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A phase II, multicenter, single-arm clinical trial of response-adapted definitive radiotherapy and cemiplimab-rwlc immunotherapy for locally advanced, unresectable cutaneous squamous cell carcinoma: RAMPART.
9506 Background: Locally advanced (T3-4/N+/M0) and unresectable cutaneous squamous cell carcinoma (LAUCSCC) patients (pts) have been historically treated with definitive radiotherapy (RT) +/- chemotherapy, yielding poor outcomes (18m progression-free survival [PFS] rates of ~38%). More recently, anti-PD1 immunotherapy with cemiplimab (cemi) led to an 18m PFS rate of ~55% in locally advanced pts that were not candidates for RT or surgery. In this prospective, multicenter trial, we assessed definitive RT with neoadjuvant, concurrent, and adjuvant cemi for LAUCSCC pts. Methods: Pts with T3-4/N+/M0 LAUCSCC according to local multidisciplinary consensus, ECOG ≤2, were enrolled and treated with 2 doses of cemi (350 mg IV q3w). Those with progressive disease (PD) after 2 doses received RT (70 Gy/35 fractions). Those without PD received 2 additional doses of cemi followed by response-adapted RT (50-70 Gy/25-35 fractions) with concurrent cemi followed by adjuvant cemi for a maximum of 1y. The primary endpoint was event free survival (EFS) at 18m after cemi start. Secondary endpoints included safety, response (by RECIST v1.1, see table), quality of life, overall survival (OS) and PFS (after RT start). To test the hypothesis that the 18m EFS was 60%, compared to a historic 18m PFS rate after RT of 38% with 80% power and 5% type 1 error rate, 34 pts were planned for enrollment (accounting for 40% attrition). Results: 34 pts (median age 77y, 82% men, ECOG 0/1/2 in 41/53/6%) were enrolled with stage III (41%) and IV/M0 (59%) LAUSCC (56% recurrent, 91% head/neck) between 2022-2024. 85% completed 4 doses of neoadjuvant cemi and 94% completed RT as planned. With median follow up of 18m (range 2-36m), 18m EFS is estimated to be 86% (1 sided 95% CI lower bound of 73%) among all pts. Adverse events were consistent with prior studies of cemi or RT. 18m PFS and OS are estimated to be 86% and 92%. Quality of life analyses are in progress. Conclusions: The study met its primary endpoint demonstrating the highest rate of EFS, PFS and OS after treatment of LAUCSCC ever reported. As the largest prospective study of definitive RT for LAUCSCC, the data suggest integrating cemi with RT may benefit appropriate pts. Future studies identifying pts who are best served with this approach are warranted. Clinical trial information: NCT05574101 . Response over time. Complete response Partial response Stable disease Progressive disease Non-response/Non-progression 1 NA 2 Time 6w post cemi 1 (3%) 11 (32%) 15 (44%) 3 (9%) 4 (12%) 0 12w post cemi 4 (12%) 15 (44%) 6 (18%) 1 (3%) 4 (12%) 4 (12%) 12w post RT 10 (29%) 10 (29%) 4 (12%) 3 (9%) 4 (12%) 3 (9%) 18m post cemi 11 (32%) 6 (18%) 0 1 (3%) 4 (12%) 12 (35%) 1 Pts with non-target lesions only. 2 Pts not assessed (response assessment pending or not performed because of PD at 6w post cemi, or withdrawal).
Readmissions after CNS tumor surgery and associations with social determinants of health.
e14040 Background: Socioeconomic status (SES) and social determinants of health (SDOH) may impact outcomes in patients with central nervous system (CNS) tumors. Prior studies suggest public or absence of insurance coverage, neighborhood-level deprivation, and structural inequities are associated with higher 30- and 90-day hospital readmission rates following craniotomy and tumor-directed neurosurgical care. This study evaluated the association between SES and SDOH-related factors and unplanned readmissions among adults undergoing surgery for primary CNS tumors at an urban, tertiary-care hospital. Methods: This retrospective cohort study assessed adult patients with primary CNS tumors who underwent craniotomy or biopsy between 01-2023 and 12-2024. Patient demographics, tumor characteristics, insurance status, and neighborhood-level socioeconomic data were abstracted from an institutional registry. Unplanned readmissions within 30 and 90 days of discharge were identified. Neighborhood SES was estimated using ZIP code–level poverty data from the U.S. Census. Descriptive and inferential statistical analyses compared readmission patterns across demographic, clinical, and SES variables. Results: Among 233 patients, 132 (56.7%) were female; the median age was 60 years (range, 18–85). 34 patients (14.6%) experienced unplanned readmissions within 30 days, and 55 (23.6%) within 90 days. Readmissions were more frequent in patients with malignant tumors. Tumor histology demonstrated a statistically significant association with readmission (p=0.033); glioblastoma accounted for most 90-day readmissions (31/55; 54.4%) and had the highest tumor-specific readmission rate (34.4%) relative to meningioma (17.5%) or pituitary adenoma (8.7%). Male patients showed a trend toward higher readmission rates than female patients (28.7% vs. 19.7%; p = 0.12). No statistically significant associations were noted between readmission and insurance status, payer class, or race/ethnicity, likely reflecting limited statistical power and small subgroup sizes. Conclusions: Approximately 24% of patients with primary CNS tumors experienced unplanned readmission within 90 days of surgery. Tumor biology, particularly malignant tumors like glioblastoma, was the strongest risk factor for readmission in this cohort. Sex-based differences demonstrated a trend toward higher readmission among male patients. SES- and SDOH-related factors showed no significant association. This study supports the role of tumor invasiveness as a key driver of postoperative readmissions and highlights the need for larger, multi-institutional studies to evaluate the impact of SDOH on and strategies to mitigate unplanned readmissions.
Subtype-specific PI3K-pathway and TP53 alteration patterns in breast cancer: A cross-cohort comparison of TCGA-BRCA and AACR GENIE.
e13011 Background: The PI3K pathway is among the most actionable signaling axes in breast cancer, yet its alteration frequency and genomic context may differ between research-grade primary tumor datasets and real-world clinico-genomic cohorts. We compared PI3K-pathway alteration prevalence and TP53 co-mutation patterns between TCGA-BRCA and AACR GENIE (breast). Methods: We analyzed TCGA-BRCA (n = 971) and GENIE breast cancer (n = 1221) using a harmonized gene set: PIK3CA, AKT1, PTEN, TP53. “PI3K-pathway altered” was defined as any mutation in PIK3CA and/or AKT1 and/or PTEN. Within-pathway relationships (mutual exclusivity/co-occurrence) were assessed using Fisher’s exact tests (odds ratios [OR]). TP53 co-mutation was evaluated across PI3K alteration classes (PIK3CA-only, AKT1-only, PTEN-only, ≥2 PI3K genes, PI3K-wildtype). Subtype-stratified analyses were limited to subtype-annotated samples. Results: Overall, PI3K-pathway alterations were common in both cohorts but higher in TCGA than GENIE (40.3% vs 35.7%, p = 0.0298). TP53 alterations were more frequent in GENIE than TCGA (46.3% vs 34.4%, p = 2.12×10⁻⁸). Within the PI3K pathway, PIK3CA and AKT1 were mutually exclusive in both cohorts (GENIE OR = 0.23, p = 0.00688; TCGA OR = 0.15, p = 0.00172).  In subtype-annotated samples, PI3K alteration prevalence was highest in HR+/HER2− disease (TCGA 48.8%) and lower in TNBC (TCGA 17.7%, GENIE 12.2%). TP53 co-mutation was enriched in TNBC (TCGA 82.3%, GENIE 89.9%) compared with HR+/HER2− (TCGA 20.9%), and TP53 rates varied across PI3K alteration classes within each subtype.  Conclusions: PI3K-pathway alterations are frequent across both TCGA and GENIE breast cancer cohorts, but their prevalence and TP53 genomic context differ, including in a subtype-dependent manner. These findings highlight how real-world and research cohorts can yield distinct actionable-landscape estimates and support interpreting PI3K-targeted strategies within subtype-specific, co-mutational contexts.
Interstitial lung disease risk and outcomes across HER2-targeted therapies commonly used in breast cancer: Analysis of real-world FAERS data.
e24206 Background: Anti-HER2 therapies, including the monoclonal antibody Trastuzumab and antibody-drug conjugates (ADCs) TDM-1 and TDX-d, have transformed treatment for HER2-positive breast cancers. While effective, all these agents carry the risk of interstitial lung disease (ILD), a serious adverse event with newer ADCs, particularly TDX-d, may pose a higher ILD risk. Assessing the real-world comparative risk is vital for clinical decision-making. This study uses the FAERS database to compare the reporting risk of ILD among Trastuzumab, TDM-1, and TDX-d. Methods: We conducted a retrospective FAERS data review to assess the ILD risk of Trastuzumab, TDM-1, and TDX-d from 2020 to 2026. The chi-square test was used to compare categorical variables across drugs and age groups ( < 65 vs ≥65 years). Results: Among 47,068 total cases (Trastuzumab n = 30,067; TDM-1 n = 5,805; TDX-d n = 11,196), TDX-d demonstrated the highest risk of ILD toxicity rate at 13.1% compared to 2.7 % for TDM-1 and 1.9 % for Trastuzumab (χ² = 2339.3, p0.001). Age-stratified analysis revealed persistence of the pattern of ILD toxicity rate across the three treatment groups, for < 65 and ≥65 years. For < 65 years, TDX-d demonstrated the highest risk of ILD toxicity rate at 11.7% compared to 2.04 % for TDM-1 and 1.2 % for tratsuzumab (χ² = 1021.6, p0.001). For ≥65 years, TDX-d demonstrated the highest risk of ILD toxicity rate at 15.3% compared to 4.6% for TDM-1 and 3.4% for Trastuzumab (χ² = 347.4, p0.001). Older patients ≥65 years have a significantly higher risk of ILD compared with patients < 65 years across all three treatment groups (TDX-d: 11.7% vs 15.3%, p000.2; TDM-1: 2.04% vs 4.6%, p0.001; Trastuzumab: 1.27% vs 3.46%, p0.001). Among patients who developed ILD, deaths and hospitalization were assessed across the drugs. TDX-d demonstrated the highest death rate of 4.04%, followed by TDM-1 with 0.49%, and Trastuzumab with 0.34% (χ² = 941.4, p0.001). The hospitalization rate was also noted to be higher for TDX-d (5.18%) compared to TDM-1 (1.06%) and Trastuzumab (0.81%), p0.001. Conclusions: The findings in this study highlight the trends of ILD among various HER2-targeted therapies. TDX-d demonstrated disproportionately lower hospitalization rates relative to the mortality burden compared to TDM-1 and Trastuzumab. This underscores the need for enhanced monitoring, early detection strategies, and lower thresholds for hospitalization in patients receiving TDX-d.
Digital symptom monitoring using Careology at Guy’s and St Thomas’ NHS Foundation Trust (GSTFT).
e13715 Background: Careology is a digital health platform for cancer patients receiving Systemic Anti-Cancer Therapy, enabling real-time toxicity reporting to healthcare teams. Patients grade symptom severity using the embedded UK Oncology Nursing Society red/amber/green triage system. Those reporting red or two amber symptoms are signposted to GSTFT’s 24-hour Acute Oncology Service (AOS). Operational staff monitor the Careology dashboard and proactively follow up to triage patients to appropriate services such as AOS or ED. Patients with mild symptoms can access Boots Macmillan Information Pharmacists for advice and prescriptions. This study reports anonymised real-world usage and downstream clinical impact. Methods: A retrospective analysis was conducted using anonymised data from 881 Careology users at GSTFT between July 2024 and December 2025. Outcomes for patients reporting red or multiple amber symptoms were extracted from electronic health records to assess downstream impact. Patient experience was evaluated via a feedback session and satisfaction survey. Results: Careology was rolled out at GSTFT, one of the UK’s largest tertiary cancer centres, in July 2024. Since deployment, 881 patients registered, including those with upper and lower GI (23.4%), breast (19.4%), and gynaecological cancers (11.1%). The most reported toxicities were fatigue (13.9%), pain (11.9%), and nausea (10.2%). Feature engagement increased over time, with symptom, mood and medication tracking, and educational content most used. In a patient focus group, one participant taking 40 daily medications described Careology as “absolutely brilliant for medication reminders.” From the satisfaction survey (n = 35), 80% would recommend Careology, 75.8% felt more in control of their care, and 84.4% felt clinician access to Careology data would be beneficial. Between July 2024 and October 2025, 273 patients reported at least one red or two amber symptoms. In this group, the most prevalent diagnoses were breast (24.5%), gynaecological (15.4%), and lung cancer (12.8%); the most reported symptoms are detailed in Table 1. Outcomes included clinician review (17.7%), in-person assessment (8.9%), ED attendance or advice to attend ED (7%), AOS referral (19.6%), no further action following discussion (11.1%), and hospital admission (6.6%). Conclusions: Digital symptom monitoring using Careology enabled proactive outreach, timely escalation, and improved toxicity management and patient experience at GSTFT. Further integration into routine consultant and nursing workflows may enhance early identification of high-risk toxicities and improve visibility of patient health between visits. Most reported symptoms by patients logging a red or at least two amber symptoms. Red symptoms Amber symptoms Pain (17.7%) Fatigue (15%) Neurosensory issues (14.8%) Neurosensory issues (10.7%) Fever (14.3%) Pain (10.5%)
The future mortality trends in multiple myeloma (SEER analysis 2000–2030).
7550 Background: Novel therapies have transformed Multiple Myeloma (MM) from a rapidly fatal diagnosis into a chronic condition. However, this extended survival exposes patients to a new set of competing risks. We utilized the SEER database to quantify the evolving burden of cause-specific mortality in the modern era and project future mortality trends. Methods: We identified 129,837 patients diagnosed with MM from 2000–2022 using SEER-17 registries. Patients were stratified by era: Pre-Novel (2000–06), Early-Novel (2007–14), and Modern (2015+). Median overall survival (mOS) and cumulative incidence function of death (CIF) were analyzed using Kaplan-Meier estimates and Gray’s test, respectively. Fine-Gray competing risk regression was used to estimate sub-distribution hazard ratios (sHR) for non-cancer death. Non-cancer mortality burden was projected from 2021-2030 using linear regression models based on 2010–2021 trends. Results: Median Overall Survival (mOS) improved from 32 months (Pre-Novel era) to 49 months (Early-Novel era) and 63 months (Modern era) (p<0.001). Modern-era patients had lower odds of dying from MM compared to the Pre-Novel era (OR 0.68, 95% CI 0.66–0.71, p<0.001). The 5-year CIF of MM-specific death decreased from 46.5% (Pre-Novel) to 28.0% (Modern) while the non-cancer death remained stable (20.2% vs 20.7%). Among 82,585 total deaths recorded, Myeloma remained the primary cause (62.5%), while non-cancer causes accounted for 37.5%. Cardiovascular disease was the most common specific non-cancer cause, accounting for 11.4% (n=9,383) of all deaths. Early decedents (<3 years) had significantly higher odds of dying from Myeloma compared to late survivors (65.1% vs 58.5%; OR 1.32, p<0.001). In contrast, late survivors (≥3 years) had significantly higher odds of death from cardiovascular disease (OR 1.16, 95% CI 1.11–1.21, p<0.001) and Infections (OR 1.16, 95% CI 1.05–1.28, p=0.003) as compared to early decedents. In Fine-Gray competing risk models, the modern era was associated with a reduced relative hazard of non-cancer death (sHR 0.80, p<0.001). The population of MM is projected to grow by 34.5% (from ~47,200 to ~63,500) between 2022 and 2030 and annual Myeloma-specific deaths are projected to increase by 6.1% (~2,980) by 2030, annual non-Cancer deaths are projected to rise by 38.8% (~3,600). Conclusions: Novel therapies have nearly doubled median survival in MM, narrowing the "mortality gap" as non-cancer causes as now approach half of annual deaths. Despite reduced relative hazards, the absolute non-cancer burden is projected to rise 49% by 2030. This necessitates the need for comprehensive survivorship care for the management of MM.
Early-onset colorectal cancer trends and risk exposures in Ghana and the United States: A comparative ecological analysis based on Global Burden of Disease, 2023.
e15691 Background: Early-onset colorectal cancer (EOCRC), defined as colorectal cancer (CRC) diagnosis before age 50, is increasing globally. By 2030, it is projected to become one of the leading causes of cancer-related mortality among this age group. Although rising global incidence, there is limited population-level evidence describing the national trends and associated risk exposures in low- and middle-income countries. By comparing Ghana and the United States, our study aims to assess EOCRC incidence trends and explore ecological associations with life-course risk exposures across settings with differing disease burden, surveillance capacity and screening guidelines. Methods: Country-level data on CRC incidence by year, sex and age group were obtained from the Global Burden of Disease (GBD) 2023 from 1990 to 2023. EOCRC was defined as CRC incidence among individuals aged 15-49 years, estimated by aggregating age-specific incidence rates across 5-year age groups. Temporal trends were assessed using log-linear regression models to estimate the average annual percent change (AAPC) in EOCRC incidence, with sex-stratified trends. Early-life exposures (ages 0-19) were assessed using summary exposure values (SEVs) for sub-optimal breastfeeding and child growth failure, while young-adult lifestyle risk exposures (ages 20-49) were alcohol and tobacco use, high body mass index, and poor dietary patterns. Linear regression models were used to evaluate the ecological associations of EOCRC incidence and SEVs in both countries. Results: EOCRC incidence increased in both countries, from 1.36 to 2.13 per 100,000 in Ghana and 5.46 to 7.69 per 100,000 in the U.S. Ghana experienced a higher rise (AAPC = 1.31% per year; 95% CI: 0.63-1.99) compared to the U.S. (AAPC = 0.92%; 95% CI: 0.80-1.04). Females had higher incidence in Ghana, whereas incidence remained higher among males in the U.S. In Ghana, EOCRC incidence was positively associated with tobacco use (β = 2.71; 95% CI: 2.03-3.40), low-fiber diet (β = 0.32; 95% CI: 0.24-0.39), processed meat intake (β = 0.39; 95% CI: 0.33-0.44), and suboptimal breastfeeding (β = 0.12; 95% CI: 0.10-0.15), while child growth failure was inversely associated (β = -0.50; 95% CI: -0.73 to -0.27). In contrast, no risk exposures were significantly associated in the U.S. Conclusions: Early-onset colorectal cancer is rising in Ghana and the U.S., but study findings show that patterns differ. Early-life and lifestyle exposures observed in Ghana highlight the influence of life-course factors in a broader epidemiological and geographic context. This is especially relevant where early CRC screening and surveillance are limited. As these findings are based on ecological associations, further studies of individual-level exposures are needed to complement population-level evidence and inform timely prevention strategies.
Exploring the effects of T cell senescence in RCC and HGSOC.
e16542 Background: T cell senescence is an emerging mechanism of immune dysfunction characterized by impaired proliferation and reduced effector capacity. Although stressors such as obesity and chemotherapy can promote senescence, their effects on T cell senescence are less clear, as are the downstream consequences for therapy outcomes. Obesity increases the risk of both renal cell carcinoma (RCC) and high-grade serous ovarian cancer (HGSOC). We have reported that obesity is associated with poor outcomes in advanced RCC patients receiving anti–PD-1 immunotherapy, but the mechanistic basis for this observation remains unclear. In HGSOC, standard of care remains neoadjuvant chemotherapy followed by tumor resection. We hypothesized that obesity and chemotherapy independently promote T cell senescence, thereby decreasing responsiveness to standard of care therapies. Methods: To investigate the contribution of T cell senescence across these tumor types, we profiled intratumoral T cell senescence in RCC using diet-induced obese (DIO) and lean tumor-bearing mice by flow cytometry and evaluated human RCC tumor specimens from patients with or without obesity using COMET multiplex immunofluorescence. In parallel, we also evaluated intratumoral T cell senescence in HGSOC using COMET multiplex immunofluorescence in women with or without obesity using matched pre- and post-neoadjuvant chemotherapy to assess potential changes in intratumoral T cell senescence. Results: RCC tumors from patients with obesity exhibited increased senescent T cell populations compared to lean patients. Similarly, tumors from DIO mice demonstrated increased expression of senescence-associated markers, particularly among CD4+ T cells. Importantly, blockade of KLRG1, an inhibitory receptor associated with senescence and reduced T cell function, in combination with anti–PD-1 restored therapeutic responsiveness in DIO mice and improved outcomes to levels comparable to lean mice treated with anti–PD-1 alone. Conclusions: Collectively, these findings support a role for T cell senescence in impaired responses to therapy and highlight targeting senescence-associated pathways, including KLRG1 blockade, as a potential strategy to improve anti-tumor immunity, a strategy that could be applied across obesity-associated cancers.
Untargeted baseline metabolomic profiling to identify candidate markers of long-term severe cancer-related fatigue (CRF) in breast cancer (BC) survivors.
12118 Background: CRF is common and debilitating among BC survivors; however its predictors and underlying biology remain partially defined. We sought to identify baseline plasma metabolomic markers of subsequent CRF to inform risk prediction and symptom mechanisms. Methods: Baseline (pre-treatment [tx]) plasma samples from women with stage I-III ER+/HER2− BC in the CANTO cohort (NCT01993498) underwent untargeted metabolomic profiling (liquid chromatography and high-resolution mass spectrometry with electrospray ionization), yielding metabolic features for analysis. CRF was measured using EORTC QLQ-C30 (severe CRF: score≥40/100). Three penalized regression approaches (lasso, adaptive lasso, elastic net) were used to select baseline metabolites associated with severe CRF, adjusting for clinical covariates, including pre-tx CRF, age, body mass index, comorbidities, socioeconomic status, psychological distress, health behaviors, and tx. The cohort was split 2/3:1/3 (train:test); penalization factor λ was tuned in the train set by cross-validation. Clinical-only and clinical+metabolite features models were compared using test-set AUC, with bootstrap confidence intervals from resampled predictions (B = 1000). Covariate missingness was addressed by multiple imputation on 15 datasets. Metabolite annotation was conducted computationally using W4M, with manual curation and interpretation of spectra to identify key metabolites relevant to CRF. Results: In the train set (N = 645), mean age was 58 years (SD 10), 44% received chemo- and 90% endocrine-tx, 20% reported severe pre-tx CRF (similar characteristics in the test set; N = 325). 1935 metabolic features were analyzed. For severe global CRF at year-4 (prevalence 31%) the adaptive lasso clinical+metabolite features model included a 51-feature signature and had AUC = 0.70, specificity = 0.89, and sensitivity = 0.39 (sensitivity difference vs. clinical-only +0.17 [95% CI +0.06 to +0.29; p < .001]). Features with the largest penalized coefficients were concordant with univariate associations (all in the same direction) and showed clear differences in standardized levels between severe vs non-severe CRF. Nineteen features belonged to the annotated reference dataset, enabling putative identification of metabolites spanning endogenous pathways (including glycine [inverse association] and chenodeoxycholic acid [positive association]) and a likely exogenous/xenobiotic-related feature (mandelonitrile [positive association]). Conclusions: Baseline untargeted metabolomics identified a 51-feature signature associated with severe global CRF at year-4 after ER+/HER2− BC. Adding features selected via adaptive lasso to clinical covariates increased model sensitivity, and putative pathway mapping highlighted candidates for targeted validation and mechanistic studies.
Safety, PK/PD, and efficacy results from Expand-1: A phase 1 dose escalation study of the novel PD-1 targeted IL-2R-βγ agonist sunekafusp alpha (ANV600) as a single agent and in combination with pembrolizumab in patients with advanced solid tumors.
2587 Background: Sunekafusp alpha (ANV600) is a novel PD-1-targeted, IL- 2Rβ/γ agonist, which binds, without blocking, a unique epitope distinct from pembrolizumab, or other PD-1 checkpoint inhibitors. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of ANV600 administered intravenously in two different dosing regimen were investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab. A Bayesian Optimal Interval design guided the dose escalation to determine the MTD and RP2D. Results: 63 patients were treated: 44 in monotherapy at 10 to 150 μg/kg ANV600 and 19 in combination therapy at 30 to 90 μg/kg ANV600. The median (range) number of previous lines of treatment was 4 (1-16) in monotherapy and 4 (2-10) in combination therapy. In mono- and combination therapy 27 (61%) and 9 (47%) patients were previously treated with a checkpoint inhibitor (CPI). ANV600 was generally well tolerated. Most common treatment related adverse events were pyrexia, transient and self-limiting transaminase elevations, and low-grade (≤G2) cytokine release syndrome. No treatment-related death was reported. The recommended phase 2 dose of ANV600 was determined to be 90 μg/kg Q1W as starting dose for 4 weeks followed by 150 µg/kg Q2W as maintenance dose. Selective targeting of PD-1-expressing cells was demonstrated, with preferential induction of proliferation of PD-1⁺ CD8⁺ T cells compared to PD-1⁻ CD8⁺ T cells. In the monotherapy setting, 12 patients (32%) experienced target lesion shrinkage; 4 of these (33%) were CPI treatment-naïve. Disease control was observed in 16 patients (42%). Clinical benefit was in general long lasting. A complete response was confirmed in 1 patient with bronchial adenocarcinoma, starting at 6 months after initiation of monotherapy treatment and still ongoing after 9 months of treatment. The patient was previously progressing under 1 st line anti-PD-L1 therapy and 2 nd line chemotherapy with carboplatin and paclitaxel. Similarly, in the combination therapy setting, 4 patients (24%) experienced target lesion shrinkage; 2 of these (50%) were CPI treatment-naïve. Disease control was observed in 10 patients (59%). Conclusions: ANV600 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing complete response, several long-lasting partial responses and stable diseases were reported in CPI-naïve and CPI pre-treated patients, including CPI-resistant tumors. Clinical trial information: NCT06470763 .
Whole-genome profiling to identify chromosomal instability as a distinct feature of lung cancer brain metastases.
e20554 Background: Brain metastases in lung cancer are associated with substantial clinical heterogeneity and poor outcomes, yet underlying molecular mechanisms remain incompletely understood. Previous studies on brain metastases have been limited by the scarcity of in-depth whole-genome sequencing (WGS) data , resulting in insufficient characterization of chromosomal instability (CIN) and fine-scale genomic architecture. This knowledge gap has significantly hindered our understanding of brain metastasis initiation, evolutionary trajectories, and inter-lesion heterogeneity. Methods: Patients diagnosed with lung cancer and brain metastases were retrospectively identified, and frozen samples from these brain metastases, with or withou primary tumors, were available for analysis. High depth whole-genome sequencing (WGS) at 200× coverage was performed to characterize somatic driver alterations and chromosomal instability (CIN). CIN was assessed using genome-wide copy number alteration burden, whole-genome doubling (WGD), and structural variation profiles. Genomic differences between brain metastases and non-brain lesions were evaluated through comparative analyses, with exploratory links to clinical features examined. Results: Whole-genome sequencing of 83 lung cancer brain metastases revealed a high prevalence of chromosomal instability. Among these tumors, 26 were near-diploid, while 57 exhibited whole-genome doubling (WGD; 68.7%). Biallelic inactivation of CDKN2A/2B was common, primarily via homozygous deletion (22/83, 26.5%). Additionally, chromothripsis-like events identified in 33 tumors (39.8%), and high-level focal amplifications( > 10 copies gain) of oncogenic drivers, including EGFR, CDK4, ERBB2, MET, MDM2, MYC and CCNE1, were observed in 30 cases (36.1%). Ongoing analyses integrate transcriptomic and single-cell data to further expand these findings. Conclusions: Comprehensive whole-genome profiling reveals chromosomal instability as a prominent genomic feature of lung cancer brain metastases, supporting its potential role in shaping brain-specific tumor evolution and inter-metastatic heterogeneity, and providing a rational foundation for future biomarker development and clinical practice.
Clinical utility of liquid <i>KRAS</i> -mutation screening in advanced pancreatic cancer patients referred for early-phase trials.
3049 Background: Approximately 90% of pancreatic ductal adenocarcinomas (PDAC) harbor a KRAS mutation. Clinical trials targeting oncogenic KRAS mutations, including mutant-specific, pan-KRAS/-RAS inhibitors, have shown promising activity. As tissue next-generation sequencing (NGS) is a multi-step process that can affect turnaround time (TAT), a liquid biopsy (LB) approach is of interest. We investigated the clinical utility of LB testing for common KRAS variants to facilitate matching pts with PDAC to early phase trials. Methods: In this single-center, prospective enrollment/retrospective analysis study, we included pts with locally advanced (LA) or metastatic PDAC seen at Princess Margaret Cancer Centre (PM) phase I clinical trials and gastrointestinal (GI) cancer clinics between Jan 2025 - Jan 2026. Medical records were reviewed to collect clinicopathologic characteristics and treatment data. Plasma ddPCR assessed 4 KRAS codon 12 variants (G12C/D/R/V) at the CAP-CLIA-accredited Advanced Molecular Diagnostics Laboratory at PM. TATs for KRAS ddPCR vs tissue NGS were compared using the Wilcoxon signed-rank test. Results: Of 98 pts with LA/metastatic PDAC, the median age was 67 years, 59% were male, and 67 pts were ECOG 1 (88%). 84 pts had disease stage IV (86%), 43 (44%) pts were chemotherapy-naïve, and 33 (34%) pts had 1 prior L of therapy. Median number of metastatic sites was 2 (range [r] 1-5), and median CA19-9 was 343 (IQR 35-1767). KRAS G12 mts were detected by ddPCR in 38% (37/98) of pts: G12D (46%), G12V (46%), G12R (5%), G12C (2.7%). The median ddPCR VAF was 4.8% (r: 0.4 - 42.2), median TAT of 5 days (r: 1 - 8). Among pts with KRAS detected by ddPCR, 4 (11%) were enrolled in phase I trials targeting KRAS . Tissue NGS was performed in 40 pts (41%), KRAS was detected in 90% (36 pts), with a median VAF of 45% (r: 5-90), and median TAT of 54 days (r: 10-92; p<0.0001 compared to ddPCR TAT). Reported KRAS variants: G12D (50%), G12V (19.4%), G12R (19.4%), Q61H (8.3%), G12C (2.8%). Co-mts in TP53 were seen in 22/36 pts (61%). Concordance between ddPCR and tumor NGS metrics are shown in Table 1. Median NGS VAF of concordant vs discordant cases: 48% vs 21% (p=0.047). Conclusions: Plasma-based KRAS screening using ddPCR was significantly faster than tissue NGS in advanced PDAC. A liquid-first strategy can accelerate matching pts to RAS-targeted trials, but intense competition for trial allocations limits access to these agents. ddPCR has excellent specificity and PPV across KRAS variants but limited sensitivity, thus serves as a rapid rule-in assay. Tissue NGS remains relevant, especially in ddPCR negative pts, and to assess co-mutations. N=36 pts ddPCR(+/-) NGS (+/-) Sens Spec PPV NPV Concordance Discordance G12C 1 / 35 1 / 35 100% 100% 100% 100% 100% 0% G12D 11 / 25 18 / 18 61% 100% 100% 72% 81% 19% G12R 1 / 35 7 / 29 14% 100% 100% 83% 84% 16% G12V 5 / 31 6 / 30 83% 100% 100% 97% 97% 3% All 4 variants 19 / 17 32 / 4 59% 100% 100% 24% 64% 36%
Orbital cancer: Historical trends in histological composition and cause-specific mortality based on SEER database analysis.
e18138 Background: Malignant orbital tumors are rare cancers encompassing a broad spectrum of lymphoid and epithelial histologies with variable clinical course and outcomes. In the United States, cancers of the eye and orbit are estimated to account for 3,140 new cases and 490 deaths annually. Data on orbital cancer all-cause mortality and competing causes of death remain limited. We set out to examine the histological distribution and causes of mortality among patients with primary malignant orbital cancers using the Surveillance, Epidemiology, and End Results (SEER) Research Plus database. Methods: Patients were identified using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) topography and morphology codes for orbital malignancies. The cohort included patients diagnosed with primary malignant orbital tumors between 2000 and 2022. Demographic, socioeconomic, tumor-related, and treatment variables were examined. Histologic subtypes were grouped into mucosa associated lymphoid tissue (MALT) lymphomas, non-MALT lymphomas, epithelial malignancies, and other orbital malignancies. Trends in histologic composition were evaluated. Causes of death were classified as orbital cancer-specific or non-cancer-related. Cancer-specific mortality was analyzed using cumulative incidence functions and Fine-Gray competing risk regression. Results: Among 2,154 patients, lymphoid malignancies predominated, including MALT lymphomas (48.6%), non-MALT lymphomas (29.6%), epithelial malignancies (11.8%) and other malignancies (10.1%). Over time, MALT lymphomas increased to half of the diagnoses after 2015, while non-MALT lymphomas declined and epithelial malignancies showed no significant trend. At the last follow-up in 2022, 59.1% of patients were alive. Orbital cancer-specific death accounted for 15.3% of mortality, while non-cancer causes, especially cardiovascular disease, represented an important competing risk, especially among indolent lymphoid histologies. Cancer-specific mortality varied by histology and was highest among epithelial malignancies. In multivariable Fine-Gray models, increasing age was independently associated with higher cancer-specific mortality across all histologies except epithelial malignancies. Lack of surgery was also associated with increased mortality among epithelial malignancies. Conclusions: This study highlights that malignant orbital tumors are characterized by shifting histologic patterns and heterogeneity in cancer-specific mortality. As survival improves for indolent lymphoid malignancies, non-cancer mortality becomes an increasingly important determinant of long-term outcomes. Histologic-specific risk analyses are essential to accurately characterize prognosis and optimize survivorship care in this patient population.
De-escalated chemotherapy and endocrine therapy outcomes in young women with stage I HR+/HER2+ breast cancer: An international real-world study.
e12512 Background: Treatment of stage I HER2-positive breast cancer has shifted toward increased use of taxane-only chemotherapy (CT), which is associated with lower rates of treatment-related amenorrhea and other long-term toxicities. In hormone receptor–positive disease, this evolution may influence outcomes through preserved ovarian function and subsequent adjuvant endocrine therapy (ET) selection. Data focusing on ET type in young premenopausal women are limited. Methods: We identified patients with Stage I breast cancer from a retrospective international multicenter registry of premenopausal women (≤45 years) with HR+/HER2+ early breast cancer treated between 2013-2020 with (neo)adjuvant CT and ET. CT was categorized as multiagent or taxane-only. ET was categorized as tamoxifen alone, tamoxifen with ovarian function suppression (OFS), or aromatase inhibitor with OFS (AI+OFS). The primary endpoint was invasive disease-free survival (IDFS) from ET initiation. Kaplan–Meier estimates were reported at 80 months with log-rank testing. Results: Among 1,231 patients, 258 met inclusion criteria; 246 had complete follow-up data. Median age at diagnosis was 39 years (range 23-45), and median follow-up was 65.2 months (IQR 45.7-86.0). Multiagent CT (92.9% anthracycline-containing) was administered to 168/258 patients (65.1%), taxane-only regimens to 69/258 (26.7%) and CT data were unavailable for 21/258 (8.1%) patients. ET included tamoxifen alone in 117/258 (45.3%), tamoxifen+OFS in 78/258 (30.2%), and AI+OFS in 51/258 (19.8%). Over time, taxane-only CT use increased from 9% (≤2015) to 53% (≥2020), while AI+OFS use increased from 9.3% to 51.4%. Patients treated with taxane-only CT more often received trastuzumab without additional anti-HER2 therapy (100.0% vs 83.3%, p=0.001) and were more likely to receive tamoxifen alone as adjuvant ET (55.1% vs 39.9%, p=0.039). Fourteen IDFS events occurred (14/246, 5.7%); distant recurrences were uncommon (4/246,1.6%). At 80 months, IDFS was 95.0% with multiagent CT and 94.1% with taxane-only CT (p=0.21). By ET type, 80-month IDFS was 91.0% with tamoxifen alone, 97.3% with tamoxifen+OFS, and 100% with AI+OFS (p=0.18). Eighty patients (31.0%) were aged <35 years; neither treatment patterns nor 80-month IDFS differed significantly compared with older patients (91.8% vs 93.7%, p=0.17). Conclusions: In this international real-world cohort of premenopausal women with stage I HR+/HER2+ breast cancer, IDFS at 80 months was high across CT, ET, and age subgroups. As de-escalated taxane-only regimens become more common and ET strategies evolve, these data provide clinically relevant context for systemic therapy selection in young women with excellent-prognosis disease.
Overall survival of Black patients with newly diagnosed multiple myeloma in the era of triplet and quadruplet therapies.
11055 Background: Black individuals have been shown to have a higher incidence of multiple myeloma, as well as worse survival, compared with White patients. A single VA-based study demonstrated that with equal access to myeloma therapy, Black patients have superior survival compared to White individuals. Nevertheless, it is unknown whether this finding holds in other settings. Methods: This retrospective cohort study included adult patients newly diagnosed with multiple myeloma between January 1, 2017, and December 31st, 2023, in one health system in Ohio and Florida. We captured receipt of triplet or quadruplet therapy within one year of diagnosis, as well as patients’ overall survival (OS) through September 30, 2025, using the Cleveland Clinic electronic health record, including linked state and federal death records. A multivariable logistic regression model examined the association of race with the receipt of either triplet or quadruplet therapy within one year of diagnosis, and a multivariable Cox regression model examined the association of race with 5-year all-cause mortality. The Cox model was adjusted for receipt of either a triplet or quadruplet regimen within 1 year, age at diagnosis, sex, Charlson comorbidity index (CCI), ECOG performance status, baseline eGFR, urbanicity of patient’s residence, area deprivation index based on Census Block Group, insurance type, and year of diagnosis. Results: We identified 1230 patients, 54.1% male, 74.1% White, 22.8% Black, 3.1% other races. Mean (SD) age at diagnosis of 67.2 (11.1); it was 67.7 (10.8) for White and 65.9 (11.7) for Black patients. Overall, 66.3% of the cohort had an ECOG performance score of 0-1, 59.9% had baseline eGFR ≥60, and 51.1% had a CCI of ≤2. Within one year of diagnosis, 707 patients (57.5% of the cohort) received either triplet or quadruplet therapy, including 56.6% (n=516) of White and 58.9% (n=165) of Black individuals. Both univariable and multivariable analyses did not indicate a significant association between race and receipt of either a triplet or quadruplet therapy (aOR for Black race vs. White, 0.91, 95% CI, 0.64-1.28). According to Kaplan-Meier estimate, the probability of 5-year OS in the overall cohort was 62.1% (95% CI, 59.0%-65.4%). In the multivariable Cox regression model for all-cause mortality at 5 years, aHR for death for Black patients vs. White was 0.76 (95% CI, 0.58-1.00). Conclusions: In this large and diverse cohort of patients who had equal access to triplet or quadruplet therapies for newly diagnosed multiple myeloma, Black patients did not have a higher risk of all-cause mortality at 5 years compared to White individuals. Our findings indicate that health equity initiatives aimed at improving access to multiple myeloma care among minority patients have the promise of addressing race-based disparities in survival.
Impact of proton pump inhibitors on the pathological complete response rate in luminal breast cancer during neoadjuvant therapy.
e12631 Background: Breast cancer (BC) is one of the most prevalent neoplasms, with a prognosis dependent on hormonal receptor (ER, PR) and HER2 expression. Neoadjuvant therapy (NAT) allows for tumor downsizing before surgery and assesses chemotherapy sensitivity. Pathological complete response (pCR) is a key prognostic marker, but rates are low in hormone receptor-positive (HR+) tumors. The enzyme fatty acid synthase (FASN), overexpressed particularly in HER2-positive tumors, has been associated with therapeutic resistance. Preclinical studies suggest that proton pump inhibitors (PPIs) may inhibit FASN and enhance chemosensitivity. Objective: To evaluate whether the concomitant use of PPIs (Esomeprazole) during NAT is associated with a higher pCR rate in patients with luminal breast cancer. Methods: A retrospective analysis was conducted on patients with luminal breast cancer (stages IIa–IIIb) treated at the Instituto Oncológico de Córdoba between January 2015 and January 2025. Patients who received NAT with or without continuous PPIs were included. Clinical variables, tumor characteristics, and pathological response were analyzed. Chi-square tests were applied (p < 0.05). Results: 130 patients were included; 61 used PPIs. The pCR rate was higher in the group that used PPIs (33.4% vs. 14.5%; p = 0.05). This difference was statistically significant in the Luminal B subtype (36.1% vs. 15.4%; p = 0.033) and was even more marked in the Luminal B/HER2+ subgroup (50% vs. 21.1%; p = 0.084). Conclusions: The use of PPIs during NAT was associated with a higher pCR rate in luminal breast cancer, with the greatest benefit observed in the Luminal B/HER2+ subtype. In this subgroup, the highest FASN expression is present, which could explain the increased chemotherapy sensitivity. These findings suggest a potential role for PPIs as therapeutic sensitizers.
Prognostic indicators and socioeconomic disparities in teratoma with malignant transformation: An NCDB analysis.
e22613 Background: Teratomas with malignant transformation (TMT) are rare germ cell tumors in which a typically benign mature teratoma undergoes transformation into a non-germ cell malignancy such as squamous cell carcinoma, adenocarcinoma, or sarcoma. TMT has a median age of diagnosis of 38 years of age. Given the rarity of TMT, current literature relies on small institutional case series and focuses primarily on tumor characteristics and clinical outcomes. This study leveraged the National Cancer Database (NCDB) to explore demographic and socioeconomic factors of TMT. Methods: A retrospective cohort study using data from the National Cancer Database (NCDB) from (2004-2020) analyzed patients diagnosed with TMT (ICD-O-3 code: 9084). The study examined demographic factors such as age, sex, race, primary site of occurrence, insurance coverage and Charlson- Deyo score. Demographic factors were analyzed by descriptive statistics, and incidence trends were interpreted by regression analysis. Results: We identified 212 patients with a confirmed diagnosis of TMT from 2004-2020. Most patients in the cohort were women at (62.7%). Most patients were White (79.2%) and 13.7% were Hispanic. Of the 122 patients with facility data, most were treated in academic/research programs (37.7%), and comprehensive community center cancer programs (35.2%). The majority resided in metropolitan areas with populations over 1 million (49.5%) and had household incomes between $57,857-$74,062 (27.4%). Most patients were privately insured (60.8%), while 17.9% and 12.3% had Medicaid and Medicare respectively. Most patients (86.3%) had no comorbidity burden, with a Charlson-Deyo score of 0. Treatment consisted largely of surgical excision (93.8%). The most common site of occurrence was in the ovaries (58.5%), followed by the testicles (22.7%). Most patients presented with Stage I (35.8%), and pairwise analysis showed significant differences in survival between Stage I compared to Stages 2-4, and Stage 2 compared to Stage 4 (p = 0.001). Mean overall survival time was 140 months with survival rates of 76.2% at 2 years, 69.3% at 5 years, and 65.1% at 10 years. Conclusions: To the best of our knowledge, this study represents one of the first studies to analyze the influence of socioeconomic and demographic factors on TMT, thereby addressing a gap in literature. Most TMT patients were White and resided in high income metropolitan areas. The majority were treated in academic centers with surgery as the primary treatment. Most patients were privately insured. These findings emphasize the need for research on the impact of socioeconomic factors on diagnosis, treatment access and long-term survival outcomes Future studies should focus on addressing the need for further data collection to better understand the incidence of TMT originating in different sites.
Durvalumab plus platinum-etoposide in extensive-stage extrapulmonary small cell carcinoma (ES-EPSCC): Second safety assessment of the DURVASCC trial (GOIRC-01-2021).
e14572 Background: EPSCC is a rare and highly aggressive malignancy with a poor prognosis. The low incidence has limited prospective evidence for first-line (1L) treatment. Given histological similarities with small cell lung cancer, where immunotherapy plus chemotherapy (CT) is the standard of care, an agnostic strategy was adopted. The DURVASCC trial aims to evaluate the clinical activity and safety of durvalumab plus platinum–etoposide as 1L treatment in ES-EPSCC. Methods: DURVASCC is an Italian, multicenter, phase II, single-arm study. Patients received durvalumab 1500 mg with carboplatin AUC5-6 or cisplatin 75-80 mg/m 2 on day1 plus etoposide 80-100 mg/m 2 day1-3 Q2W for 4-6 cycles, followed by durvalumab 1500 mg Q4W in patients achieving disease control until progression or unacceptable toxicity, for a max of 24 months. Safety assessment was pre-specified using a continuous toxicity monitoring design based on a Pocock-type group sequential approach, with planned evaluations every 10 patients up to 30 enrolled, each with a minimum follow-up of one month. Early stopping rules were based on the cumulative number of clinically relevant adverse events (AEs). At the second assessment, trial discontinuation would have been triggered if ≥6 relevant AEs (defined as events leading to treatment interruption or withdrawal) had been observed. Safety data and stopping rules were periodically reviewed by an independent data and safety monitoring board. Results: As of November 2025, 20 patients were evaluable for safety. Fifteen patients (75%) experienced at least one AE considered possibly related to durvalumab, with or without concomitant attribution to CT. Seven Grade 4 AEs occurred in five patients; three were serious, and one (thrombocytopenia) led to temporary treatment interruption. Eight Grade 3 AEs occurred in four patients: one (pan-uveitis) was unresolved and resulted in permanent treatment discontinuation.According to the primary safety definition, two AEs were classified as relevant, corresponding to a rate of 10% (95% confidence interval [CI]: 1.2%–31.7%).In a sensitivity analysis including additional Grade 3–4 events more likely attributable to concomitant CT, three patients experienced relevant AEs (two neutropenia—one unresolved and one leading to treatment delay—and one serious febrile neutropenia), corresponding to a rate of 25% (95% CI: 8.7%–49.1%). In both analyses, the pre-specified early stopping threshold of six relevant AEs was not exceeded. Conclusions: Based on the second safety assessment, durvalumab plus platinum–etoposide showed a manageable safety profile, supporting continuation of the DURVASCC trial. Clinical trial information: NCT06464068 .
Bridging the gap between clinical utility and coverage: Real-world impact of unreimbursed NGS testing.
11194 Background: Genomic testing is the cornerstone of precision oncology, revealing rare yet clinically actionable alterations that define diagnosis, risk stratification, and treatment choice. Despite its proven clinical utility, inconsistent coverage and inadequate reimbursement constrain routine use, reflecting a persistent misalignment between clinical value and payer policy. Evaluating real-world utilization and clinical impact of unreimbursed testing can highlight critical gaps in standard oncology care. Methods: Molecular profiles of 7,271 patients were analyzed by integrating Neogenomics sequencing data (09/2025 – 12/2025) with standardized clinical data (cancer diagnoses, ICD-10 codes, medication records, molecular testing results) extracted from comprehensive electronic medical records using the xCures platform. Results: Cohort of 7,271 patients insured by commercial (58%), managed (22%), or government (20%) plans had unreimbursed tests with orders originating primarily from hospitals (49%) and physician groups (42%). Testing predominantly targeted hematologic malignancies ( > 90%), with solid tumors representing 8%. Among patients with available medical records (n = 3,409), hematologic panels remained most common (67%), led by the Neo Comprehensive Myeloid (n = 1,064), NeoTYPE MDS/CMML Profile (n = 485), Neo Comprehensive Heme (n = 385), NeoTYPE CLL Profile (n = 299) and NeoTYPE Lymphoid Disorders Profile (n = 211). Abnormal molecular findings were identified in 1,056 patients (%), including 470 patients with pathogenic or likely pathogenic variants (SNVs, deletions, insertions, fusions and substitutions), with 23% (104/470) of alterations (i.e. ABL1, ERBB3, KDR, MAP2K1, TOP1, TSC1, TSC2) not identified by previous methods. Of 66 patients receiving targeted therapy after testing, 4 (6%) were treated within 60 days for pathogenic alterations (, JAK2, KIT, BCR-ABL1) identified by Neogenomics. Eleven (17%), initially with unspecified diagnoses, received therapies (venetoclax, obinutuzumab, lenalidomide) for newly defined indications, and 2 (3%) were treated (venetoclax, lenalidomide) based on relevant biomarkers (NPM1, SF3B1) of sensitivity, all guided by test results within 60 days. Among 386 patients with initially unspecified conditions, EMR for 137 patients (36%) confirmed diagnoses within 60 days. Conclusions: Genomic testing delivers substantial clinical value by enabling rapid, definitive diagnoses and informing timely, targeted treatment decisions. Despite inconsistent payer coverage, these data show that NGS testing frequently identifies actionable alterations and biomarkers not previously identified by standard testing that directly impact patient management. Aligning reimbursement policies with anticipated clinical utility is critical to closing gaps in standard care and expanding equitable access to precision oncology.
Spatial RNA–protein profiling of antibody–drug conjugate (ADC) targets in leiomyosarcoma (LMS).
11509 Background: LMS remains a therapeutically challenging sarcoma with limited targeted options. Although ADCs are a promising strategy, none are FDA approved for sarcoma. Prior studies relying on bulk RNA or single-marker immunohistochemistry fail to capture spatial localization, co-expression, and intratumoral heterogeneity. Methods: LMS tissue microarrays were profiled using GeoMx DSP to generate spatial RNA and protein expression of ADC targets across multiple regions of interest (ROIs) per tumor. Cases were classified as soft-tissue (ST-LMS; n=23 patients; 94 ROIs) or uterine LMS (U-LMS; n=32 patients; 92 ROIs). A prespecified panel of 35 clinically relevant ADC targets was interrogated. Expression values were normalized to housekeeping genes with group-level scaling. Unsupervised clustering grouped ROIs by spatial expression. Intratumoral and inter-tumoral heterogeneity was quantified using coefficients of variance (CV) across ROIs. RNA–protein concordance and dual target co-expression were quantified using Spearman correlation (ρ). Survival differences between high- and low-expression groups, dichotomized by the median, were evaluated using Kaplan–Meier analysis. Results: Of the 35 ADC targets interrogated, 33 were evaluable at the RNA level and 10 at the protein level. Spatial profiling identified four distinct expression clusters. At the RNA level, F3, AXL, and PTK7 showed the highest expression, whereas CDH11, CD99, and ITGA11 exhibited lower expression. At the protein level, Tissue Factor, AXL, and CD70 showed the highest expression, while HER2, and CD99 were lower. Most ADC targets exhibited positive log₁₀ (CV) values, indicating substantial spatial variability. Across most targets, U-LMS showed greater intratumoral and intertumoral heterogeneity than ST-LMS. RNA–protein concordance was greatest for CD99, CD47, and Fibronectin/EDB (ρ≈0.44–0.69) and minimal for PDGFRA, AXL, ERBB2, EGFR, and MET (ρ≈-0.15-0.19). RNA co-expression identified seven significant pairs in ST-LMS (e.g., ROR2–FAP, ρ=0.54) and eighteen in U-LMS, including MRC2–CD248 (ρ=0.73). Dual protein co-expression revealed a strong ERBB2–EGFR correlation in both ST and U-LMS (ρ≈0.79–0.81), with moderate correlations of these two ADC targets to PDGFRA, AXL, and Tissue Factor (ρ≈0.53–0.70). High expression levels CD47 and AXL were associated with improved survival in ST-LMS (CD47 HR = 0.76, 95% CI 0.08–0.88, p = 0.021; AXL HR = 0.67, 95% CI 0.07–0.72, p = 0.0067). Conclusions: This study provides the first spatially resolved RNA–protein map of ADC targets in LMS, revealing differential expression, spatial heterogeneity, variable RNA–protein concordance, dual co-expression patterns, and survival associations. These findings establish a foundation for rational ADC development, biomarker-driven patient stratification, and dual ADC combination strategies in LMS.