed local-only progression without new distant metastases. QoL was stable or improved in 83.9% (function) and 90.3% (health). ETA-guided therapy achieved a cost per month of PFS of ~$6k–10k, compared with $10k–25k for sequential standard-of-care monotherapy. Reduced neutropenia translated into an estimated $24k–48k cohort-level cost avoidance. Metastatic containment (2.4% new distant metastases) mitigated the 2–3× cost escalation associated with multi-organ progression. A single ETA profile ($5k–8k) replaces multiple sequential single-gene tests ($500–2k per test). Achievement of 90.5% disease control and QoL preservation—critical outcomes in palliative refractory cancer—aligns with emerging value-based palliative care frameworks prioritizing quality-adjusted survival. Conclusions: ETA-guided personalized therapy achieves superior efficacy, toxicity control, and putatively cost-effective outcomes by reducing failed treatment sequences, preventing chemotherapy-dose-reducing complications, avoiding febrile neutropenia, limiting metastatic dissemination, and preserving quality of life. Integration into refractory cancer management may provide clinically superior and economically justifiable value in healthcare systems facing escalating metastatic cancer costs.
Two-cycle versus three-cycle induction chemotherapy followed by concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A phase III randomized noninferiority trial.
6003 Background: Although two- and three-cycle induction chemotherapy are both widely utilized and confer significant survival benefits in locoregionally advanced nasopharyngeal carcinoma, direct comparative evidence remains lacking. Furthermore, given the cumulative treatment-related toxicity, economic burden, and potential delays in the initiation of radiotherapy, the optimal number of induction chemotherapy cycles remains undefined. Methods: We conducted a phase 3, open-label, multicenter, randomized controlled noninferiority trial in an endemic area. Patients with previously untreated, stage III-IVB (except T3-4N0, AJCC 8 th edition) nasopharyngeal carcinoma, aged 18-70 years without severe comorbidities were enrolled. Eligible patients were randomly assigned to receive two cycles or three cycles induction chemotherapy followed by concurrent chemoradiotherapy in a 1:1 ratio. The primary endpoint was failure-free survival (FFS) and the noninferiority margin was defined as an 8% absolute between-group difference, with an 80% statistical power and a one-sided α of 0.025. The secondary endpoints included overall survival, distant metastasis-free survival, locoregional relapse-free survival, and toxicity, , among others. Results: Among 654 eligible patients, 327 were allocated to each group (two-cycle vs three-cycle). Two groups were well-balanced in all prognostic factors. After a median follow-up of 34.3 months, intention-to-treat analysis showed that estimated 3-year FFS was 85.4% (95% CI 80.9-89.9) in the two-cycle group and 86.7% (95% CI 82.4-91.0) in the three-cycle group, with a difference of -1.3% (95% CI, -7.54% to 4.94%; hazard ratio 1.11, 95% CI 0.72-1.71; P = 0.0031 for noninferiority). Similar result was found in the per-protocol analysis: estimated 3-year FFS for two-cycle group and three-cycle group was 86.5% (95% CI 82.0-91.0) and 87.0% (95% CI 82.7-91.3), respectively, with a difference of -0.5% (95% CI, -6.74% to 5.74%; hazard ratio 1.10, 95% CI 0.69-1.75; P = 0.0014 for noninferiority). No differences were observed between groups in terms of overall survival and the cumulative incidences of locoregional relapse and distant metastasis. Patients in the three-cycle group developed significantly more grade 3-4 adverse events such as neutropenia (three-cycle group 34.3% vs two-cycle group 24.8%), leukopenia (32.7% vs 24.5%) and vomiting (15.9% vs 10.4%). No patients died from treatment-related causes. Conclusions: Two-cycle induction chemotherapy followed by concurrent chemoradiotherapy provides comparable disease control and survival, with less toxicity, compared to three-cycle counterpart in locoregionally advanced nasopharyngeal carcinoma. Clinical trial information: ChiCTR1800018417 .
Predictors of treatment (tx) duration in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA): A post hoc analysis of ARCHES.
5093 Background: In ARCHES (NCT02677896), ENZA + androgen-deprivation therapy (ADT) significantly improved radiographic progression-free survival (primary: data cutoff, Oct 14, 2018) and overall survival (prespecified secondary: data cutoff, May 28, 2021; 5-year follow-up: data cutoff, Jul 31, 2024) vs placebo + ADT in mHSPC. This post hoc analysis explored factors associated with different ENZA tx durations (5-year follow-up). Methods: Reasons for tx discontinuation (DC) including toxicity and progression, and baseline and on-treatment factors underlying tx persistence, were compared descriptively among pts with short (0–2 years [y]; STx), medium (2–5 y; MTx), and long Tx duration (> 5 y; LTx) (STx pts represent non-responders; MTx/LTx pts represent tx responders). Results: Of 572 ENZA-treated pts, 204 (36%) were STx; 140 (24%) MTx; 228 (40%) LTx. STx pts were more likely to be older vs MTx and LTx, with high-volume disease (HVD) and Eastern Cooperative Oncology Group performance status (ECOG PS) 1, although 55.3% of LTx had HVD and 73.2% had synchronous metastases. Progressive disease and tx-emergent adverse events (TEAEs) were the most common reasons for tx DC. Drug-related TEAEs (per 100 pt-y) were more common in STx (156.0) vs MTx (89.5) and LTx (47.1), as were those leading to tx DC (STx: 12.4; MTx: 1.5; LTx: 0.1). Rates (per 100 pt-y) of TEAEs leading to ENZA dose reduction were higher in STx (6.2) vs MTx (5.8) and LTx (2.0). The rate (per 100 pt-y) of drug-related TEAEs of special interest were generally higher in STx vs MTx and LTx: convulsions (1.0 vs 0.0 vs 0.0); fatigue (19.0 vs 10.7 vs 4.8), select cardiovascular events (1.0 vs 0.6 vs 0.1); falls (2.4 vs 3.2 vs 1.1); fractures (0.5 vs 1.5 vs 0.5). Conclusions: Our findings demonstrate that LTx and MTx tended to have more favorable pt and disease characteristics vs STx, although majority of LTx had adverse prognostic features. While progressive disease was the most common reason for DC, AEs/withdrawals were the second most common. Most TEAEs of special interest were more frequent in STx. Reasons for AE-related tx changes are multifactorial, and optimal management of AEs and comorbidities, as well as dose modifications, can optimize ENZA tx. Clinical trial information: NCT02677896 . Pt characteristics STx (n = 204)n (%) MTx (n = 140)n (%) LTx (n = 228)n (%) Age: ≥ 18 to 64/≥ 65 to ≤ 84/≥ 85 y 45 (22.1)/150 (73.5)/9 (4.4) 38 (27.1)/100 (71.4)/2 (1.4) 65 (28.5)/159 (69.7)/4 (1.8) Prostate-specific antigen nadir < 0.2 ng/mL post-baseline 84/189 (44.4) 97/123 (78.9) 181/198 (91.4) ECOG PS 0/1 147 (72.1)/57 (27.9) 110 (78.6)/30 (21.4) 190 (83.3)/37 (16.2) HVD 148 (72.5) 80 (57.1) 126 (55.3) Synchronous disease 162 (79.4) 108 (77.1) 167 (73.2) Reasons for tx DC Progressive disease 106 (52.0) 63 (45.0) 19 (8.3) AE + withdrawalAEWithdrawal 74 (36.3)40 (19.6)34 (16.7) 40 (28.6)25 (17.9)15 (10.7) 7 (3.1)2 (0.9)5 (2.2) Death 10 (4.9) 10 (7.1) 10 (4.4)
Mortality rates for upper gastrointestinal cancers as a cause or contributing factor in adults aged 45 and older in the United States: A retrospective analysis from 1999-2024.
e16050 Background: Upper Gastrointestinal (UGI) cancers, including esophageal, stomach, and small bowel cancers, have significant health impacts worldwide. This study investigates trends in UGI cancer mortality among adults aged ≥45 years in the U.S. from 1999 to 2024. Methods: Utilizing the CDC WONDER database, death certificate data was analyzed for UGI cancers using ICD-10 codes C15, C16, and C17.0. Age-adjusted mortality rates (AAMRs) were calculated, and trends were assessed using Joinpoint regression in order to determine annual percent changes (APCs) in the mortality rates. Results: Among 7,31,086 UGI cancer-related deaths, AAMR decreased from 28.0 per 100,000 in 1999 to 19.5 per 100,000 in 2024. The decline was most pronounced from 1999 to 2017 (APC -1.65, 95% CI: -1.75 to -1.56), with a slower decrease from 2017 to 2024 (APC -0.80, 95% CI: -1.09 to – 0.28). Gender-specific analysis revealed higher AAMRs for males compared to females, with males showing a decline from 44.8 in 1999 to 32.1 in 2018 (APC -1.68, 95% CI: -1.73 to -1.62) and a further decrease to 30.7 by 2024 (APC -0.96, 95% CI: -1.19 to -0.54). For females, AAMR decreased from 15.7 in 1999 to 10.2 in 2024, with a steeper decline from 1999 to 2014 (APC -2.27, 95% CI: -2.51 to -2.03) followed by a slower rate from 2014 to 2024 (APC -0.79, 95% CI: -1.14 to -0.26). Race/ethnicity-specific trends showed a significant decline in AAMR for Non-Hispanic Black individuals from 1999 to 2015 (APC -3.73, 95% CI: -3.96 to -3.55), with a continued decrease until 2024 (APC -2.37, 95% CI: -2.81 to -1.67). Non-Hispanic Asian or Pacific Islander groups also experienced a substantial decrease in AAMR from 1999 to 2020 (APC - 3.09, 95% CI: -3.75 to -1.72), while trends for other racial/ethnic groups showed variable rates of decline. Geographically, the Northeast had the highest AAMRs and exhibited a consistent decline from 1999 to 2024 (APC -2.00, 95% CI: -2.10 to -1.91). Mortality rates in nonmetropolitan areas were higher compared to metropolitan areas, though both regions experienced similar declining trends. Conclusions: The study reveals a notable decline in UGI cancer mortality rates over the past two and a half decades, with important variations based on gender, race, and geographic region. While overall trends are promising, ongoing disparities highlight the need for targeted public health strategies to address these inequities and improve cancer outcomes.
Personalized N-of-1 combinations based on molecular profiles in advanced malignancies: Immunotherapy group analysis of the I-PREDICT N-of-1 precision oncology study.
2628 Background: While current precision oncology typically targets a single biomarker, most cancers have multiple pathogenic alterations that often differ from patient to patient. We evaluated whether individualized, N-of-1 biomarker-based combinations that included immune checkpoint inhibitors (ICIs) would improve outcomes in patients (pts) with advanced cancers. Methods: In the I-PREDICT prospective trial (NCT02534675), 70 pts with advanced poor-prognosis cancers received ICI-based regimens. Personalized combinations were based on tissue/ctDNA next-generation sequencing (NGS) and Molecular Tumor Board review. An "i-Matching Score" was developed using TMB ≥16 mut/Mb—selected because analysis showed it was a more robust outcome predictor than TMB ≥10 or continuous TMB (though both correlated with some outcome parameters)—alongside scores reflecting the matching of other targeted therapies (TT) to tumor alterations. Regimens used individualized dose reductions and intra-patient dose titration for safety. Results: Tumors harbored a median of five pathogenic alterations (range, 1–18); 97% of pts had unique molecular profiles. To optimize biomarker-matching, pts received 48 distinct therapy regimens, many previously unstudied; for the first-in-human (FIH) combinations, initial doses were lowered, and intra-patient dose modifications were made for tolerance. Regimens included ICI monotherapy (20%), ICI + TT (61%), and others. Mean initial dose was 79.5% of the FDA-approved dose; 26% of pts had dose adjustments (6% increase; 20% decrease). Initial doses were lower for multi-drug regimens (P=0.002), ICI+TT (P<0.001), and FIH regimens (P=0.005) vs. established regimens. Grade ≥3 treatment-related serious adverse events (SAEs) occurred in 14% of 70 pts; notably, the SAE rate for ICI monotherapy (established safety profile) was 15%, and no combination subgroup significantly exceeded this rate. FIH regimens and high i-Matching groups (>50% vs. ≤50%) trended towards fewer SAEs (P=0.06/0.08). TMB ≥16 independently predicted improved disease control rate (DCR; SD ≥6mo/PR/CR), PFS, and OS (P=0.006/0.001/0.016); i-Matching Score >50% vs. ≤50% significantly correlated with higher DCR (74% vs 27%, P<0.001), longer PFS (10.4 vs 3.8 mo, P<0.001) and OS (19.1 vs 9.1 mo, P=0.016). In pts receiving ICI+TT (n=51), the i-Matching Score outperformed TMB as an outcome predictor. Conclusions: Individualized, N-of-1 ICI-based combinations, molecularly matched to complex genomic profiles, can be safely given with initial dose reduction and intra-patient dose modification. Higher TMB and higher degrees of biomarker matching (i-Matching Score) correlated with improved outcomes, with the latter performing best in pts receiving ICI+TT combinations. This molecularly guided multi-agent therapy paradigm warrants further study. Clinical trial information: NCT02534675 .
CircRNA signatures to identify candidate biomarkers of treatment resistance in <i>BRCA1</i> -mutant ovarian cancer.
e17558 Background: Most patients with high grade serous ovarian cancer (HGSOC) ultimately relapse with chemotherapy resistant disease, and resistance to Poly (ADP ribose) polymerase inhibitors (PARPi) is increasingly recognised. The mechanisms underlying inherent and acquired resistance remain poorly understood, and no validated biomarkers exist to guide treatment beyond BRCA status. circularRNAs (circRNAs) are stable non-coding RNAs with regulatory roles in gene expression and may capture transcriptional reprogramming associated with treatment resistance. This study examined circRNA expression in chemotherapy and PARPi resistant ovarian cancer (OC) models to identify candidate biomarkers of resistance. Methods: Chemotherapy (carboplatin and paclitaxel) and PARPi resistant (olaparib) COV362 (BRCA1 mutant) sublines were generated using progressive dose escalation. Resistance was confirmed using CCK-8 and BrdU proliferation assays. This was a preclinical, exploratory biomarker discovery study. The primary endpoint was the identification of circRNAs differentially expressed between parental (drug-sensitive), chemotherapy-resistant and PARPi-resistant cell lines. circRNA expression profiling was performed using the Arraystar circRNA microarray platform. Differential expression was assessed using normalised signal intensity, fold-change thresholds and associated statistical outputs, with adjustment for multiple testing. Candidate circRNAs were prioritised based on magnitude of differential expression and annotation quality, and were validated using divergent primers and quantitative PCR. Results: Chemotherapy and PARPi resistant COV362 sublines were successfully established over 10 and 14 months, respectively. circRNA profiling revealed distinct segregation of parental (drug sensitive), chemotherapy and PARPi resistant cell lines using hierarchical clustering. Although global circRNA patterns remained broadly conserved, each model showed a distinct set of upregulated transcripts. At the individual transcript level, however, a subset of circRNAs demonstrated resistance-associated differences and were prioritised for further evaluation. hsa_circ_0085803 (p <0.05) was upregulated in the chemotherapy resistant model, whereas hsa_circ_0003258 (p <0.05) was predominately expressed in the PARPi resistant mode compared to matched parental cell line. Conclusions: Distinct circRNA signatures were associated with chemotherapy and PARPi resistance in COV362, with hsa_circ_0085803 and hsa_circ_0003258 identified as candidate biomarkers of resistance. These findings support the potential of circRNAs as indicators of treatment resistance in HGSOC.
AI-powered characterization of the tumor microenvironment landscape in HER2-overexpressing non–small cell lung cancer.
8545 Background: Antibody-drug conjugate (ADC) targeting HER2 in NSCLC is an opportunity for biomarker-guided therapy independent of oncogenic driver status. As such, HER2 overexpressing (OE) tumors remain a clinically relevant yet under-characterized subgroup of NSCLC patients. Given the role of the tumor microenvironment (TME) in modulating response to ADCs, we applied AI-powered spatial analysis to comprehensively characterize the immunological landscape of NSCLC stratified by HER2 expression. Methods: We performed a retrospective analysis of a proprietary dataset comprising 2,054 H&E whole-slide images (WSIs) of NSCLC cases collected globally and enriched for HER2 OE tumors. HER2 OE was defined as IHC 3+ by pathologist reading based on ASCO/CAP guidelines and compared against IHC 0-2+. An AI-powered H&E analyzer (Lunit SCOPE IO) was used to quantify tumor-infiltrating lymphocytes (TILs) in the epithelial and stromal compartments. Immune phenotypes were classified as inflamed, excluded, or desert. For a subset of 1,099 cases with paired HER2 IHC WSIs, the proportion of tumor cells with 3+ intensity was quantified using an IHC analyzer (Lunit SCOPE HER2). Findings were further validated using 318 H&E WSIs and differential gene expression analysis of the TCGA Lung Adenocarcinoma (LUAD) cohort, stratified by ERBB2 protein expression (RPPA). Results: Of the 2,054 NSCLC cases, the primary analysis focused on adenocarcinoma cases (n = 1,641), which included 229 (14.0%) HER2 OE tumors. These tumors exhibited a significantly lower proportion of inflamed immune phenotype compared to the non-OE group (10.2% vs 22.1%, P < 0.0001). Intratumoral TIL and stromal TIL densities were reduced by 26.1% (P < 0.0001) and 14.7% (P < 0.001), respectively. Notably, even among HER2 OE tumors, a subset with high 3+ cell proportion (≥50% 3+ tumor cells) demonstrated a dose-dependent trend with an even lower inflamed proportion (3.7% vs 14.0%, P = 0.004) and reduced intratumoral TIL density (-36.7%, P < 0.001). The non-adenocarcinoma cohort (n = 413), where HER2 OE was present in 57 (13.8%) cases, showed a trend towards reduced intratumoral TIL density (-20.6%, P = 0.080). Analysis of H&E WSIs in TCGA LUAD validated that ERBB2-high tumors had significantly lower intratumoral TIL density (-16.1%, P = 0.027). Furthermore, gene expression analysis revealed that these tumors had downregulation of immune effector (GZMB, PRF1) and exhaustion (LAG3) markers, while maintaining an epithelial phenotype (OCLN, CDH1) with decreased mesenchymal markers (CDH2). Conclusions: NSCLC with HER2 OE is characterized by a distinct, immune-cold phenotype that is more pronounced with higher HER2 expression. These findings highlight a unique TME landscape that warrants further investigation to understand its potential impact on therapeutic responses.
Geographic and etiologic heterogeneity of liver cancer in the United States: A comprehensive analysis of prevalence, mortality, DALYs, and risk factors.
e16333 Background: Liver cancer remains a major cause of morbidity and mortality in the United States. Understanding the contribution of specific etiologies and risk factors across states is essential for targeted prevention. We used Global Burden of Disease (GBD) 2023 estimates to describe national patterns, state variation, and age and gender disparities. Methods: Age standardized prevalence, mortality, and DALY rates were obtained from the Institute for Health Metrics and Evaluation Global Burden of Disease 2023 study for all 50 states and the District of Columbia. Etiology specific burdens were assessed for hepatitis B, hepatitis C, alcohol use, NASH, and other causes. Age and gender patterns and state rankings for major metabolic and behavioral risk factors were evaluated. Results: Across etiologies, the highest burden was liver cancer due to hepatitis C (3.96 per 100,000), followed by alcohol use (3.34), hepatitis B (1.55), other causes (1.09), and NASH (1.07). Hepatitis B burden was highest in Hawaii (3.03), the District of Columbia (2.31), and Alaska (2.21) and lowest in Michigan (0.50). Hepatitis C burden was highest in Hawaii (6.98) and California (6.16) and lowest in Mississippi (2.28) and Florida (2.57). Alcohol related burden was highest in Hawaii (6.76) and lowest in Michigan (1.28). Burden due to other causes peaked in Minnesota (2.40), while NASH related burden was highest in Hawaii (1.93) and Minnesota (1.68). Prevalence was highest in males aged 80 to 84 years (121.25) and females aged 80 to 84 years (57.57). DALY rates peaked in males aged 65 to 69 years (940.62) and females aged 75 to 79 years (385.73). Gender differences were largest in Hawaii (24.96) and smallest in Michigan (4.07). No states showed reversed gender distribution. Risk factor attributable DALYs were highest for high alcohol use (48.26), followed by drug use (22.51), high BMI (19.28), tobacco (10.93), and high fasting plasma glucose (1.63). Michigan had the highest drug use attributable burden (52.76), Texas the highest alcohol related burden (39.24), West Virginia the highest BMI burden (26.79), and Arkansas the highest tobacco related burden (12.96). Conclusions: Liver cancer in the United States is driven mainly by hepatitis C and alcohol use, with substantial state level variation. Hawaii consistently shows the highest burden across etiologies, while states such as Michigan and Mississippi show lower levels. The strong influence of alcohol, drug use, and high BMI highlights the need for state specific strategies focused on addiction treatment, metabolic risk reduction, and early detection. Strengthened coordination between hepatology and public health programs is essential to reduce liver cancer burden nationwide.
Efficacy and safety of tecotabart vedotin plus toripalimab with or without chemotherapy as first-line treatment for CLDN18.2-positive advanced gastric or gastroesophageal junction adenocarcinoma: Phase II study results.
4045 Background: Tecotabart vedotin (TV; LM-302) is a novel and potent MMAE-based ADC targeting CLDN18.2. Previous data (ASCO 2025, abstract#4039) demonstrated promising efficacy and manageable safety profile of TV plus PD-1 inhibitor in patients (pts) with systemic therapy-naive advanced gastric or gastroesophageal junction (G/GEJ) cancer. Updated phase II results of TV plus toripalimab (T) with or without chemotherapy in this first-line setting are presented. Methods: Eligible pts had histologically confirmed, no prior systemic therapy, HER2-negative G/GEJ adenocarcinoma with CLDN18.2 positivity (IHC 2+/3+ in ≥1% of tumor cells). Pts received TV (1.8 mg/kg Q2W) plus T (3 mg/kg Q2W), with or without capecitabine or S-1. The primary endpoint was PFS per RECIST v1.1. Secondary endpoints were efficacy, safety, PK, and biomarker analysis. Data cutoff: November 25, 2025. Results: A total of 71 pts with G/GEJ adenocarcinoma were enrolled: 39 in the TV+T cohort and 32 in the TV+T+Chemo cohort. Baseline CLDN18.2 high expression (≥25%) was presented in 82.1% of pts in the TV+T cohort and 84.4% in the TV+T+Chemo cohort. PD-L1 CPS ≥1 was observed in 61.5% and 81.3% of pts, respectively. Median follow-up was 16.16 months in the TV+T cohort and 14.82 months in the TV+T+Chem cohort. The median PFS (95% CI) was 10.68 months (6.28, NE) and 12.55 months (6.80, NE), respectively. Among pts with CLDN18.2 ≥25%, the median PFS (95% CI) was 12.22 months (6.87, NE) and NE (8.44, NE), the median DOR (95% CI) was 13.86 months (9.36, NE) and NE (7.10, NE), ORR was 64.5% and 69.2%, and DCR was 96.8% and 96.2%, respectively. Median OS was not reached in either cohort. In pts with CLDN18.2 <25%, TV+T (N=7) and TV+T+Chemo (N=5) showed a median PFS (95% CI) of 5.72 (1.15, NE) and 6.80 (5.55, NE) months, ORR of 14.3% and 40.0%, DCR of 71.4% and 100%, and OS (95% CI) of 10.78 (2.56, NE) months and NE (8.25, NE), respectively. TRAEs occurred in all pts. Grade ≥3 TRAEs occurred in 66.7% of pts in the TV+T cohort and 81.3% of pts in the TV+T+Chemo cohort. The most common Grade ≥3 TRAEs (incidence ≥20%) were decreased neutrophil count in the TV+T cohort, and decreased neutrophil count and decreased white blood cell count in the TV+T+Chemo cohort. TEAEs leading to dose reduction occurred in 17.9% (Grade ≥3: 12.8%) and 43.8% (Grade ≥3: 18.8%) of pts, respectively. TEAEs led to treatment discontinuation occurred in 15.4% (Grade ≥3: 7.7%) and 31.3% (Grade ≥3: 28.1%), respectively. No treatment-related deaths were reported. Conclusions: TV+T, with or without chemotherapy, demonstrated encouraging anti-tumor activity and manageable safety as first-line treatment for CLDN18.2-positive advanced G/GEJ cancer. The doublet shows comparable efficacy to the triplet with enhanced tolerability, supporting further large-scale clinical investigation. Clinical trial information: NCT05934331 .
A multi-agent AI platform for clinical trial operations: Specialized agents to accelerate feasibility assessment while ensuring data accuracy.
e13646 Background: Clinical trial feasibility assessment typically requires 3-4 weeks of manual data gathering across regulatory databases, site performance records, and protocol requirements. While large language models offer potential automation, single-model approaches risk data hallucination and inconsistent outputs across complex multi-source queries. We developed a multi-agent AI platform where specialized agents query validated databases under human expert oversight to accelerate feasibility workflows while maintaining data integrity. Methods: The platform employs a five-layer architecture with four specialized AI agents: (1) Query Agent converts natural language questions into structured database calls with 98% intent accuracy; (2) Compliance Agent validates outputs against GCP, ICH-E6, and 21 CFR Part 11 requirements; (3) Analytics Agent performs statistical correlation and anomaly detection across historical data; (4) Reporting Agent generates formatted documents from validated data sources. Critical differentiator: agents retrieve data from actual databases rather than generating information, eliminating hallucination risk at the architectural level. A human-in-the-loop (HITL) orchestration layer routes queries to appropriate agents and presents results for expert verification before finalization. Results: Deployment across 23 feasibility studies demonstrated: feasibility cycle time reduced from 28 to 11 days (61% reduction); report generation time decreased from 8 hours to 45 minutes (91% reduction); 98% natural language query accuracy; 23 regulatory compliance gaps identified that manual review missed; 100% QA audit pass rate with zero data integrity findings. HITL checkpoints showed 14% modification rate by human experts, with changes primarily reflecting local regulatory nuances (42%), recent personnel updates (31%), and sponsor-specific preferences (27%) not captured in training data. Conclusions: A multi-agent architecture with specialized database-querying agents and human oversight achieves 61-91% efficiency gains in clinical trial feasibility assessment while eliminating AI hallucination risk. The 14% HITL modification rate validates the necessity of expert oversight while demonstrating that AI can reliably handle 86% of routine queries. This approach offers a scalable model for AI-augmented clinical operations that maintains regulatory compliance and data integrity.
Palliative care utilization patterns in chimeric antigen receptor T-cell therapy hospitalizations: A six-year nationwide analysis.
e23165 Background: Chimeric antigen receptor (CAR) T-cell therapy is commonly administered with curative intent for hematologic malignancies; however, a subset of patients experiences severe inpatient complications requiring high-acuity care. National patterns of palliative care consultation (PCC) during CAR T-cell therapy hospitalizations and their associations with mortality, goals-of-care decisions, complications, length of stay (LOS), and healthcare costs remain poorly characterized. Methods: We conducted a retrospective cohort study using the Nationwide Inpatient Sample (2017–2022). Adult hospitalizations for acute lymphoblastic leukemia, non-Hodgkin lymphoma (NHL), or multiple myeloma (MM) in which CAR T-cell therapy was administered were identified using ICD-10-PCS codes. PCC was defined using ICD-10-CM diagnosis codes. Survey-weighted analyses generated national estimates. Multivariable logistic and linear regression models assessed associations between PCC and clinical outcomes, adjusting for demographics, comorbidity burden, payer status, and hospital characteristics (two-sided p < 0.05). Results: Among an estimated 5,850 CAR T-cell therapy hospitalizations, 405 (6.9%) involved PCC. Patients receiving PCC were most likely to have NHL (70.4%) followed by MM (21.0%), higher comorbidity burden (Charlson Comorbidity Index > 2: 56.8% vs. 44.8%, p < 0.05), and protein-energy malnutrition (50.6% vs. 16.4%, p < 0.05). There were no differences in age, sex, race, income quartile, or insurance type. PCC independently predicted in-hospital mortality (23.5% vs. 1.1%; adjusted odds ratio [aOR], 32.4; 95% CI, 12.2–85.7) and was strongly associated with Do-Not-Resuscitate status (aOR, 34.5; 95% CI, 13.5–87.7) and discharge to hospice or post-discharge supportive care (aOR, 2.5; 95% CI, 1.4–4.3). PCC was associated with sepsis (aOR, 4.4; 95% CI, 2.1–9.5), acute kidney injury (aOR, 2.0; 95% CI, 1.03–3.72), respiratory failure (aOR, 4.3; 95% CI, 2.2–8.0), shock (aOR, 5.5; 95% CI, 2.7–11.2), mechanical ventilation (aOR, 11.0; 95% CI, 5.4–22.5), renal replacement therapy (aOR, 4.9; 95% CI, 1.4–16.5), and vasopressor use (aOR, 5.1; 95% CI, 2.2–11.9). PCC was associated with longer adjusted LOS (+13.8 days) and higher hospitalization charges (+$584,197; both p < 0.05). No significant associations were observed with cytokine release syndrome or thrombo-hemorrhagic complications. Conclusions: Findings from this nationally representative cohort of CAR T-cell therapy hospitalizations suggest that palliative care involvement reflects clinical severity rather than treatment failure and remains underutilized (6.9%). Furthermore, they align with prior literature supporting earlier integration of palliative care alongside disease-directed therapy to enhance complex inpatient decision-making.
Maintenance liposomal doxorubicin following induction doxorubicin in soft tissue sarcoma: A single-center observational study.
e23568 Background: Maintenance chemotherapy prolongs progression-free survival (PFS) in several malignancies, but its role in soft tissue sarcoma (STS) remains unclear. Conventional doxorubicin is limited by cumulative toxicities. Liposomal doxorubicin offers a safer formulation and may enable prolonged therapy. Given the absence of prospective data, real-world evidence may inform feasibility and potential clinical benefit in STS. We evaluated outcomes of patients treated with maintenance liposomal doxorubicin following induction doxorubicin. Methods: This was a single-center retrospective study using the Quebec Sarcoma Registry (SaRC-Q) data from 2015 to 2025. Eligible patients had histologically confirmed STS and received doxorubicin-based induction therapy. Those achieving disease control, defined as stable disease, partial response or complete response, were subsequently treated with maintenance liposomal doxorubicin. Clinical variables included demographics, tumor characteristics, treatment details, adverse events, and outcomes. PFS and overall survival (OS) were analyzed using Kaplan-Meier estimates. Results: Twenty-four patients were included (median age 64 years; 62.5% male). The most frequent histologies were leiomyosarcoma and undifferentiated pleomorphic sarcoma (29.2% each). At diagnosis, 62.5% had localized disease and subsequently developed recurrent metastatic disease, while 37.5% presented with metastatic disease. Median induction exposure was six cycles. Maintenance liposomal doxorubicin was administered at 40 mg/m² every 28 days in 96% of patients for a median of 5 cycles (range, 1-19). Median PFS was 12.6 months (95% CI 10.4-14.8 months) and median maintenance PFS was 6.7 months (95% CI 4.2-9.2 months). Oligoprogression occurred in 20.8% of patients and was managed with local therapy. Commonly reported adverse events included anemia (21%) and fatigue (21%), with cardiac toxicity, cutaneous reactions, and peripheral edema each occurring in 8% of patients. Treatment was discontinued in 15 patients (62.5%) due to progression and in 2 patients (8.3%) due to adverse events, while 5 patients (20.8%) remained on therapy at data cutoff. Median OS was 60.3 months (95% CI 24.2-65.6 months). Conclusions: In this retrospective real-word cohort, maintenance liposomal doxorubicin appeared feasible, durable and well tolerated, with encouraging disease control in selected patients with advanced STS. These findings provide the first dedicated real-world evidence describing maintenance liposomal doxorubicin following induction doxorubicin and support prospective evaluation of anthracycline-maintenance strategies in STS.
Development of a multivariable prognostic model for pathological response using anatomical and pathological variables in early triple-negative breast cancer treated with neoadjuvant chemo-immunotherapy: Initial results.
612 Background: The combination of chemotherapy and immune checkpoint inhibitors is the standard of care for most patients with early triple negative breast cancer (eTNBC). Higher residual cancer burden (RCB) after receiving neoadjuvant chemo-immunotherapy (NCI) is associated with worse outcomes; however, reliable tools to predict pathological response remain limited. Methods: We conducted a multicenter prospective cohort study including patients with eTNBC treated with NCI. Anatomical and pathological variables were collected. Multivariable logistic regression was used to develop a prognostic model for pathological response. RCB 0–1 was the primary outcome. p < 0.1 was used for the selection of candidate parameters, and p < 0.05 for the final assessment of the multivariate model. ROC curves and the Hosmer-Lemmershow tests were applied to assess the model performance Results: A total of 109 patients with eTNBC with NCI from six centers in Argentina were included, with tumor samples centrally collected and reviewed for centralized pathological assessment. Regarding the immune microenvironment, qualitative tumor-infiltrating lymphocytes (TILs) were categorized according to the International Immuno-Oncology Biomarker Working Group classification as low (score 1) in 44.4% and intermediate-to-high (scores 2–3) in 55.6% of patients. Pathologic complete response (pCR) was achieved in 64.8% of patients. Histological grade (Grade 3 vs. 2: OR 3.2; 95% CI 0.95–11), TIL categories (TILs score 2: OR 3.4; 95% CI 0.84–14 and score 3: OR 6.3; 95% CI 1.1–37) and axillary node involvement (present vs. absent: OR 0.28; 95% CI 0.083–0.95) were selected for the final multivariate model. The final model showed good discrimination (AUC = 0.82) with adequate calibration, confirmed by a non-significant Hosmer–Lemeshow test (χ² = 3.28, p = 0.35). Conclusions: The model enabled stratification of patients into distinct risk groups with significantly different probabilities of achieving RCB scores of 0 or 1. This approach may provide additional information for risk stratification and prognosis, improving our understanding of which patients are more likely to achieve pathological response. Further studies will assess the external validation of the model.
SWOG S2414 (INSIGHT): A randomized phase III trial incorporating pathologic complete response in participants with early-stage non-small cell lung cancer to optimize immunotherapy in the adjuvant setting.
TPS8131 Background: Neoadjuvant chemo-immunotherapy (chemo-IO) followed by surgery is a standard of care for resectable clinical stage II-IIIB non-small cell lung cancer (NSCLC). Pathologic complete response (pCR), achieved in roughly 20% of patients, is associated with a favorable overall survival rate, but the benefit of additional adjuvant immunotherapy (IO) after pCR has not been independently studied and remains uncertain. The potential for overtreatment and unnecessary toxicity is a critical question in these patients. SWOG S2414 (INSIGHT) is designed to determine the optimal adjuvant therapy strategy for patients with pCR after neoadjuvant chemo-IO. Methods: INSIGHT (NCT06498635) is an open-label, randomized phase III trial, in which patients with clinical stage II-IIIB NSCLC who achieved pCR after standard of care neoadjuvant chemo-IO are randomized to adjuvant durvalumab IV every 28 days for up to 12 cycles (durvalumab, arm A) versus no further treatment (active surveillance, arm B). The primary objective is to compare disease free survival (DFS) between participants in the two arms. Key secondary endpoints include overall survival, event-free survival, and patient-reported quality of life (using the FACT-L and FACT-BRM) and symptoms (using PRO-CTCAE). The total enrollment goal is 306 participants. The design includes 2 interim analyses. Participants must have NSCLC with no known EGFR mutations or ALK fusions, and must have received at least two cycles of an FDA-approved neoadjuvant platinum-based chemo-IO regimen with an anti-PD-1/PD-L1 agent. Pathologic complete response will be confirmed by local pathology. Current Status: S2414 was activated on 3/14/2025, the first patient was registered on 4/1/2025. Enrollment is open and ongoing. Clinical Significance: INSIGHT is a pivotal trial addressing the therapeutic dilemma of adjuvant treatment for early-stage NSCLC patients with pCR after neoadjuvant chemo-IO. The results will help determine whether adjuvant IO provides a significant DFS benefit over surveillance in patients with a pCR, potentially leading to de-escalation of therapy and reduced toxicity. Funding: NIH/NCI grants U10CA180888, U10CA180819; additional support by AstraZeneca. Clinical trial information: NCI-2024-05588 .
Impact of vorasidenib vs placebo on seizure rates and quality of life: Exploratory analysis from the phase 3 INDIGO study.
2043 Background: Grade 2 diffuse gliomas with isocitrate dehydrogenase 1/2 mutations (mIDH1/2) are incurable brain tumors with poor long-term prognosis and tumor-related symptoms, eg seizures, that negatively impact patients’ (pts) quality of life (QoL). Vorasidenib (VOR) is an oral, brain-penetrant, dual inhibitor of mIDH1/2 approved in >40 countries for treating grade 2 mIDH1/2 gliomas following the positive clinical outcomes, including tumor volume reduction, shown in the Phase 3 INDIGO study (NCT04164901). We investigated the effect of long-term VOR treatment on seizure activity and QoL in pts with mIDH1/2 glioma in INDIGO. Methods: Pts aged ≥12 years with grade 2 mIDH1/2 glioma, no prior glioma treatment other than surgery and with controlled seizures were randomized 1:1 to receive VOR 40 mg or placebo (PBO) daily. Data from the pre- and post-unblinding periods were used; PBO pts after crossover were excluded from the analyses. Exploratory analyses for the number of on-treatment seizures were conducted in pts with ≥1 seizure in the baseline or on-treatment periods using a negative binomial regression model. Seizure severity was self-reported (1 [not bad] to 10 [as bad as imaginable]). QoL was measured using the Functional Assessment of Cancer Therapy – Brain (FACT-Br) scale and FACT-Br brain cancer subscale (BrCS), and changes were estimated with time-to-event analysis. Results: During the study, 110/331 pts (33.2%) reported ≥1 seizure (VOR n=55; PBO n=55). VOR treatment showed a constant and sustained effect on seizure control, reflected by significantly lower seizure rates per person per year than in the PBO group (Table), and lower number and severity of seizures over time. In addition, in pts with a seizure burden (≥1 seizure), VOR significantly delayed time to first worsening of FACT-Br and FACT-Br BrCS scores (hazard ratio [95% confidence interval]: FACT-Br, 0.38 [0.15, 1.00], P =0.0435; FACT-Br BrCS, 0.32 [0.11, 0.91], P =0.0263). Conclusions: In pts with mIDH glioma and ≥1 on-study seizure, long-term VOR treatment generally led to a sustained decrease in seizure activity and severity and delayed worsening of QoL. These results suggest that VOR may have an additional benefit on QoL in pts who experience seizures. Clinical trial information: NCT04164901 . Exploratory analyses of VOR treatment and seizure rate in pts who reported ≥1 seizure in the baseline or on-treatment periods in INDIGO. VOR(n = 56) PBO(n = 56) Patients with ≥1 on-treatment seizure, n (%) 55 (98.2) 55 (98.2) Rate of on-treatment seizures per person-year* (95% CI) 13.2 (5.8, 29.8) 64.9 (26.5, 159.1) Ratio of rates: VOR vs PBO (95% CI) 0.20 (0.08, 0.52) Two-sided P value † 0.0008 *Estimated using negative binomial regression model adjusted by number of seizures and tumor size at baseline. † Not prespecified and not adjusted for multiplicity; should be interpreted with caution. Data cut-off: January 17, 2025. CI, confidence interval; PBO, placebo; VOR, vorasidenib.
Assessing site-central baseline imaging discordance in oncology clinical trials.
11028 Background: Eligibility determination is a critical and rate-limiting step in oncology clinical trials and directly influences endpoint interpretability. Across oncology indications, eligibility frequently depends on prespecified imaging criteria that function as binary gatekeepers to enrollment, with blinded independent central review (BICR) commonly used to standardize image interpretation. In many solid tumor trials using RECIST 1.1, participants must demonstrate measurable disease; in many lymphoma trials using Lugano criteria, FDG-avid disease is required; and in prostate cancer trials using PCWG3 criteria, the presence of a bone scan superscan is typically exclusionary. Often participant eligibility is established by site investigators, while BICR radiologists independently assess baseline and on-study imaging without determining enrollment, creating potential site–central discordance at baseline. We hypothesized that baseline imaging discordance exists between site and BICR and evaluated its frequency and potential relevance to clinical trial endpoint interpretation. Methods: We performed a preliminary analysis of 17,104 baseline BICR reviews among enrolled participants evaluated using RECIST 1.1 requiring measurable disease (n = 7,189), Lugano criteria requiring FDG-avid disease (n = 2,653), and PCWG3 (n = 7,262) criteria. Results: For the RECIST 1.1 subset, BICR determined that 11.0% (n = 791) of enrolled participants lacked measurable disease at baseline. Among these participants, subsequent responses included CR (n = 36), PD (n = 93), and SD (n = 207). Because partial response under RECIST 1.1 requires measurable target lesions, participants without measurable disease are inherently constrained in the spectrum of evaluable responses, potentially biasing response rate. For the Lugano subset, BICR determined that 1.5% (n = 41) of enrolled participants lacked FDG-avid disease at baseline, with subsequent anatomic-only responses of CR (n = 1), PR (n = 5), SD (n = 9), and PD (n = 2). Though infrequent, site-central differences under Lugano criteria may influence response assessment, as BICR evaluated anatomic change while site incorporates metabolic response. For the PCWG3 subset, 7.0% (n = 548) of enrolled participants demonstrated a baseline superscan by BICR, with subsequent responses of CR (n = 20), PR (n = 25), SD (n = 90), and PD (n = 91). In these cases, response assessment is largely limited to soft tissue disease. Conclusions: The observed site-central imaging discordance reflects differences between eligibility and imaging assessments rather than incorrect site enrollment decisions and is not uncommon across major oncology response criteria, with potential implications for efficacy assessment in trials where eligibility is site-determined but response is centrally adjudicated. This analysis supports further investigation incorporating additional criterion-specific analysis.
Circulating tumor DNA (ctDNA) from a phase II study of adjuvant dostarlimab with pelvic radiation in locally advanced, mismatch repair–deficient (MMR-D) endometrial cancer (D-RT study).
5613 Background: Although ctDNA is a promising, non-invasive tool for cancer evaluation and monitoring, it’s use in endometrial cancer (EC) is currently limited. We sought to evaluate ctDNA dynamics and associations with clinical outcomes as part of a novel study of adjuvant immune checkpoint blockade (ICB) with radiation (RT) in locally advanced MMR-D EC. Methods: The D-RT study was an investigator-initiated, single-arm, phase II trial evaluating the safety and efficacy of 5 cycles of dostarlimab given concurrently with standard pelvic intensity modulated RT (IMRT), NCT04774419. The study included patients with newly diagnosed clinical stage III/IVA MMR-D EC. Primary endpoint was progression-free survival (PFS) at 2 years defined by RECIST V1.1 compared with historical control. All patients consented to MSK-IMPACT tumor-normal genetic testing. We performed MSK-ACCESS targeted ctDNA sequencing in a subset of patients with at least 3 timepoints (baseline post-surgery, on-treatment, post-treatment/follow-up) and correlated with baseline tumor genomics and clinical outcomes. Results: We previously reported the primary endpoint in 31 evaluable patients with 2-year PFS of 80.6% (95% 1-sided CI 65.3-100%), meeting pre-specified threshold for a positive study (data cutoff 8/1/2025). Here, we report ctDNA results from a subset of 15 patients with 58 total samples. Median age was 62 years (range 51-89 years) with 1 stage IB (i+), 3 stage IIIA, 9 stage IIIC1, and 2 stage IIIC2 MMR-D ECs (FIGO 2009). Histology included 8 endometrioid grade I/II, 5 endometrioid grade III, and 2 dedifferentiated carcinomas. Six patients (40%) had detectable baseline ctDNA post-surgery, with 5/6 (84%) having visible/residual disease at baseline. Of these, 3/6 (50%) had eventual disease recurrence post adjuvant treatment. In 8 patients with visible disease post-surgery, only 2 did not have detectable baseline ctDNA. ctDNA cleared post-treatment in all but 2 patients who had aggressive, dedifferentiated carcinomas. Among the 5 patients with recurrence (4 distant, 1 local), ctDNA detection preceded or coincided with radiographic detection of disease in the 4 patients (80%) with distant disease. One patient had a biopsy-proven, vaginal cuff recurrence only and never had detectable ctDNA. In the 10 patients without disease recurrence, none had detectable ctDNA post-treatment. Conclusions: In patients with locally advanced MMR-D EC, ctDNA detection after surgery correlated with visible disease. ctDNA levels declined during dostarlimab and RT treatment for most patients, and ctDNA detection was correlated with disease recurrence in distant but not local disease, suggesting its potential as a non-invasive marker of disease. Future studies should explore the utility of ctDNA as a disease monitoring tool to guide therapy decisions. Clinical trial information: NCT04774419 .
Temporal trends in ischemic heart disease mortality among lymphoma patients in the United States, 1999–2023: A 25-year nationwide analysis.
7092 Background: Enhanced lymphoma survival has transitioned clinical priorities toward non-malignant late effects, particularly cardiovascular morbidity. Although life-extending therapies like radiation and anthracyclines are effective, their cardiotoxic profiles significantly increase Ischemic Heart Disease (IHD) risk. Despite this, longitudinal trends and demographic disparities in lymphoma-IHD mortality remain under-investigated. This study analyzes 24 years of data to characterize mortality shifts and identify vulnerable populations, aiming to optimize integrated cardio-oncology management. Methods: We conducted a population-based retrospective analysis using the CDC WONDER Multiple Cause of Death database from 1999 to 2023. Deaths among individuals with lymphoma were identified using ICD-10 codes C81–C85, and IHD-related deaths were identified using ICD-10 codes I20–I25. Age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated and stratified by sex, race/ethnicity, geographic region, urbanization status, and place of death. Temporal trends were analyzed using Joinpoint regression to estimate annual percent change (APC) and average annual percent change (AAPC). Results: Between 1999 and 2023, a total of 61,480 deaths were reported among individuals with both lymphoma and IHD in the United States. The overall AAMR declined from 0.93 in 1999 to 0.62 in 2023. Females had a lower overall AAMR compared with males (0.43 vs 1.13). By race/ethnicity, Non-Hispanic individuals had a higher AAMR than Hispanic individuals (0.74 vs 0.46). Regionally, the Midwest had the highest overall AAMR (0.84), while the South had the lowest (0.64). A higher AAMR was observed in non-metropolitan compared with metropolitan areas (0.84 vs 0.69). Most deaths occurred in inpatient medical facilities (22,633 deaths; 36.8%), followed by deaths at home (18,922 deaths; 30.8%). Conclusions: While mortality has declined overall, continued excess risk among males, rural residents, and Midwestern populations highlights inequities in care delivery. Expanding integrated cardio-oncology programs in non-metropolitan areas may further reduce national mortality. Comparative analysis of age-adjusted mortality rates (AAMR) for comorbid lymphoma and ischemic heart disease by demographic and geographic subgroups (1999–2023). Category Group with Highest AAMR Group with Lowest AAMR Sex Males (1.13) Females (0.43) Ethnicity Non-Hispanic (0.74) Hispanic (0.46) Region Midwest (0.84) South (0.64) Urbanicity Non-metropolitan (0.84) Metropolitan (0.69)
Fetal-like epithelial niches at the invasive margin to inform prognosis in colorectal cancer.
e15118 Background: The development of metastases remains a major unmet challenge in colorectal cancer (CRC), due to limited mechanistic understanding and a lack of effective preventive therapies. Adjuvant chemotherapy provides only modest benefit and is not tailored to individual tumor biology. Whereas neoadjuvant chemotherapy trials show limited impact on metastatic risk, prompting exploration of immunotherapy and targeted approaches aimed at controlling metastasis-initiating cells. Emerging evidence indicates that epithelial plasticity and fetal-like reprogramming enable tumor cells to persist at the invasive margin (IM) through interactions with the tumor microenvironment. Tissue-based machine learning on H&E whole-slide images (WSIs) allow identification of high-risk histologic regions at the IM. We and others have shown these tissue features are strongly prognostic, highlighting them as potential targets for drug development within tumors and circulation. In this study we aimed to define the spatial, biological, and histologic features of such epithelial niches in CRC. Methods: We analyzed 20 CRC scRNA-seq and 16 matched Xenium spatial transcriptomics datasets (322-gene colon panel plus 100 custom genes) to define cell states and map their spatial organization. INSIGHT, a graph neural network on paired H&E WSIs, identified histologic regions associated with recurrence risk and integrated spatial single-cell abundances. Results: A fetal-like ANXA1⁺ epithelial subtype, defined by loss of adult colonic identity and reactivation of regenerative programs, was identified by scRNA-seq and exhibited extracellular matrix remodeling and inflammatory pathway engagement. Spatial neighborhood analysis on Xenium defined ten niche types along the tumor core–to–IM axis. Fetal-like cells, mapped via single-cell–to–spatial label transfer, were enriched in IM-associated niches versus core (16.54 vs 5.22 cells/mm²; p < 1 × 10⁻³) and co-localized with SPP1⁺ macrophages. Spatial trajectory analysis revealed a gradual shift from adult stem-like to fetal-like programs toward the IM, with downregulation of canonical WNT and colon lineage genes (AXIN2, CDX2) and upregulation of fetal/matrix remodeling genes (ANXA1, MMP7) (|ρ| ≥ 0.1, FDR < 0.05). Integration with INSIGHT showed high-risk regions were enriched for fetal-like cells and SPP1⁺ macrophages at the IM, both positively associated with regional survival risk scores (β = 0.0033 and 0.0042; p < 10⁻⁴). Conclusions: Fetal-like epithelial niches at the CRC invasive margin, co-localized with SPP1⁺ macrophages, define high-risk tissue states. Integration with AI-based histologic analysis underscores the prognostic relevance of these niches and their potential as targets for tailored (neo)adjuvant interventions.