Browse Articles

A phase II open-label, single-arm study to evaluate the efficacy of pembrolizumab for leukoplakia.

10544 Background: Oral leukoplakia and erythroleukoplakia represent high-risk premalignant lesions of the oral cavity, with malignant transformation to head and neck squamous cell carcinoma reported in up to 36% of cases. Therapies are limited, with surgical resection remaining the standard of care despite high recurrence rates. Immune checkpoint inhibitors (ICIs) have emerged as a potential preventive strategy. We evaluated whether the efficacy of the PD-1 inhibitor pembrolizumab may serve as a preventive strategy to reduce progression to invasive carcinoma in patients (pts) with these premalignant lesions. Methods: This nonrandomized, open-label, multi-center phase II clinical trial enrolled pts between June 2019 and December 2025. Eligible pts had oral leukoplakia, erythroleukoplakia, or proliferative verrucous leukoplakia with moderate dysplasia, severe dysplasia, or carcinoma in situ. Patients with previously treated squamous cell carcinoma (SCC) were included. Pts received pembrolizumab 200 mg intravenously every 3 weeks for 6 months. The primary endpoint was clinical response at 6 months, defined as the proportion of patients achieving a complete response (CR) or partial response (PR). CR was defined as complete lesion resolution on visual inspection sustained for ≥4 weeks. PR was defined as a ≥50% reduction in the product of the two largest perpendicular dimensions of a single lesion or the sum of all measurable lesions. The secondary objectives included clinical response rate at 9 and 12 months, and toxicity. Results: Sixteen pts received at least one dose of pembrolizumab. The median age was 63.5 years (range, 33–82), and 44% were female. Three patients had previously treated SCC. Baseline pathology demonstrated moderate dysplasia in 31% and severe or high-grade dysplasia in 69% of patients. At 6 months, the clinical response rate was 44% (7/16; 95% CI, 23–67%), including CR in 19% (3/16) and PR in 25% (4/16) of pts. Progressive disease occurred in 38% (6/16) of patients. Clinical response rates were 31% at 9 months (5/16) and 19% at 12 months (3/16). Median follow-up was 9 months. Treatment-related adverse events (TRAE) occurred in 69% of pts, most commonly fatigue (31%), mucositis/oral discomfort (31%), hypothyroidism (25%), and gastrointestinal immune-related events, including diarrhea or colitis (25%). Grade ≥3 treatment-related adverse events occurred in 19%, with no grade 4–5 events or treatment-related deaths. One pt discontinued due to TRAE. Conclusions: These findings suggest that PD-1 blockade may represent a feasible preventive approach for high-risk oral premalignant lesions and warrants further investigation as a preventive option. Biomarker evaluation of pre-treatment and on-treatment biopsies are ongoing to inform predictors of response. Clinical trial information: NCT03603223 .

Genomic differences between primary and metastatic melanoma: Insights from AACR GENIE.

e21585 Background: Melanoma is a highly aggressive malignancy that is characterized by a complex and heterogeneous genomic profile. The most common somatic driver mutations occur in the BRAF, NRAS, and NF1 genes. KIT mutations are also frequent in acral and mucosal melanoma. Genomic profiling is integral to melanoma management as it guides the use of targeted therapies especially in the metastatic setting. The variation in genomic profile between primary and metastatic tumors is poorly understood and can have implications in patient’s care. Methods: We utilized the AACR Project GENIE v.18.0 database to extract data from patients with a malignant melanoma diagnosis. We compared the genomic alterations identified in samples obtained from primary tumors versus those obtained from metastatic tumors. Samples with unclear site (primary vs metastatic) were excluded from analysis. Only genes sequenced in more than one fourth of each category were included in the analysis. Results: We included a total of 8,142 samples (3,277 samples obtained from primary tumors and 4,865 samples obtained from metastatic tumors). In primary tumor samples, the most frequent gene mutations were found in the BRAF (32%, n = 1049), TERT (28.5%, n = 634), NRAS (22.5%, n = 737), and NF1 (21.3%, n = 463) genes. The most frequent copy number alterations were identified in the CDKN2A (19.2%, n = 306), CDKN2B (15.3%, n = 243), and MTAP genes (9.5%, n = 82). The most common structural variants were seen in the BRAF (1.0%, n = 21), CDKN2A (0.8%, n = 16) and NF1 genes (0.8%, n = 17). In metastatic tumor samples, the most frequent gene mutations were found in the TERT (44%, n = 1,494), BRAF (37.9%, n = 1,843), NRAS (25.5%, n = 1,239), and NF1 (23.4%, n = 788) genes. The most frequent copy number alterations were identified in the CDKN2A (23.5%, n = 645), CDKN2B (17.9%, n = 490), and MTAP genes (10%, n = 130). The most common structural variants were seen in the BRAF (1.9%, n = 61), NF1 (0.7%, n = 22), and RAF1 genes (0.5%, n = 16). Variations according to melanoma subtypes were observed and were consistent with the overall analysis. Conclusions: While similarity exists in the molecular profile of primary and metastatic melanoma samples, relative variations in prevalence highlights the importance of sequential testing. The confounding role of prior targeted therapy in the adjuvant setting and prognostic role of some genomic alterations cannot be excluded.

FALCON-Lung: Evolving global real-world treatment choices and outcomes for metastatic NSCLC in different patient populations.

1553 Background: Despite rapid global adoption of immune checkpoint inhibitors (ICI) for metastatic non–small cell lung cancer (mNSCLC), real-world treatment access, selection, time on treatment and transitions between regimens remain poorly characterized across health systems and patient populations. Whether observed outcomes are consistent across regions, data sources, and age groups is largely unknown. Addressing these gaps at scale requires a federated analytic approach with standardized analyses across sites, enabling reliable and comparable results while preserving patient privacy. Methods: We launched FALCON (Federated Alliance for Large-scale Cancer Observational Network), the largest federated, most diverse oncology network supporting observational cancer research, and its subnetwork FALCON-Lung. FALCON-Lung includes 23 sites (hospitals, registries, public-private) providing longitudinal cancer data from 2015 onwards standardized to OMOP common data model, from 11 countries in Europe, US and Australia. All sites completed data quality assessments and targeted improvements to improve completeness and overall cancer data quality. Analyses were executed locally using shared analytic code without sharing patient-level data. Results: Among 111,574 NSCLC pts included, 62% developed metastatic disease, of whom 59% initiated antineoplastic drugs within three months; 88% received a guideline-recommended 1 st line regimen. ICI uptake rose sharply between 2017 - 2019; by 2022 59% received ICI (± platinum) in 1 st line. ICI monotherapy showed a tendency toward longer overall survival (OS) compared with platinum (±ICI), although no single regimen demonstrated a consistent advantage across all databases. OS decreased with age across sites. Patients aged ≥81 years were less likely to receive systemic therapy and, when treated, more often received ICI monotherapy. No clear or consistent differences in OS were observed between different treatment regimens in this age group. Conclusions: In this global federated study, ICI uptake showed consistent patterns across sites and regions. OS varied across sites and no consistent survival advantage was observed for ICI regimens, either as monotherapy or in combination, although higher OS with ICI monotherapy was observed in some settings. Older patients (aged ≥81 years) were more frequently treated with ICI monotherapy without a corresponding survival advantage, possibly reflecting real-world treatment selection driven by tolerability rather than biomarkers. Total 18-64y 65-81y ≥81y NSCLC 111,574 36,239 62,328 13,007 Metastatic NSCLC 68,678 24,059 36,397 8,222 1st line systemic therapy 40,619 15,226 21,397 3,980 1st line guideline-approved systemic therapy 35,560 13,458 18,725 3,361 1st line in 2022 (%) ICI monotherapy 17 12 18 32 ICI + platinum doublet 42 43 45 26 Other guideline-approved regimen 41 45 37 43

Patient-reported telehealth experiences, medication adherence, symptom burden, and financial toxicity: A survey-based study.

e23258 Background: Telehealth may reduce geographic and logistical barriers to oncology care. Data on real-world uptake and patient-reported outcomes remain limited, yet are essential to inform telehealth delivery and policy. This study evaluated telehealth utilization, perceived barriers and benefits, medication adherence, symptom burden, and financial toxicity among cancer patients at a regional cancer center. Methods: In this cross-sectional pilot study, adults with cancer receiving care at the Wellstar Georgia Cancer Center were recruited over two months (November-December 2025). Surveys were administered in person and completed using secure electronic software. Collected data included demographics and cancer type; telehealth utilization and barriers; selected domains from the Telehealth Usability Questionnaire (usefulness, ease of use, reliability, satisfaction); self-reported medication adherence; treatment-related side effects; and financial toxicity measured using the 12-item Comprehensive Score for Financial Toxicity (COST). Descriptive statistics summarized responses. Differences in patient-reported outcomes by telehealth use were assessed using chi-square and Wilcoxon rank-sum tests. Results: Among 53 participants, the median age was 68 years (IQR 59-73), 50% were female, and 19% resided in rural areas. Solid tumors were the most common diagnoses. Telehealth utilization was low, with 26% (14/53) reporting use of at least one modality (electronic messaging or phone/video visits). Most participants reported no barriers to telehealth use (74%, 39/53); lack of awareness or understanding of telehealth options was the most frequently reported barrier (8%, 4/53). Despite limited uptake, 62% (33/53) perceived telehealth as improving access to care or reducing travel burden, 60% (32/53) reported satisfaction with telehealth, 51% (27/53) reported ease of use and 23% (12/53) perceived telehealth as reliable. Medication adherence was high, with 85% (45/53) reporting full adherence over the prior 7 days. At least one treatment-related side effect was reported by 49% (26/53). COST scores (median 19) indicated moderate financial toxicity with substantial heterogeneity across participants. Patient-reported outcomes did not differ statistically by telehealth use; however, telehealth users numerically reported higher symptom burden (64% vs 44%) and slightly higher financial toxicity (median COST 20 vs 18) compared with nonusers. Conclusions: Telehealth utilization was low despite favorable patient perceptions and minimal barriers, suggesting that system-level factors may be limiting adoption. Higher reporting of side effects among telehealth users reflects its potential role in symptom management. Larger studies are needed to identify determinants of telehealth uptake and its associated patient-reported outcomes in oncology.

Effects of SGLT2 inhibitor dapagliflozin on anticancer resistance and alpelisib- and fulvestrant-induced cardiomyocyte injury under hyperglycemic conditions.

1091 Background: Activating PIK3CA mutations occur in approximately 40% of hormone receptor–positive (HR+)/HER2-negative breast cancers and drive resistance to endocrine therapy. The PI3Kα-selective inhibitor alpelisib combined with fulvestrant significantly improves progression-free survival, as demonstrated in the SOLAR-1 trial, but its clinical benefit is limited by frequent treatment-induced hyperglycemia. Beyond metabolic toxicity, hyperglycemia promotes oxidative stress, inflammation, and mitochondrial dysfunction, thereby increasing cardiovascular vulnerability and potentially reactivating oncogenic PI3K/AKT signaling through compensatory hyperinsulinemia. Retrospective clinical evidence suggests that sodium–glucose cotransporter-2 (SGLT2) inhibitors may mitigate these effects. We investigated the direct redox-dependent cardiotoxic effects of alpelisib and fulvestrant under hyperglycemic conditions and evaluated whether dapagliflozin confers cardioprotection in human cardiomyocytes. Methods: Human iPSC-derived cardiomyocytes were exposed to alpelisib and fulvestrant under hyperglycemic conditions (25 mM glucose) in the absence or presence of dapagliflozin. Cell viability (MTS), mitochondrial membrane potential, reactive oxygen species generation, lipid peroxidation (MDA and 4-HNE), intracellular antioxidant defenses (GSH/GSSG, SOD, catalase/GPx), inflammatory and inflammasome-related mediators (IL-1β, IL-18, IL-6, TNF-α, NLRP3, MyD88), and apoptotic signaling (caspase-3/7 activity) were quantified. Cardiac injury was assessed by high-sensitivity cardiac troponin I and T release. Transcriptomic profiling was performed to interrogate cardiometabolic and redox signaling pathways. Results: Alpelisib and fulvestrant synergistically induced a pro-oxidative and pro-inflammatory injury phenotype characterized by mitochondrial depolarization, increased ROS and lipid peroxidation, depletion of antioxidant defenses, activation of the NLRP3/IL-1 axis, and caspase-dependent apoptosis. Dapagliflozin markedly restored redox homeostasis, preserved mitochondrial integrity, suppressed inflammasome and cytokine signaling, and reduced troponin release, indicating robust cardioprotection. Transcriptomic analysis confirmed coordinated downregulation of oxidative stress, inflammatory, and insulin-stress pathways. Conclusions: Dapagliflozin directly protects human cardiomyocytes from hyperglycemia-driven, PI3Kα inhibitor–associated oxidative injury by restoring redox and mitochondrial homeostasis. These findings provide a strong mechanistic rationale for repurposing SGLT2 inhibitors as dual cardio-metabolic protectants in precision oncology.

Some features of the energy metabolism of primary cell cultures of sarcomas.

e23540 Background: Cellular bioenergetic profiles are critical determinants of tumor biology and can vary significantly between different malignancies. Characterizing the metabolic dependencies of primary sarcoma cultures is essential for understanding their pathophysiology and potential therapeutic vulnerabilities. This study aimed to define the energetic phenotypes of primary sarcoma cell cultures by assessing their metabolic response to glucose. Methods: Five primary sarcoma cell cultures were established from patient samples via enzymatic dissociation with collagenase I and cultured in DMEM medium supplemented with 10% FBS, ITS, and NEAA. Metabolic profiling of adherent cells was performed using a Seahorse XFp analyzer. Assays included the mitochondrial stress test, FCCP titration, and the glycolytic stress test according to the manufacturer's protocols, utilizing media optimized for specific energetic substrates to accurately measure cellular respiration and glycolysis. Results: Analysis of the respiratory response to glucose addition revealed two distinct metabolic phenotypes. Group 1 (three cultures) exhibited a low mitochondrial ATP production rate (<5% of total respiration linked to ATP synthesis) but high reserve respiratory capacity (>150% of baseline) and glycolytic reserve (>1600% of baseline). As expected, these cultures increased oxygen consumption upon glucose addition, proportional to their high reserve capacities. In contrast, Group 2 (two cultures) demonstrated a high mitochondrial ATP production rate (>10%) but low reserve respiratory capacity (<90%) and low glycolytic reserve (<700%). These cultures decreased oxygen consumption following glucose addition, corresponding to a reduction in their spare metabolic capacities. Conclusions: Primary sarcoma cultures display two distinct energetic phenotypes: a "high-reserve" phenotype with low baseline mitochondrial ATP production but substantial capacity to upregulate both oxidative phosphorylation and glycolysis in response to glucose; and a "low-reserve" phenotype with high baseline mitochondrial ATP dependence but limited ability to further enhance metabolism with increased glucose. This phenotypic stratification may reflect underlying biological heterogeneity in sarcomas and could inform strategies for metabolic targeting.

RNA-based next-generation sequencing for identification of clinically actionable gene fusions missed by conventional cytogenetics in hematologic malignancies.

e18534 Background: Accurate detection of genomic alterations with diagnostic, prognostic, and therapeutic relevance is critical in hematologic malignancies. Conventional cytogenetic methods, including karyotyping and fluorescence in situ hybridization (FISH), are routinely used but may fail to detect cryptic or complex gene fusions. European LeukemiaNet (ELN) guidelines recommend assessment for KMT2A rearrangements due to their prognostic significance. RNA-based next-generation sequencing (RNA-NGS) interrogates expressed fusion transcripts and may identify clinically actionable alterations missed by standard cytogenetic testing. We evaluated the clinical utility of RNA-NGS in patients with negative conventional cytogenetic results. Methods: We retrospectively reviewed RNA-NGS testing performed in patients with hematologic malignancies at our institution between 2022 and 2024. Among 194 patients with positive RNA-NGS results, we identified cases with clinically relevant alterations detected despite negative karyotype and/or FISH studies. Analyses were conducted at the patient level to assess potential impact on risk stratification and treatment decisions. Results: RNA-NGS identified clinically relevant genomic alterations in a substantial subset of patients with negative conventional cytogenetic testing. At the patient level, 23% harbored actionable RNA-NGS findings despite both negative karyotype and FISH results, with additional patients demonstrating RNA-NGS–positive findings in the setting of either negative karyotype or negative FISH alone. Discordant cases most commonly involved cryptic or complex gene fusions with established clinical significance, including ELN-relevant rearrangements such as KMT2A::ELL and KMT2A::MLLT4 , as well as NUP98::NSD1 , KAT6A::CREBBP , RUNX1::USP42 , and ETV6::ABL1 . Identification of these alterations would have directly informed ELN risk classification and therapeutic planning. Conclusions: RNA-NGS detects clinically actionable gene fusions, including ELN guideline–defined KMT2A rearrangements, that are frequently missed by conventional cytogenetic methods. Notably, nearly one quarter of patients with negative karyotype and FISH results harbored significant RNA-NGS findings, highlighting a clinically meaningful false-negative rate with standard testing alone. Incorporation of RNA-NGS into routine diagnostic workflows may improve guideline-aligned risk stratification and support more informed treatment decisions in hematologic malignancies.

Preclinical data of IBI3028, the first clinical-stage bispecific dual-payload ADC, targeting EGFR/c-MET–positive advanced solid tumors.

e15020 Background: Acquired and intrinsic resistance to topoisomerase-1i ADCs are emerging as key unmet need, driven by heterogeneous target expression, impaired internalization/lysosomal processing, altered DNA damage response, and drug efflux. Dual-payload ADCs are designed to mitigate these escape mechanisms by co-delivering a mechanistically distinct cytotoxin along a Topo1i within a single, tumor-targeted construct. This strategy can broaden intra-tumoral coverage, enhance bystander killing, and reduce reliance on multi-agent combinations. Both EGFR and c-Met are transmembrane tyrosine kinase receptors that play critical roles in tumorigenesis, metastasis, and treatment. Aberrant EGFR activation or overexpression, common in various cancers, drives uncontrolled cell proliferation and tumor progression, while dysregulated c-Met signaling is associated with EGFR-TKI resistance, enhancing tumor invasion and drug resistance through pathway cross-talking. Methods: Aimded at addressing the emerging challenges of Topo1i ADC & EGFR TKI resistance, we developed IBI3028, the first bispecific dual-payload ADC in clinical development, targeting EGFR/c-MET-positive advanced solid tumors. Preclinical efficacy and safety of IBI3028 was comprehensively evaluated via in vitro cytotoxicity, in vitro by-stander, in vivo efficacy, monkey toxicology and PK studies. Results: IBI3028 exhibited superior in vitro cytotoxicity on cancer cell lines with various EGFR/c-Met expression profile. Notably, IBI3028 maintained high efficacy in EGFR-TKI-resistant cell lines. It also showed good in vitro bystander killing effects in the mixture of EGFR/c-Met-positive and EGFR/c-Met-negative cells, due to the cleavable linker design. IBI3028 demonstrated superior efficacy to AZD9592 in xenograft models with varying EGFR/c-Met expression levels. Furthermore, IBI3028 shows good efficacy in Topo1i-resistant model. IBI3028 was well tolerated in GLP-compliant toxicology studies in cynomolgus monkeys. Conclusions: IBI3028 demonstrates outstanding preclinical efficacy and safety profile, and is well positioned as a promising broad-spectrum therapeutic for advanced solid tumors with EGFR/c-MET expression or EGFR/c-Met-driven pathogenesis.

Clinical performance of novel exosomal liquid RNA biopsy assay in breast cancer segment.

e12561 Background: Exosomal RNA captures dynamic tumor biology and may overcome limitations of tissue biopsy and imaging, which, in the breast cancer segment, provide high false positivity and overdiagnosis (10-40%) and limitations with dense breast tissue with screening mammography and no reliable blood biomarkers for early recurrence or post-surgical risk stratification. A minimally invasive, real-time assay could improve detection and monitoring. Data suggest that gene expression signatures may predict indolent or aggressive breast cancer. CTOAM’s Liquid RNA (L-RNA) assay capitalizes on tumor-derived exosomal RNA. Unlike relatively static DNA, RNA expression dynamically reflects cellular and functional changes, providing real-time biological insights. Methods: CTOAM’s L-RNA assay uses AmpliSeq RNA NGS to quantify differentially expressed exosomal RNA in plasma relative to normal reference profiles. 35 retrospective cases were analyzed. Combined Positive Score (CPS) performance was compared with integrated clinical reference standards (biopsy and imaging) and with blood biomarkers alone. Results: Of 35 patients, 29 had breast cancer (19 HR +ve, 7 TNBC, 3 HER2+ve, stage 1 to 4), and 6 were true negatives. Compared with biopsy and imaging, the L-RNA assay demonstrated 100% sensitivity, 87.50% specificity, and 96.43% PPV, with an AUC of 93.80%. It identified molecular progression significantly earlier than imaging. CPS correlated with clinical tumor activity, ranging from 227 (low while on treatment) to 4035 (high), supporting its utility for early detection, treatment monitoring, and clarifying ambiguous imaging findings. Conclusions: CTOAM’s exosomal L-RNA assay demonstrates high diagnostic accuracy for early breast cancer detection, outperforming blood-based biomarkers alone and offering earlier insight than imaging modalities. As a minimally invasive adjunct to standard diagnostics, the assay has the potential to reduce unnecessary invasive procedures, resolve indeterminate imaging findings, and support longitudinal treatment monitoring. Larger prospective studies are needed to validate its clinical utility. L-RNA Efficacy data. Metric L-RNA vs Biopsy+Imaging (%) 95% CI L-RNA vs Blood biomarkers (%) 95% CI Sensitivity 100 (87.23-100.00) 88.89 (51.75-99.72) Specificity 87.50 (47.35-99.68) 75.00 (34.91-96.81) PPV (Precision) 96.43 (81.19-99.41) 80.00 (54.09-93.14) NPV 100 (59.04-100.00) 85.71 (47.53-97.55) Accuracy 97.14 (85.08-99.93) 82.35 (56.57-96.20) F1 Score 98.20 (92.00-99.60) 81.9 (61.00-93.00) ROC AUC 93.80 (78.50-98.90) 84.20 (60.00-95.00)

Real-world outcomes and subsequent treatment utilization following anti-B-cell maturation antigen antibody-drug conjugate exposure in patients with multiple myeloma.

e19503 Background: The anti-B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin is approved in the USA and EU for relapsed/refractory multiple myeloma (RRMM). Understanding treatment options and patient outcomes following ADC failure is clinically important. This study describes post-ADC treatment patterns and clinical outcomes in real-world patients with RRMM. Methods: Adult patients with MM who received an ADC and initiated ≥1 subsequent line of therapy (LOT) were included. The index date was the start of the first post-ADC LOT. Data were obtained from chart reviews at International Myeloma Foundation International Myeloma Working Group (IMF IMWG) academic sites, and US electronic health records from largely community sites (COTA and Guardian Research Network [GRN]). Patient characteristics and index regimens were summarized descriptively. Time to next treatment (TTNT) and overall survival (OS) were estimated with the Kaplan-Meier estimator. Results: The IMF IMWG cohort (n=40) had a mean age of 70.8 years, median of 7 prior LOTs and 82.5% were triple-class refractory (TCR). Overall, 85% received ADC monotherapy (70% belantamab mafodotin) and 15% combination therapy. Pre-ADC and not considering corticosteroids, patients were commonly exposed to lenalidomide (R; 100%), bortezomib (V; 92.5%), daratumumab (D) and pomalidomide (P; 90% each). Over a median follow-up of 26 months after index date, 29 unique index post-ADC regimens were reported, frequently selinexor (27.5%) and bispecific antibodies (15%). CAR T-cell therapy was administered to 5%, with 60% re-treated with a pre-ADC drug class (PI/IMiD/anti-CD38) after ADC. Median (95% CI) TTNT and OS were 10.8 (7.0–20.6) and 19.0 (13.4–25.1) months, respectively. The COTA-GRN cohort (n=39) had a mean age of 67.5 years, median of 8 prior LOTs, and 51.3% were TCR. Overall, 56% received ADC monotherapy (belantamab mafodotin) and 44% combination therapy. Pre-ADC and not considering corticosteroids, patients were commonly exposed to D and R (97.4% each), and carfilzomib, V and P (94.9% each). Over a median follow-up of 9.2 months, 32 unique index post-ADC regimens were reported, frequently selinexor (23.1%) and venetoclax (17.9%) based; 0% received CAR Ts and 54% were re-treated with a pre-ADC drug class (PI/IMiD/anti-CD38) after ADC. Median (95% CI) TTNT and OS were 4.9 (2.8–non-estimable [NE]) and 12.0 (4.9–NE) months, respectively. Conclusions: Findings highlight that most patients with heavily pretreated BCMA-ADC exposed MM were re-treated with similar classes. Academic centers used novel therapies (ie, CAR T, bispecific antibodies) more often and their patients had longer survival than those treated at community sites. However, clinical outcomes remained sub-optimal, emphasizing the unmet need for effective, accessible post-ADC treatments.

Refining clinical trial eligibility for minimal residual disease in patients with colorectal cancer: The MD Anderson INTERCEPT experience.

3609 Background: Detection of circulating tumor DNA (ctDNA) is prognostic for recurrence after completion of curative-intent therapy for patients (pts) with colorectal cancer (CRC). Our MD Anderson INTERCEPT platform enrolls ctDNA(+) CRC pts onto matched clinical trials, with the goal of eradicating minimal residual disease (MRD) and curing more pts with CRC. To gain insights on how to identify CRC pts most likely to have true MRD, we retrospectively reviewed the role of non-specific radiographic abnormalities in forecasting CRC recurrence. Methods: For this retrospective review of CRC pts included in ctDNA intervention trials (Table) from 1/2019-12/2025, MRD at baseline was defined as (1) having no radiographically evident disease at time of study enrollment and (2) detection of ctDNA on an MRD assay (Signatera). ctDNA levels were quantified as mean tumor molecules (MTM) per mililiter (mL) plasma. Radiographic sites of disease progression on clinical trials were compared with pre-treatment imaging. Median recurrence-free survival (RFS) was estimated using Kaplan Meier and compared with Cox regression. Results: 54 pts with definitively treated CRC prior to subsequent ctDNA(+) were enrolled across 4 trials (Table); 45 pts (83%) had stage IV disease. No pts had radiographically evident CRC at trial start. Median ctDNA levels were 0.45 MTM/mL (IQR 0.12 – 2.4). After a median follow up of 6.4 months (IQR, 3.5-9.5), 42 (78%) pts had recurred after treatment on a ctDNA intervention trial. Median RFS was 8.1 months (95% CI 4.4 - 9.4). Sites of recurrence were liver (N=20, 48%), lung (N=13, 31%), lymph nodes (N=10, 24%), and peritoneum (N=3, 7%). Upon retrospective review, minute but discernible lesions were identified at the sites of recurrence in 25 (60%) of the pts who had a recurrence on MRD trials. At eligibility evaluation these were characterized as “benign” in 14 (56%) or as “post-procedural” in 11 (44%) of the cases. The presence of indistinguishable CRC deposits at the start of the trial was associated with inferior RFS (4.2 vs 9.3 months; HR 1.96 (95% CI 1.04-3.70; p = 0.04). Conclusions: Subclinical radiographic findings may confound true identification of pts with CRC MRD for clinical trials. Optimizing definitions of radiographically detectable disease is warranted in order to ensure homogenous populations of CRC that are the most likely to benefit from novel MRD therapies. Demographic characteristics across four trials.   Number of Patients Percentage (%) Age at Enrollment < 30 1 2.4   30-39 3 7.3   40-49 8 19.5   50-59 12 29.3   60-69 14 34.1   70+ 3 7.3 Gender Male 34 63.0   Female 20 37.0 Race/Ethnicity White or Caucasian 34 63.0   Black or African American 5 9.3   Hispanic or Latino 11 20.4   Asian 1 1.9   Other 3 5.6 Stage at Enrollment I 0 0.0   II 0 0.0   III 9 16.7   IV 45 83.3 Trial Bintrafusp alfa 4 7   NK cells with cetuximab 15 27.8   Lifestyle interventions 16 29.6   Trifluridine/tipiracil 19 35.2

Real-world prevalence, co-occurrence, and descriptive analysis of ESR1 and PIK3CA mutations in metastatic breast cancer: A retrospective analysis.

e13060 Background: The approval of alpelisib for PIK3CA-mutated breast cancer in 2019 and elacestrant for ESR1-mutated cases in 2023 has significantly changed the therapeutic landscape. However, real-world data on the prevalence and demographic association of co-occurrence of these mutations remain limited. Understanding how these mutations coexist and influence clinical outcomes is essential for better patient management. This retrospective study aims to provide comprehensive insights into mutation prevalence and clinical characteristics in a real-world setting. Methods: This is a single institution retrospective chart review of patients diagnosed with metastatic breast cancer at Loyola University Medical Center who underwent next-generation sequencing (NGS) using commercial platforms (e.g., Tempus, Guardant360, FoundationOne) between 2018 and 2025. Data extracted included NGS evidence of mutation in PIK3CA and ESR1, demographics (age, sex), clinical comorbidities, and prior treatment history, including the type and line of endocrine and targeted therapies. Results: A total of 42 patients with hormone receptor–positive, HER2-negative metastatic breast cancer (MBC) with either ESR1 mutations, PIK3CA mutations, or both were included. Among these, 26.2% (11/42) demonstrated co-occurring ESR1 and PIK3CA mutations, with the number of detected mutations per patient ranging from 2 to 6. The most frequently observed mutations included ESR1 D538G, Y537S, and PIK3CA H1047R, H1047Y. The median age at diagnosis of metastatic disease in the co-occurrence group was 60 years (range: 48–76). Racial distribution included 72.7% White, 18.2% Black or African American, and 9.1% Other. The median time from diagnosis of MBC to detection of both ESR1 and PIK3CA mutations was 33.8 months (range 8.2–120.8 months). Among 11 patients with actionable ESR1 and/or PIK3CA mutations in the cohort, six (54.5%) received ESR1- and/or PIK3CA-targeted therapy following mutation detection. Prior to initiation of targeted therapy, patients had received a median of four prior lines of systemic therapy (range, 1–8). In the co-occurrence group, the median overall survival was 47.6 months, and the median progression-free survival was 15.1 months. Conclusions: Co-occurring ESR1 and PIK3CA mutations were observed in ~26% of patients with HR-positive, HER2-negative metastatic breast cancer. These patients were mostly older, White, and had received a median of four prior lines of therapy, with only half receiving mutation-directed treatment, likely reflecting the recent approval of these targeted agents.

Global context matters: Knowledge distillation–enabled ResNet modeling for noninvasive stratification of adrenal tumors.

e13681 Background: Adrenal tumors are increasingly detected as incidental findings on cross-sectional imaging, yet accurate differentiation of benign adenomas from malignant or hormonally active lesions remains clinically challenging. Overlapping radiologic features on CT and MRI often lead to unnecessary surveillance, invasive testing, or delayed diagnosis. Although deep convolutional neural networks demonstrate strong diagnostic performance, their computational complexity limits real-world deployment. Knowledge distillation enables transfer of diagnostic capability from high-capacity models to lightweight architectures while preserving accuracy. We evaluated a distilled ResNet-based framework for efficient adrenal tumor classification. Methods: We analyzed a curated adrenal imaging dataset from the adrenalAI study, including benign adrenal adenomas, adrenocortical carcinoma, pheochromocytoma, and non-neoplastic adrenal findings. Ground truth was established by multidisciplinary consensus incorporating imaging features, biochemical evaluation, histopathology, and longitudinal follow-up. Images were standardized and split into training and validation cohorts. A ResNet152 mentor model pretrained on ImageNet was trained for multi-class classification. A compact ResNet18 student model was trained using temperature-scaled knowledge distillation with soft probabilistic targets and regularized cross-entropy loss. Performance was evaluated using accuracy, sensitivity, specificity, F1 score, and AUROC. Results: The distilled ResNet18 achieved robust diagnostic performance across adrenal tumor subtypes, with overall accuracy exceeding 90% and AUROC greater than 0.90, closely approximating mentor performance. Knowledge distillation reduced model parameters by more than 80% and significantly decreased inference latency. Performance remained stable across CT and MRI protocols and lesion sizes, including challenging lipid-poor adenomas and pheochromocytomas. Conclusions: Knowledge distillation enables computationally efficient ResNet-based modeling for accurate, noninvasive adrenal tumor stratification. This scalable approach supports broader clinical deployment of AI-assisted adrenal imaging and complements attention-based transformer methods. Prospective studies are warranted to assess workflow integration and impact on diagnostic decision-making.

Dynamic genetic and nongenetic RAS pathway activation drives resistance to FLT3 and BCL2 inhibitor therapy

Bulk sequencing of relapsed tumors reveals mutations associated with resistance to cancer therapy but is insufficient to fully assess all causes of relapse. Due to inherent tumor heterogeneity, on-treatment tumor evolution may select for genetically distinct clones or shifts in malignant transcriptional states not resolvable by bulk sequencing. We performed multiomic single cell (SC) DNA/protein and RNA/protein profiling of a clinical trial cohort of acute myeloid leukemia (AML) patients treated on the Phase 1b clinical trial of the BCL2 inhibitor venetoclax and the FLT3 inhibitor gilteritinib (Ven/Gilt) to characterize immunophenotypic, transcriptional, and genetic clonal evolution driving resistance. We found that while Ven/Gilt effectively eliminated FLT3 mutant clones, resistance was associated with RAS activation via multiple mechanisms including selection for RAS mutant clones, non-mutational upregulation of RAS transcriptional programs and a shift to RAS-associated monocytic AML differentiation. In an in vitro model of monocytic differentiation associated with non-mutational RAS transcriptional activation, we demonstrated that RAS pathway inhibition re-sensitized to Ven/Gilt. These data illustrate that convergent resistance pathways in patients can be activated via diverse genetic and non-genetic mechanisms. These results underscore that RAS signaling is central to FLT3 and BCL2 inhibitor resistance, is tightly coupled to AML monocytic differentiation and highlight RAS pathway inhibition as a viable clinical strategy to combat resistance. CT# NCT03625505

QbD-engineered development and in vivo evaluation of an Articaine-loaded nanostructured lipid carrier in situ gel: A painless drug delivery platform for sustained periodontal anesthesia

Daily briefing: What it will take to stop the spiralling Ebola outbreak

Upcycling Waste PET Into Ionic Liquid‐Derived Small‐Molecule Adhesives

ABSTRACT The chemical upcycling of polyethylene terephthalate (PET) presents a critical pathway toward a circular plastics economy, yet existing methods are often hampered by high energy demands and downcycled products. Herein, we report a catalyst‐ and solvent‐free aminolysis strategy that depolymerizes waste PET into a versatile molecular precursor under mild conditions. This precursor is subsequently engineered into a series of low‐molecular‐weight ionic adhesives via strategic functionalization and supramolecular assembly. By leveraging a rich network of noncovalent interactions, such as hydrogen bonds and electrostatic forces, these materials achieve remarkable cohesion and interfacial adhesion. An alkoxy‐functionalized variant demonstrated an adhesion strength of 12.4 MPa on glass, ranking among the strongest small molecular‐based supramolecular adhesives reported. This work establishes a sustainable paradigm for converting waste polyester into value‐added functional materials, bridging the gap between plastic pollution and high‐value manufacturing, promotes the circular economy.

Prevalence and clinical relevance of Janus kinase 2 (JAK2) mutation in myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.

e18586 Background: MDS/MPN is a group of myeloid malignancies characterized by overlapping dysplastic and proliferative features. JAK2 mutations are rare in isolated MDS (2-5%), while previous studies on MDS/MPN overlap syndromes report 19-25%. We evaluated the prevalence and impact of JAK2 mutations on outcomes in MDS/MPN overlap syndromes. Methods: We identified adults aged ≥18 years with MDS/MPN, unclassifiable from the National Cancer Database (NCDB) between 2010 and 2022 using ICD-O3 code 9975. We obtained sociodemographic and clinical characteristics, including age, sex, race/ethnicity, insurance, Charlson Deyo comorbidity index, socioeconomic status, treatment received, and JAK2 mutation status. Median overall survival(OS) was estimated using Kaplan-Meier methods, and differences between groups were compared with log-rank tests. Multivariable Cox analysis was used to assess factors independently associated with OS. A p-value <0.05 was considered statistically significant. Results: We identified 5,759 patients with MDS/MPN-U, median age 77 years, and 56% men. Most individuals were non-Hispanic White (82%), insured by Medicare (74%), and resided in metropolitan areas (78%). Based on the area of residence, 13.4% lived in a locality of lowest-income quartile and 16% in lowest-education quartile. Overall, 34% had a JAK2 mutation, which was more frequent among women (37% vs 32%) and ranged from 28% in non-Hispanic Black (NHB) individuals to 39% in other minorities (p <0.01). Allogeneic stem cell transplantation was rare in 2%, with 19% of transplanted individuals having JAK2 mutation. Overall, only 2% of patients received palliative care during their lifetime. Prevalence of JAK2 mutation did not vary with other demographics or comorbidity burden. JAK inhibitors/chemotherapy was reported in 45% of all comers (55% JAK2 mutated vs 23% JAK2 unmutated). Among all comers, survival varied by race (p = 0.02), with a median OS ranging from 17.5 months (m) in NHB to 22.3m in Hispanic individuals. On unadjusted survival analysis, JAK2-positivity (28.4 m vs 15.2 m) and receipt of chemo/JAK inhibitor therapy were associated with longer survival (20.8 vs 16.2 m)(all p< 0.001). In a multivariable cox analysis adjusted for age, sex, race, insurance status, comorbidity and chemo receipt, female sex (hazard ratio (HR) 0.87) and JAK2 positivity were associated with improved OS (HR 0.64) while older age, higher comorbidity burden, and NHB individuals (HR 1.2) were found to have worse survival (all p< 0.001). Conclusions: This is the largest cohort of MDS/MPN-U to be reported. It showed significant racial differences, while both race and JAK2 mutation were independently associated with survival in this cohort. Lack of granularity is a major limitation to this study, and larger multi-center studies are needed to further understand this rare entity.

Use of <i>NECTIN4</i> expression inferred from circulating chromatin to predict response and survival to enfortumab vedotin (EV) in metastatic urothelial carcinoma.

4588 Background: APEX (Associating Plasma Epigenomics with eXpression) is a machine-learning framework that infers genome-wide gene expression in cancer from plasma cell-free chromatin Immunoprecipitation sequencing (cfChIP) by integrating signal from multiple histone marks and fragmentomic features, enabling enhanced transcriptional readouts from liquid biopsy without tissue sampling. We investigated whether APEX can noninvasively quantify NECTIN4 expression to predict outcomes with EV, a NECTIN4-targeted antibody-drug conjugate, in metastatic bladder cancer. Methods: Baseline plasma (1 mL) was collected from patients with metastatic bladder cancer within 90 before to 8 days after start of EV monotherapy and profiled by cfChIP-seq, followed by APEX-based tumor gene-expression inference. APEX-inferred NECTIN4 expression was dichotomized into high and low groups by the cohort median and tested for association with objective response (CR/PR vs SD/PD). Progression-free survival (PFS) and overall survival (OS) were analyzed using log-rank test and multivariable Cox regression model, accounting for the presence of bone or liver metastases and cfDNA tumor fraction. APEX performance was then compared against NECTIN4 locus signal from individual histone marks, plasma tumor fraction, and NECTIN4 copy-number status/amplification. Results: In the EV-treated cohort ( n =24), baseline APEX-inferred NECTIN4 expression was significantly higher in responders versus non-responders (p = 0.002) and outperformed NECTIN4 estimates derived from single histone-mark features, tumor fraction, and NECTIN4 copy number. Patients with high plasma-inferred NECTIN4 had an objective response rate of 58%, whereas no responses were observed among those with low inferred NECTIN4 , supporting strong negative predictive value. High baseline APEX-inferred NECTIN4 was also significantly associated with improved progression-free and overall survival (HR = 0.22, 95%CI: 0.08 – 0.65, p = 0.005 and HR = 0.27, 95%CI: 0.10 – 0.75, p = 0.008, respectively), with stronger associations than plasma tumor fraction, NECTIN4 copy number/amplification, or individual histone-mark coverage. In multivariable Cox models, APEX-inferred NECTIN4 remained independently associated with survival. Moreover, responders were enriched for urothelial luminal genes known to associate with NECTIN4 expression and favorable outcomes, while non-responders showed increased activation of epithelial-mesenchymal transition-related genes, known to associated with worse outcomes. Conclusions: A machine learning framework for plasma-based inference of tumor gene expression identifies plasma-based NECTIN4 as a clinically actionable, expression-based biomarker that predicts EV response and survival in metastatic bladder cancer.

Racial disparities in cancer-specific survival of estrogen receptor–negative, progesterone receptor–positive breast cancer: A focus on the American Indian population.

e12708 Background: Estrogen receptor–negative, progesterone receptor–positive (ER−/PR+) breast cancer is a raresubtype (2–8% of cases) that remains biologically incompletely characterized. Prior studiessuggest aggressive behavior and shared molecular and morphologic features with triple-negativebreast cancer, yet racial and ethnic disparities in outcomes, particularly among AmericanIndian/Alaska Native (AI/AN) patients, are poorly defined. We used population-based data tocompare cancer-specific survival (CSS) between ER−/PR+ and ER+/PR+ breast cancer acrossracial and ethnic groups. Methods: Female patients with first primary invasive, HER2-negative, PR-positive breast cancer diagnosedbetween 2010 and 2022 were identified from the SEER 17 database. ER status was classified aspositive or negative; PR-negative, borderline, and unknown cases were excluded. Patientsidentified by death certificate only or autopsy only were excluded from survival analyses. CSSwas estimated using Kaplan–Meier methods. Cox proportional hazards models compared ER-negative versus ER-positive disease, adjusting for age, stage, and year of diagnosis, and werestratified by race/ethnicity. Analyses were conducted using SEER*Stat v9.0.42.0 and SAS v9.4. Results: Across the cohort, ER-negative status was associated with inferior CSS compared with ER-positive disease (adjusted HR 3.3, 95% CI 3.1–3.6; p&amp;lt;0.001). This association was observedacross all racial and ethnic groups. Adjusted HRs were 3.5 for non-Hispanic Whites, 2.4 for non-Hispanic Blacks, and 2.5 for AI/AN patients, though estimates for AI/AN patients were limitedby small sample size and wider confidence intervals. Notably, ER-positive disease demonstratedexcellent five-year CSS among AI/AN patients, comparable to that observed in White patients. Conclusions: In this population-based analysis of PR-positive breast cancer, ER-negative status was associatedwith worse cancer-specific survival across racial and ethnic groups. ER-positive disease wasassociated with favorable outcomes among AI/AN patients compared to outcomes observed inWhites, challenging assumptions of uniformly poor prognosis in this population. These findingshighlight heterogeneity within PR-positive breast cancer and underscore the need for furtherstudy in understudied populations. Adjusted Cox proportional hazards models for breast cancer–specific survival comparing ER-negative versus ER-positive disease within progesterone receptor–positive breast cancer stratified by race/ethnicity. Group HR (95% CI) P-value Overall (adjusted) 3.3 (3.1–3.6) &lt;0.001 Non-Hispanic White 3.5 (3.2–3.9) &lt;0.001 Non-Hispanic Black 2.4 (2.0–2.8) &lt;0.001 American Indian/Alaska Native 2.5 (1.1–5.9) 0.032 Asian/Pacific Islander 2.4 (1.7–3.3) &lt;0.001 Hispanic (all races) 3.5 (3.0–4.2) &lt;0.001