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Geospatial hotspot analysis of breast cancer in Ohio: Environmental and rural–urban disparities informing targeted prevention and treatment.

e22566 Background: Breast cancer is the most commonly diagnosed malignancy among women in the United States. In 2022, 10,627 new cases were reported in Ohio (Ohio Department of Health; Centers for Disease Control and Prevention). Breast cancer incidence varies geographically due to differences in access to care, demographics, socioeconomic factors, and environmental exposures. County- and ZIP code–level analyses can identify spatial heterogeneity and high-incidence clusters. This study evaluates Ohio county- and ZIP code–level breast cancer incidence to characterize rural–urban disparities, identify geographic hot spots, and assess associations with environmental toxic release patterns to inform targeted prevention strategies. Methods: This retrospective, population-based study analyzed deidentified data from 2018 to 2025 from the Ohio Cancer Incidence Surveillance System. Following Ohio Department of Health IRB approval and a Data User Agreement, analyses were conducted at the University of Toledo. ZIP code-level toxic release data were obtained from the Toxic Release Inventory program. Breast cancer incidence was evaluated at the ZIP code level using two-way ANOVA by rural-urban classification (0–4) and toxicity quartiles, with Tukey post hoc testing for interaction effects. Multivariable regression assessed associations among socioeconomic, demographic, and healthcare access factors, and spatial mapping identified geographic hotspots and social determinants of health. Statistical significance was defined as p < 0.05. Results: Two-way ANOVA demonstrated a significant elevation in breast cancer rates in ZIP codes located in rural counties (p = 0.0012), Toxicity quartiles were not independently associated with breast cancer rates (p = 0.0984), and no significant urban–rural–toxicity interaction was observed (p = 0.5229). Conclusions: Breast cancer rates in Ohio demonstrates geographic variation, with higher rates in the most rural counties. Identification of rural hot spots may inform targeted interventions addressing healthcare access and socioeconomic disparities. Limitations in environmental exposure assessment and disease latency support the need for studies using refined exposure metrics. Breast cancer incidence by urban–rural classification and environmental toxicity. Factor Categories Statistic (F) P value Urban-Rural Classification 0–4, (0 = most rural, 4 = most urban 4.65 0.0012 Toxicity level Quartiles (1=lowest 4=highest) 2.12 0.0984 Urban–rural × toxicity Interaction term 0.91 0.5229 Tukey post hoc (urban-rural) Pairwise comparisons (0–4) – < 0.05 Tukey post hoc testing demonstrated higher breast cancer rates in more rural categories (0-1) compared with more urban categories (2-3).

Large genomic rearrangements in germline <i>BRCA1/2</i> pathogenic variant architecture across tumor types.

e22636 Background: Germline BRCA1/2 pathogenic variation is structurally heterogeneous, comprising small sequence variants and large genomic rearrangements that differ in their genomic architecture and biological consequences. Real-world data defining the contribution of these variant classes across BRCA genes and tumor types remain limited. Methods: We analyzed germline BRCA1/2 findings from 3,248 individuals undergoing comprehensive hereditary cancer testing for small sequence variants (single nucleotide variants and short insertions/deletions) and large genomic rearrangements (deletions and duplications) using a multigene panel. Pathogenic and likely pathogenic variants were classified using standard criteria and evaluated by gene, variant class, tumor type, and clinical actionability. Results: Overall, pathogenic or likely pathogenic BRCA variants were identified in 8.9% (288/3,248) of individuals. Small sequence variants were identified in 258 individuals, while large genomic rearrangements were identified in 39 individuals, with 9 individuals harboring both variant types. At the cohort level, this corresponds to approximately one pathogenic BRCA large genomic rearrangement per 83 individuals analyzed. Among BRCA -positive cases, 58% (167/288) involved BRCA1 and 42% (122/288) involved BRCA2 , with one individual carrying pathogenic variants in both BRCA1 and BRCA2 . Variant-level analysis revealed that large genomic rearrangements were more frequent in BRCA1 than BRCA2 (15.2% vs 10.2%), with deletions predominating over duplications (82.1% vs 17.9%). BRCA pathogenic variants demonstrated marked enrichment in ovarian cancer (16.1%, 77/477), compared with breast (7.7%, 118/1,541), prostate (4.4%, 11/250), and pancreatic cancers (4.1%, 15/362).Large genomic rearrangements were also most prevalent in ovarian cancer (2.1%), compared with breast (1.0%), prostate (0.8%), pancreatic (0.6%), indicating relative enrichment of rearrangements in ovarian tumors. Pathogenic variants in cancer predisposition genes were identified in 14.6% (475/3248) of individuals, with non- BRCA genes accounting for 41.7% of findings. Overall, 12.1% of individuals harbored germline alterations with direct therapeutic relevance including eligibility for PARP inhibitor therapy. Conclusions: Large genomic rearrangements constitute a non-trivial component of germline BRCA pathogenic variation, show preferential involvement of BRCA1 , and demonstrate enrichment in ovarian cancer, consistent with HRD-driven tumor biology. Together, these findings provide population-level insight into pathogenic germline alterations across BRCA and other therapeutically relevant hereditary predisposition genes, underscoring the broader relevance of inherited cancer susceptibility in informing targeted and immunotherapy strategies within precision oncology.

Comparative study on the mechanical and durability performance of concrete incorporating nanomaterials

Stabilizing Sputtered NiO _x via In Situ Dissociative Adsorption Passivation for Efficient Perovskite Solar Cells

ABSTRACT Sputtered nickel oxide (NiO x ) is an industrially compatible hole transport layer for perovskite solar cells (PSCs), yet its practical deployment is limited by interfacial instability arising from disordered Ni 3+ species and unfavorable reactions with perovskite absorbers. Here, we introduce an in situ dissociative adsorption passivation (IDAP) strategy using bromoacetamide (BAA) to stabilize sputtered NiO x . In this approach, Br − ions act as site‐blockers by coordinating with surface Ni, suppressing interfacial disorder and stabilizing Ni 3+ species, while the amide group provides dual anchoring: N−H···O hydrogen bonding strengthens attachment to NiO x , and the carbonyl group (C═O) passivates the uncoordinated Pb 2+ located at or near the interface between the NiO x and the perovskite films. These cooperative efforts reduce trap states, suppress interfacial redox reactions, and mitigate defect‐driven degradation under thermal stress. PSCs incorporating BAA‐NiO x achieve a champion power conversion efficiency (PCE) of 26.31% along with a certified PCE of 26.07%, while the larger‐area PSCs (1 cm 2 ) maintain 25.48% efficiency. This is one of the highest efficiencies reported for NiO x ‐based PSCs. In addition, the encapsulated cell retains 93% of its initial performance after 1500 h of continuous operation.

AI-based pre-screening of <i>BRCA1/2</i> mutation likelihood from routine H&amp;E histopathology in unselected breast cancer cases using peakPredictBRCA.

546 Background: BRCA1/2 mutation status is essential for precision oncology in breast cancer, directly guiding therapy decisions such as eligibility for PARP inhibitors. However, not all patients globally have reimbursed access to genetic BRCA testing, due to cost and a lack of uniform global implementation, leading to actionable mutations being missed. We developed a scalable artificial intelligence pre-screening algorithm that estimates BRCA1/2 mutation likelihood from routine whole-slide H&amp;E images, to enable systematic prioritization of patients for genetic testing. Methods: peakPredictBRCA, a deep learning-based algorithm, was developed to predict likelihood of BRCA1/2 mutations from H&amp;E whole-slide images of primary and metastatic breast cancer cases, independent of hormone receptor or HER2 status. Breast cancer images were collected from 6 institutions across 5 countries using different whole-slide scanners (Argentina, Brazil, Germany, Jordan, and USA), with slide-level BRCA mutation labels derived from clinical sequencing (n=725 images, 60% mutated). Training data was augmented with open-access TCGA datasets for breast, prostate, and ovarian cancer (n = 1,633 images), resulting in 2,358 total images (21% mutated). Model performance was evaluated on the collected breast cancer images using five-fold cross-validation. The model was trained end-to-end without manual annotations using multiple-instance learning. Results: On the breast cancer cohort, peakPredictBRCA achieved a mean AUC of 0.81±0.13. At a screening-oriented operating point, the model identified most BRCA1/2 mutated cases (mean sensitivity 0.82±0.23) while excluding a substantial proportion of non-mutated cases (mean specificity 0.56±0.38), without additional calibration on held-out images. Additional analyses during development demonstrated that robust generalization to unseen data depends on appropriate tumor tissue detection and model architecture selection. Conclusions: Our results demonstrate that BRCA1/2 mutation likelihood can be effectively triaged from routine H&amp;E breast cancer histology with consistent performance across institutions, scanners, and slide preparations. Implementation of the peakPredictBRCA algorithm in routine pathology workflows could enable systematic prescreening of unselected breast cancer cases at diagnosis and prioritization for confirmatory genetic testing, particularly in resource-constrained settings. Ongoing work focuses on incorporating human-interpretable features and on prospective validation in real-world workflows.

Comparative survival disparities and outcome in primary vs secondary central nervous system lymphoma (CNSL): A population-based analysis using Surveillance, Epidemiology, and End Results (SEER) program (2000-2022).

e14111 Background: Primary CNSL (PCNSL) is a rare, aggressive B-cell non-Hodgkin lymphoma limited to the CNS, while secondary CNSL (SCNSL) represents CNS involvement from systemic lymphoma. Previous observations focused on CNSL have limited data clinically comparing PSNSL and SCNSL. We aimed to evaluate overall survival and associated factors in patients with PCNSL vs SCNSL using a large population database. Methods: We conducted a retrospective cohort study using the SEER-22 database to identify patients diagnosed with CNSL between 2020-2022. Group comparisons used t-tests or ANOVA for continuous variables, chi-square tests for categorical variables, and Kaplan–Meier survival analysis, with all analyses performed in RStudio 4.1.1 and significance deemed as p&lt;0.05. Results: 14,964 patients with CNS lymphoma were identified, with 84.6% PCNSL and 15.4% SCNSL cases. The overall median age was 65 years (IQR 20), with 52% male, 66% White patients, residing in urban areas (90%) and median household income of $50,000–$75,000 (52%). Compared with PCNSL, patients with SCNSL were significantly older (72 vs 64 years, p&lt;0.0001). SCNSL more frequently involved the cerebrum (39% vs 34%) and cerebellum (5.5% vs 4.5%), but less commonly affected the nerves (12.0% vs 12.5%) and spinal cord (4.2% vs 5.1%) (p&lt;0.05). Disease was predominantly unilateral (95.8%) in both groups. Chemotherapy (55% vs 56%) and radiotherapy (19% vs 18%) utilization did not differ significantly, with external beam radiation comprising 94.3% of radiated cases. PCNSL patients were more likely to undergo surgical intervention than SCNSL patients (31.8% vs 28.7%; p=0.0027). Diffuse large B-cell lymphoma was the most common histologic subtype in both PCNSL (70.1%) and SCNSL (74.3%). Median overall survival was shorter in SCNSL (1.64 years) than PCNSL (1.99 years). Survival improved significantly across diagnostic eras (2000–2005 to 2016–2020; log-rank p&lt;0.001), while lower income (&lt;$50,000) and rural residence were associated with inferior outcomes (p=0.028 and p=0.033). Conclusions: Survival in CNS lymphoma remains poor, with SCNSL associated with worse outcomes compared with PCNSL. Greater understanding of treatment variation and disease differences is needed to optimize therapy and improve patient outcomes. Characteristic PCNSL SCNSL Total p-Value N 12667 2297 14964 Population Distribution 0.033 Urban 11426 2038 13464 Rural 1241 259 1500 Surgery 0.0027 Yes 3630 730 4360 No 9037 1567 10604 Months from Diagnosis to Rx(Mean, SD) 0.31 (0.86) 0.27 (0.65) 0.30 (0.83) 0.0077 Death Status &lt;0.0001 Dead 8603 1772 10375 Alive 4064 525 4589 Overall Survival (in years, Mean, SD) 1.99 (2.85) 1.64 (2.31) 1.93 (2.77) &lt;0.0001

Integrating multimodal data with artificial intelligence to predict postoperative recurrence in intrahepatic cholangiocarcinoma after curative resection.

e16294 Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy and carries a poor prognosis. Although curative resection remains the only potentially curative treatment, nearly half of patients experience postoperative recurrence, which substantially compromises long-term survival. Therefore, we aimed to develop and validate a real-world, multimodal artificial intelligence (AI)–based prognostic framework that integrates imaging, pathology, and clinical information while accommodating incomplete data, to enable more precise prediction of recurrence after curative resection in ICC. Methods: This retrospective multicenter study included 426 patients with pathologically confirmed ICC who underwent curative resection at 10 medical centers between January 2013 and August 2024. The multimodal data included clinical variables, preoperative contrast-enhanced CT (CECT) images, and hematoxylin and eosin (H&amp;E)–stained whole-slide pathology images (WSIs). Patients were randomly assigned to training and validation cohorts at an 8:2 ratio. An AI–based multimodal prognostic framework was developed to integrate heterogeneous data sources for postoperative recurrence prediction. To address the pervasive issue of incomplete multimodal data in real-world clinical settings, modality-specific attention mechanisms were incorporated to capture salient features within each modality. Cross-modal interaction layers were employed to model inter-modality relationships and extract complementary information, enabling compensation for missing modalities. Model performance was evaluated in terms of discrimination, calibration, and clinical utility. Results: The multi-model demonstrated superior performance for recurrence prediction. It achieved an AUC of 0.912 (95% CI: 0.831–0.926) in the training cohort and 0.893 (95% CI: 0.834–0.907) in the validation cohort, outperforming models based on radiomics alone or pathomics alone (AUCs of 0.874 [95% CI: 0.789–0.960] and 0.79 [95% CI: 0.687–0.916], respectively). Moreover, the multimodal model showed good calibration and yielded greater net clinical benefit on decision curve analysis, supporting its potential utility for clinical risk stratification. Conclusions: This study developed a multimodal AI framework designed for real-world clinical settings with incomplete data. The framework integrates CECT imaging, histopathological features, and clinical variables. By leveraging complementary macroscopic and microscopic tumor characteristics, it enables accurate prediction of postoperative recurrence in ICC.

A randomized, phase II, double-blinded study of the efficacy of oleogel-S10 (AP101) gel for the treatment of grade 2/3 radiation dermatitis in breast cancer patients.

e24199 Background: Radiation therapy is a cornerstone of treatment for early-stage breast cancer; however, up to one third of patients develop grade 2–3 acute radiation dermatitis (ARD), which is associated with pain, pruritus, and impaired quality of life. Therapeutic options for established grade 2-3 ARD are limited, and not all patients respond adequately to topical corticosteroids. Oleogel-S10 (Filsuvez) is a topical betulin-based gel approved by the U.S. Food and Drug Administration for dystrophic and junctional epidermolysis bullosa that promotes keratinocyte migration and epidermal barrier regeneration. Prior phase III studies have demonstrated accelerated wound healing with Oleogel-S10. We hypothesized that Oleogel-S10 could facilitate healing of high-grade ARD following breast irradiation. Methods: This IRB-approved (Memorial Sloan Kettering Cancer Center IRB #21-091), single-center, phase II, double-blind, randomized controlled trial enrolled women ≥18 years who developed grade 2–3 ARD during conventionally fractionated whole-breast radiation therapy. Patients were randomized 1:1 to Oleogel-S10 or placebo and instructed to apply standard-of-care triamcinolone 0.1% cream daily with study gel nightly for three weeks. The primary endpoint was percent change in ARD body surface area from baseline to day 14, assessed using novel Canfield three-dimensional (3D) imaging. Secondary endpoints included ARD resolution, pigmentation changes, patient-reported outcomes (PRO-CTCAE), and adverse events. Results: Nineteen patients were enrolled, of whom 11 completed the study (six placebo, five Oleogel-S10); attrition rates were similar between groups. No significant difference was observed between groups in percent change in ARD surface area at day 14. Hyperpigmentation at follow-up was lower in the Oleogel-S10 arm, although this difference did not reach statistical significance. Skin pain severity was lower in the Oleogel-S10 group by CTCAE and PRO-CTCAE assessments, but this difference was not statistically significant. Adverse event rates were similar between groups, with no grade 4 or 5 adverse events reported. Conclusions: Although Oleogel-S10 did not improve the primary endpoint of wound surface area as calculated by a novel 3D imaging tool compared with standard-of-care triamcinolone, treatment was associated with a trend toward improvement in skin pain and hyperpigmentation. These findings may represent early signals of therapeutic activity in ARD, particularly for patient-centered outcomes. Interpretation is limited by early study closure related to COVID-19–associated recruitment challenges and small sample size. Larger, adequately powered studies are warranted to further evaluate the role of Oleogel-S10 in the management of grade 2-3 ARD. Clinical trial information: NCT05190770 .

Pharmacovigilance signals of androgen receptor pathway inhibitors in non-geriatric men with prostate cancer: A FAERS disproportionality analysis.

e17045 Background: Age-restricted real-world safety patterns of androgen receptor pathway inhibitors (ARPIs) in prostate cancer are incompletely characterized. We evaluated adverse event (AE) reporting signals for enzalutamide, abiraterone, apalutamide, and darolutamide in non-geriatric men. Methods: FAERS (Q4/2003–Q3/2025) was queried via OpenVigil 2.1. Included were male patients aged 18–64 years with an ARPI as the primary suspect drug. AEs were analyzed at MedDRA preferred term level. Disproportionality analysis was performed using reporting odds ratio (ROR) with 95% confidence intervals (CI); signals were defined as PRR≥2 and χ²≥4. Results: Among 1,594,913 background cases, 4,570 ARPI cases were identified (abiraterone n = 2,060; enzalutamide n = 1,812; apalutamide n = 394; darolutamide n = 304). Fatigue was reported across all ARPIs, with enzalutamide showing a ROR of 5.48 (4.83, 6.23) (n = 280) and darolutamide a ROR of 4.79 (3.46, 6.64) (n = 42). Rash with apalutamide showed a ROR of 4.65 (3.27, 6.61), and hypertension with apalutamide showed a ROR of 3.44 (2.02, 5.87) . Abiraterone demonstrated signals including long QT syndrome with a ROR of 12.54 (4.67, 33.72), hypokalemia with a ROR of 4.80 (3.12, 7.39) (n = 21), blood pressure increased with a ROR of 2.15 (1.51, 3.07) , and liver function test increased with a ROR of 7.92 (4.75, 13.19) (n = 15). Memory impairment with enzalutamide showed a ROR of 2.23 (1.46, 3.40) (n = 22). Seizure did not meet signal criteria and was not observed with darolutamide. Conclusions: In men aged 18–64 years, ARPIs display distinct FAERS reporting signals that may inform agent-tailored monitoring. Fatigue remains a cross-ARPI signal, including with darolutamide. Findings require validation in prospective studies. Selected disproportionality signals (ROR) for ARPIs. Adverse Event Enzalutamide (N=1,812) Abiraterone (N=2,060) Apalutamide (N=394) Darolutamide (N=304) Fatigue 5.48 (4.82–6.23) 2.80 (2.39–3.26) 3.38 (2.43–4.68) 4.79 (3.46–6.64) Seizure 0.85 (0.52–1.38) 0.32 (0.15–0.68) 0.48 (0.12–1.94) 0 (NA) Rash 0.77 (0.53–1.12) 0.53 (0.35–0.81) 4.65 (3.27–6.61) 2.02 (1.14–3.60) Hypertension 0.83 (0.51–1.36) 1.99 (1.47–2.70) 3.44 (2.02–5.87) 0.93 (0.30–2.90) Asthenia 2.11 (1.63–2.72) 1.69 (1.29–2.20) 1.60 (0.85–3.00) 4.79 (3.11–7.40) Falls 1.54 (1.04–2.26) 2.04 (1.48–2.80) 1.36 (0.56–3.28) 1.41 (0.52–3.77) Cardiac Failure 0.82 (0.37–1.84) 0.56 (0.21–1.50) 0.63 (0.09–4.49) 2.89 (0.93–9.01) Values are ROR (95% CI); n indicates the number of FAERS cases reporting the PT with the ARPI as primary suspect. Disproportionality estimates from FAERS are subject to under-reporting, reporting bias, and confounding; causality cannot be inferred. PTs with very low counts (e.g., n&lt;5) should be interpreted cautiously due to statistical instability and wide uncertainty.

Epigenetic ctDNA kinetics as a predictor of early progression in advanced E/GEJ cancers treated with CDK4/6 and VEGF inhibition therapy.

e16056 Background: Advanced esophageal and gastroesophageal junction (E/GEJ) tumors carry a poor prognosis and reliable early biomarkers for therapeutic efficacy are lacking. The utilization of ctDNA monitoring longitudinally is not standard of care at present. We hypothesized that a novel, tumor-naive, methylation-based pan-cancer assay could measure disease burden and provide a signal of early molecular response in E/GEJ patients. Methods: A Phase I/II trial (NCT04921904) evaluated the safety and efficacy of abemaciclib combined with ramucirumab in metastatic/recurrent E/GEJ adenocarcinoma patients who had progressed after frontline therapy. Primary endpoints focused on safety, with secondary endpoints including response, survival, and molecular profiling. Peripheral blood samples were collected from 20 enrolled patients pre-treatment and within 30 days on-treatment. These were analyzed using a methylation-based ctDNA assay that quantifies longitudinal changes across &gt; 500 uniquely methylated loci to yield a Tumor Methylation score and the association of this score with therapeutic response, to assess changes in disease burden. Results: Safety and efficacy have previously been reported with a disease control rate of 40% and a duration of clinical response of 6.4 months in heavily pretreated (70% of patients being third line therapy or higher) advanced metastatic E/GEJ. 13 of 20 patients provided samples to assess ctDNA. We found that early molecular progressive disease (mPD), was significantly associated with a shorter progression-free survival (PFS) measured using RECIST v1.1 (Hazard Ratio = 4.9, 95% Confidence Interval 1.1-22). Notably, this association trended toward improved OS, yet not significant. Further analysis comparing patients with rapid progression (PFS ≤ 5.2 months) versus non-rapid progression revealed significant differences in baseline methylation patterns at 128 specific loci, including CCNA1 and CHL1. Conclusions: This exploratory study demonstrates that a tumor-naive, methylation-based ctDNA approach may be a viable tool for monitoring CDK4/6 pathway response in advanced E/GEJ cancers. Early mPD detection at one month by ctDNA kinetics strongly correlates with shorter PFS, offering a rapid signal of efficacy. This provides a substantial advantage over traditional radiographic evaluations (e.g., RECIST) and expands ctDNA's utility for response evaluation. Distinct baseline methylation patterns in rapid progressors highlight the potential of upfront epigenetic profiling to risk-stratify patients pre-treatment, guiding treatment selection and avoiding unnecessary toxicities. These findings suggest broad applicability for the tumor-agnostic approach targeting CDK4/6 specific alterations across various heavily pretreated solid tumors. Clinical trial information: NCT04921904 .

De novo vs recurrent metastatic presentation and outcomes with first-line EGFR TKI in <i>EGFR</i> -mutant NSCLC.

e20766 Background: Approximately 20% of EGFR-mutant metastatic non-small cell lung cancer (NSCLC) presents as recurrent disease in real-world practice. Whether metastatic presentation (de novo vs recurrent) influences treatment durability and disease control on first-line (1L) EGFR tyrosine kinase inhibitors (TKIs) is unknown. Methods: We conducted a retrospective cohort study of patients with EGFR-mutant metastatic NSCLC treated with 1L EGFR TKI from 2012-2025 at Northwell Health. Recurrent disease was defined as metastatic progression after prior curative intent therapy. The primary outcome was time to treatment discontinuation (TTD). Secondary outcomes included early discontinuation (&lt; 6 months) and progression-free survival (PFS), defined as time from 1L TKI to disease progression or death with censoring at last follow up. Multivariable Cox models adjusted for EGFR subtype, TKI agent, performance status, age, and brain metastases. Early discontinuation (&lt; 6 months) was evaluated using Poisson regression with robust standard errors, adjusted for same covariates. Results: Among 152 patients (117 TTD events; 133 PFS events), 79% presented with de novo metastatic disease and 21% with recurrent metastatic disease. EGFR subtype distribution was similar between groups (de novo vs recurrent: Ex19del 64% vs 54%, L858R 28% vs 31%, Other 8% vs 15%). In adjusted cox models, recurrent presentation was associated with a trend toward longer TTD (median 30.4 vs 16.8 months, HR 0.68; 95% CI 0.44-1.04) and significantly longer PFS (median 28.0 vs 15.2 months; HR 0.52; 95% CI 0.34-0.80) compared with de novo presentation. L858R was associated with shorter TTD (HR 1.49; 95% CI 0.94-2.34) and PFS (HR 1.63; 95% CI 1.08-2.46) relative to Ex19del. Erlotinib (HR 1.88; 95% CI 1.21-2.94) and afatinib (HR 1.85; 95% CI 1.02-3.33) were associated with shorter TTD compared with osimertinib, with similar patterns for PFS. Early treatment discontinuation did not differ by metastatic presentation (RR 1.02; 95% CI 0.44-2.47), EGFR subtype, or TKI agent. ECOG ≥2 was the only significant predictor of early discontinuation (RR 2.34; 95% CI 1.01-5.21; p = 0.04). Conclusions: In this real-world cohort, recurrent metastatic presentation was associated with significantly longer PFS and a consistent trend toward longer treatment durability on 1L EGFR TKI, independent of mutation subtype and TKI agent. As early discontinuation rates were similar, the differences in TTD and PFS in recurrent disease appear to reflect differences in tumor biology rather than early treatment failure. If validated, metastatic presentation may inform prognostic counseling and therapeutic expectations. Prospective validation in larger, multi-institutional cohorts is warranted.

A phase 2 randomized study comparing telisotuzumab adizutecan monotherapy with standard of care in patients with post-adjuvant circulating tumor DNA–positive colorectal cancer.

TPS3688 Background: Curative intent standard of care (SOC) management of colorectal cancer (CRC) involves surgical tumor removal, followed by adjuvant therapy and active surveillance (AS). Presence of circulating tumor DNA (ctDNA) in the absence of radiographic evidence of disease is emerging as a reliable biomarker for determining molecular residual disease in CRC and in predicting recurrence after definitive therapy. Telisotuzumab adizutecan (Temab-A) is an antibody-drug conjugate that targets c-Met protein and is conjugated to a topoisomerase 1 (Top1) inhibitor payload. c-Met protein is ubiquitously expressed on CRC tumor cells. Temab-A has shown a manageable safety profile and promising antitumor activity in patients (pts) with advanced solid tumors, including CRC (NCT05029882). Herein, we describe a Phase 2 study of Temab-A monotherapy in pts with ctDNA-positive CRC after adjuvant therapy compared with AS. Methods: This open-label, randomized, global, multicenter, Phase 2 study (NCT07023289) includes adults (≥18 yrs) with histologically confirmed adenocarcinoma of the colon or rectum. Surgical tumor material must be available and submitted for Signatera personalized panel and assessment of c-Met protein levels. Pts must have received a total of ≥3 mos of perioperative and/or platinum-based doublet adjuvant therapy, have no radiographic evidence of disease as determined by CT scans and liver MRI, and be ctDNA-positive within the first year after the end of adjuvant therapy. Approximately 140 pts will be randomized (1:1) to receive either Temab-A (2.4 mg/kg, IV, Q3W, N=70) or AS only (N=70). Randomization will be stratified by oligometastatic versus nonmetastatic and by the timing of enrollment. Japan will have a separate randomization schedule stratified by the same factors. During 9 mos of treatment (12 cycles [C], 21 days [D] per C) or AS, pts will undergo monitoring for disease recurrence through CT scans (Q6W) and ctDNA testing (on C2D1, C3D1, C4D1, at 6 and 9 mos). Study follow-up will occur every 3 mos for the first 2 yrs and every 6 mos for the 3 yrs thereafter. The Table shows study objectives and endpoints. Clinical trial information: NCT07023289 . Objectives Endpoints Primary  Evaluate efficacy of Temab-A Disease-free survival by investigator  Secondary  Evaluate clinical outcomes of Temab-A ctDNA clearance at 6 mos after randomizationOverall survival Safety  Evaluate safety/tolerability of Temab-A Adverse event type, frequency, seriousness, and severityTreatment-emergent adverse events leading to treatment discontinuation and dose interruption Pharmacokinetics (PK)  Evaluate PK and immunogenicity of Temab-A Serum concentration of:Temab-A conjugateTotal antibodyPlasma concentration of Top1 inhibitor

Access to immunotherapy and molecular diagnostics for lung adenocarcinoma in Syria: A mixed-methods study from the country’s main cancer center.

1557 Background: Immunotherapy is now a standard-of-care treatment for lung cancer across most stages. Access to immunotherapy and molecular diagnostic tests in conflict-affected countries such as Syria remains poorly described. As the principal cancer center in Syria, Al-Bairouni University Hospital (ABUH) provides care for nearly three-quarters of all cancer cases nationally. We conducted this study to evaluate access to immunotherapy and molecular diagnostic services at ABUH. Methods: A mixed-methods study was performed between 2022 and 2024 at ABUH. This study included a retrospective cohort of all patients diagnosed with lung adenocarcinoma. Quantitative data included disease stage at diagnosis, molecular testing rates, and immunotherapy utilization. In addition, a qualitative patient survey was thematically analyzed to explore barriers to treatment access in a separate cohort of patients with mixed tumor types. Results: Among 2,920 patients diagnosed with lung cancer, 1,393 (47.7%) had lung adenocarcinoma. The median age at diagnosis was 61 years; 79.7% of patients were male. Smoking history was as follows: Current 792 (56.9%), Former 268 (19.2%), never smoked 318 (22.8%) At presentation, 3 patients (0.2%) had stage I disease, 40 (2.9%) stage II, 174 (12.5%) stage III, and 778 (55.8%) stage IV disease, staging was unknown for the rest of the patients. EGFR mutation testing was performed by ABUH for 226/1393 patients (16.2%) only, with positive results identified in 124 cases (8.9%). PD-L1 testing was conducted by ABUH in only 32/1393 patients (2.3%) and was positive in 23 (1.65%). Of all patients with lung adenocarcinoma, only 5 patients (0.6%) with stage IV disease received immunotherapy. All were treated with nivolumab. Thematic analysis of qualitative data (35 patients) revealed that high treatment costs and limited drug availability are the primary barriers to accessing immunotherapy. Conclusions: This study represents the first evaluation of access to immunotherapy for patients with lung cancer in Syria. Even at ABUH, the country's main cancer center, access to immunotherapy and molecular testing remains markedly limited. International collaboration is necessary to expand diagnostic infrastructure, standardize data reporting, and enhance financial protection mechanisms. These are critical steps toward achieving better cancer care in Syria.

Impact of prior malignancy on cardiac complications and mortality in patients with COVID-19.

12109 Background: Cancer accounts for approximately 600,000 deaths annually in the United States, and patients with cancer are estimated to have nearly twice the risk of death following COVID-19 infection. While active malignancy and cancer-directed therapies are known to increase the risk of cardiac complications, it remains unclear whether patients with a prior history of cancer remain at elevated risk for cardiac events or mortality after COVID-19. This study aimed to evaluate whether a prior history of malignancy is associated with increased cardiac complications or all-cause mortality among Veterans diagnosed with COVID-19. We hypothesized that Veterans with a history of malignancy would have higher rates of cardiac complications and mortality following COVID-19 infection. Methods: We conducted a prospective observational cohort study of Veterans diagnosed with COVID-19 at the South Texas Veterans Health Care Center in San Antonio, Texas, using REDCap electronic data capture. Index dates ranged from March 13, 2020, through December 31, 2021, with a 10-month follow-up period. Both inpatient and outpatient Veterans were included. Patients with active malignancy or missing post-COVID cardiac outcome data were excluded. Patients were stratified into two groups: those with a prior history of malignancy and those without. The primary outcome was a composite of acute cardiac complications (arrhythmia, myocarditis, viral pericarditis, or viral cardiomyopathy) and all-cause mortality at 30 and 365 days. Results: Among 2,042 patients identified, 90 with active malignancy were excluded, leaving 1,952 patients for analysis. Of these, 5.3% (n=103) had a prior history of malignancy and 94.7% (n=1,849) had no malignancy history. Significant differences were observed in age, race, and BMI between groups. The composite primary outcome occurred more frequently in patients with prior malignancy at both 30 days (50% vs. 26%; OR 2.87, 95% CI 1.92–4.28, p&lt;0.0001) and 365 days (53% vs. 29%; OR 3.06, 95% CI 2.05–4.58, p&lt;0.0001). All-cause mortality was higher among patients with prior malignancy at 30 days (16% vs. 7%; OR 2.51, 95% CI 1.43–4.42, p=0.0013) and 365 days (16% vs. 14%; OR 3.03, 95% CI 1.97–4.66, p&lt;0.0001). Cardiac complications alone were also more common in patients with prior malignancy (41% vs. 23%; OR 2.41, 95% CI 1.60–3.62, p&lt;0.0001). Conclusions: In this large Veteran cohort, patients with a prior history of malignancy were approximately three times more likely to experience cardiac complications or death following COVID-19 infection compared with patients without a cancer history. These findings suggest that increased risk extends beyond active malignancy and highlight the need for targeted strategies to reduce adverse cardiac outcomes in patients with any history of cancer who develop COVID-19.

Effect of metformin on clinically significant chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

e24151 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity that negatively impacts quality of life and treatment adherence in cancer patients. Preclinical studies and recent trials suggest that metformin may have neuroprotective effects in cancer patients undergoing neurotoxic chemotherapy. We performed a systematic review and meta-analysis to evaluate the effect of adding metformin to standard chemotherapy regimen on clinically significant (grade ≥2) CIPN. Methods: We systematically searched PubMed, Embase, Scopus, CENTRAL and ClinicalTrials.gov for studies assessing metformin in conjunction with neurotoxic chemotherapy. Randomized controlled trials comparing metformin versus control in cancer patients receiving neurotoxic chemotherapy and reporting grade ≥2 CIPN were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Random-effects meta-analysis of risk ratios (RR) was performed using the Mantel-Haenszel method with Hartung-Knapp adjustment. Heterogeneity was quantified with I² and tau². Prospero registration number: CRD420251248636. Results: Eight studies comprising 698 patients had reported grade ≥2peripheral neuropathy events. Metformin significantly reduced the risk of grade ≥2 CIPN compared with control (RR 0.61, 95% CI 0.51–0.74, p = 0.0005). Statistical heterogeneity was low. (I² = 0%, tau² = 0). Conclusions: Metformin is associated with a significant and consistent reduction in the risk of clinically significant CIPN, suggesting its potential as a neuroprotective adjunct during chemotherapy. Because involved studies were small and varied in chemotherapy regimens/durations; larger, high-quality randomized trials are warranted to provide conclusive evidence.

Sacituzumab tirumotecan (sac-TMT) plus pembrolizumab (P) versus pembrolizumab (P) as first-line treatment for PD-L1–positive advanced non-small cell lung cancer (NSCLC): Results from the randomized phase 3 OptiTROP-Lung05 study.

8506 Background: Pembrolizumab has been the standard first-line treatment for PD-L1 positive advanced NSCLC. Sac-TMT, a TROP2-directed antibody-drug conjugate with a unique bifunctional linker, and PD-1/L1 inhibitors demonstrate complementary mechanisms that enhance antitumor activity in the first-line treatment of NSCLC ( Hong et al., Nat Med, 2025 ). Here, we report the results from the planned interim analysis for PFS in this phase 3 OptiTROP-Lung05 study (NCT06448312). Methods: Eligible patients (pts) had treatment-naïve, locally advanced or metastatic NSCLC without EGFR/ ALK alterations and positive PD-L1 expression (defined as TPS ≥1%, 22C3 assay). Pts were stratified by PD-L1 (TPS 1-49% vs ≥ 50%), histology (squamous vs non-squamous) and ECOG (0 vs 1) and then randomized (1:1) to receive sac-TMT 4 mg/kg Q2W plus P 400 mg Q6W or P 400 mg Q6W. The primary endpoint was PFS per RECIST 1.1 assessed by blinded independent central review (BICR), and the key secondary endpoint was OS. Results: A total of 413 pts (median age 65 yrs; 84.5% ECOG 1; 40.0% squamous; 40.0% PD-L1 TPS ≥ 50%) were randomized to receive sac-TMT + P (n = 208) or P (n = 205). As of Sep 29, 2025, the median follow-up was 10.5 months. PFS by BICR was significantly longer in the sac-TMT + P group than the P group (median, not reached vs 5.7 months; HR, 0.35; 95% CI, 0.26-0.47; p &lt; 0.0001). The data for OS were not mature, and a favorable trend was observed in the sac-TMT + P group (HR, 0.55; 95% CI, 0.36-0.85). The BICR-assessed ORR was 70.2% in the sac-TMT + P group versus 42.0% in the P group. In the pre-specified PD-L1 subgroups, the HRs for PFS in pts with TPS 1-49% and TPS ≥ 50% were 0.28 (95% CI, 0.19-0.41) and 0.47 (95% CI, 0.29-0.77). In the pre-specified histology subgroups, the HRs for PFS in pts with non-squamous and squamous were 0.28 (95% CI, 0.18-0.43) and 0.44 (95% CI, 0.29-0.66). Grade ≥ 3 TEAEs were 55.3% in the sac-TMT + P group and 31.4% in the P group. Most common grade ≥3 TEAEs of special interest for sac-TMT were neutrophil count decreased (17.3%), anemia (9.1%), and stomatitis (5.3%). TEAEs led to discontinuation of sac-TMT/ pembrolizumab in 3.8%/5.3% of pts in the sac-TMT + P group while discontinuation of pembrolizumab occurred in 4.9% of pts in the P group. Conclusions: To our knowledge, this is the first phase 3 study to demonstrate the significant PFS benefit of an antibody-drug conjugate plus pembrolizumab in the first-line treatment of PD-L1 positive advanced NSCLC compared to pembrolizumab. The safety profile of sac-TMT + P was generally manageable and consistent with the safety profile of the components. No new safety signals were seen. These results from phase 3 OptiTROP-Lung05 study support sac-TMT + P as a potential new treatment option for this population. Clinical trial information: NCT06448312 .

Trends in COPD-related mortality among adults with lung cancer in the United States, 1999-2025: A CDC WONDER analysis.

e20776 Background: Both COPD and lung cancer are major concerns worldwide. Lung cancer is an important comorbidity of COPD that contributes to increased mortality rates. Conversely, COPD is associated with reduced overall survival in patients with lung cancer and COPD. The presence of COPD is frequently considered a significant risk factor for lung cancer and may contribute to its development through mutually reinforcing pathophysiological mechanisms. Methods: We analyzed death certificate data from the CDC WONDER database to assess COPD-related mortality among adults with co-morbid lung cancer from 1999 to 2025. AAMRs per 100,000 individuals and APCs and corresponding 95% CIs were determined. The data was stratified by year, sex, race, state, and census region. Results: The AAMR Values were double the rate in male compared to the female (AAMR men: 10.9 vs women: 5.4). This trend has been maintained till 2025. However, the trend in females increased to its peak of AAMR 6.0 in 2010 and then was seen to be slowly descending in its value. This is a contrast to males where its seen as a significant decrease throughout the years reaching it’s lowest in 2025 of AAMR 6.5. White (7.59) adults had the highest overall AAMR followed by American Indian/Alaska Native (5.7), Black or African American (5.5), Hispanic or Latino (2.22), Asian or Pacific Islander (1.9). AAMR varied substantially by region (overall AAMR: Northeast: 5.84; Midwest 8.35; South: 7.74; West: 6.01). Based on the 2006 NCHS urbanization classification, there is difference in AAMRs of metropolitan and non-metropolitan cities. The cities classified under Micropolitan (9.5) and Noncore (9.8) had a spike in AAMR compared to metropolitan cities (Large Central Metro (5.5), Large Fringe Metro (6.3), Medium Metro (7.6), Small Metro (8.8)). Conclusions: Based on this analysis, one can conclude that the mortality rate amongst adults with lung cancer, in relation to COPD, continues to have a critical impact upon public health in the United States. Not only has a substantial disparity been found in this mortality rate, but also disparities based upon several different levels of groups in society have been identified.

Real-world outcomes with nivolumab–ipilimumab in metastatic renal cell carcinoma by nephrectomy status: A single-center study.

e16546 Background: Following the results of the CARMENA trial, the role of cytoreductive nephrectomy in the era of targeted therapy has been substantially reconsidered. However, the relevance of nephrectomy with contemporary dual immune checkpoint therapy remains insufficiently defined. Materials &amp;. Methods: This retrospective study included 156 consecutive mRCC patients treated with IPI+NIVO at Moscow City Oncological Hospital No. 62. Median follow-up was 25.0 months. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan–Meier method and compared using the log-rank test; medians with 95% confidence intervals are reported. Results: In the overall cohort, median PFS was 11.0 months (95% CI 6.15–15.86) and OS was 40.0 months (95% CI 24.88–55.12). Median PFS differed by nephrectomy status: 6.0 months (95% CI 3.0–8.0) in patients without prior nephrectomy (n = 42), 12.0 months (95% CI 6.8–17.1) after nephrectomy for localized disease (n = 71), and 23.0 months (95% CI 6.2–39.7) after nephrectomy in the metastatic setting (n = 41) (p = 0.005). Survival showed a similar pattern: median OS was 19.0 months (95% CI 4.5–33.5) in patients without nephrectomy, was not reached after nephrectomy for localized disease, and was 55.0 months after nephrectomy in the metastatic setting (95% CI not reached). Patients with lung-only metastases had superior survival compared with those with other metastatic patterns (PFS 23.0 vs 9.0 months, p = 0.038; OS not reached vs 29.0 months, p = 0.020). PFS was strongly stratified by best overall response: median PFS was not reached in patients achieving complete response (16.8%), 45.0 months (95% CI 23.21–66.79) in partial response (23.4%), 10.0 months (95% CI 7.99–12.01) in stable disease (34.3%), and 2.0 months (95% CI 1.61–2.39) in progressive disease (25.5%) (p &lt; 0.001). PFS did not differ according to histology (clear-cell vs non–clear-cell, p = 0.327), presence of a sarcomatoid component (p = 0.820), visceral metastases (p = 0.871), or grade ≥3 adverse events (p = 0.112). Similarly, OS did not differ by sarcomatoid component (p = 0.932), visceral metastases (p = 0.852), or grade ≥3 adverse events (p = 0.275), although numerically longer OS was observed in patients without grade ≥3 adverse events (47.0 vs 37.0 months). Second-line median PFS was 10.0 months (95% CI 4.45–15.55) and did not differ according to post–IPI+NIVO therapy (immunotherapy vs targeted therapy vs immuno-targeted combinations; p = 0.702). Conclusions: Our real-world outcomes with ipilimumab–nivolumab are consistent with the long-term results of CheckMate-214. The survival advantage observed with prior or cytoreductive nephrectomy accords with real-world and meta-analytic evidence suggesting that selected patients may derive benefit from combining surgery with immunotherapy, albeit with inherent selection and timing biases.

Pharmacokinetic (PK) assessment of revumenib in patients with relapsed/refractory (R/R) acute leukemias harboring a <i>KMT2A</i> rearrangement ( <i>KMT2A</i> r) or <i>NPM1</i> mutation ( <i>NPM1</i> m): Impact of food and concomitant medications.

6528 Background: Revumenib is a first-in-class, oral, potent, and selective inhibitor of the menin-KMT2A interaction that disrupts multiple drivers of leukemogenesis such as KMT2A rearrangements ( KMT2A r) and NPM1 mutations ( NPM1 m). Revumenib is approved in the United States in patients 1 year and older for the treatment of R/R acute leukemia with a KMT2A translocation or R/R acute myeloid leukemia with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. Given the severity of disease, frequent polypharmacy, and variable clinical status in this population, dosing flexibility is essential to support consistent treatment delivery and optimize outcomes. This analysis characterizes the PK of revumenib and its major metabolite (M1), with emphasis on factors that may influence dosing flexibility, including food and concomitant medications such as CYP3A4 inhibitors (CYP3A4i) and gastric acid–reducing agents such as antacids, H2 blockers (H2Bs), and proton pump inhibitors (PPIs). Methods: PK data were obtained from 286 adult (≥18 years) and 49 pediatric (&lt;18 years) patients with KMT2A r or NPM1 m acute leukemia enrolled in the phase 1/2 AUGMENT-101 trial (NCT04065399) following single and multiple doses of revumenib. Non-compartmental analyses were performed in selected subgroups, while population PK modeling was conducted using data from all patients to systematically quantify PK variability and evaluate covariate effects. Results: As compared to fasted state, a low-fat meal (400–500 calories with &lt;25% fat content) reduced revumenib C max and AUC by 27% and 12%, respectively, and M1 C max and AUC by 14% and 18%, respectively, although exposure ranges overlapped under fasted and fed (low-fat meal) conditions. Median T max was unchanged for revumenib and delayed by 1.8 hours for M1. Co-administration with strong CYP3A4i (eg, voriconazole, posaconazole, itraconazole) resulted in ~2-fold increase in revumenib C max and AUC, whereas moderate CYP3A4i (eg, fluconazole, isavuconazole) had no meaningful effect. M1 exposure was unaffected by strong or moderate CYP3A4i. Approximately 52% of patients received antacids, H2Bs, or PPIs; revumenib and M1 C max and AUC were not altered, consistent with the high solubility of revumenib across physiological pH range (1.2–6.8). Conclusions: Revumenib exposure increases ~2-fold with strong CYP3A4i, supporting dose reduction in this setting, while M1 exposure remains unaffected. Low-fat meals do not cause clinically meaningful changes in revumenib or M1 PK. Similarly, antacids, H2Bs, and PPIs, which are frequently used in this patient population, had no impact on revumenib or M1 PK. These findings reinforce the flexible administration of revumenib that may support treatment adherence and patient convenience. Clinical trial information: NCT04065399 .

A transcriptomic signature to predict immune checkpoint inhibition efficacy in proficient mismatch repair metastatic colorectal cancer: Translational analysis of the AVETRIC and TRIPLETE studies.

3570 Background: ICIs provide limited benefit in proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC), highlighting the need for predictive biomarkers. We aimed to uncover transcriptomic profiles predictive of ICI efficacy, using tumor specimens from two matched cohorts of pMMR, RAS/BRAF wild-type (wt) mCRC patients (pts) enrolled in two academic clinical trials investigating first-line FOLFOXIRI plus an anti-EGFR agent ± ICI. Methods: The phase II AVETRIC study (NCT04513951) provided the ICI-treated cohort (mFOLFOXIRI/anti-EGFR plus avelumab), while the experimental arm of the phase III TRIPLETE study (NCT03231722) served as the ICI-untreated control cohort (mFOLFOXIRI/anti-EGFR). Bulk RNA-seq analysis was performed using the Signomax platform on naive tumor specimens of 39 and 32 pts from the ICI and control cohorts, respectively. Firstly, gene set variation (GSV) analyses compared extended PFS (e-PFS) versus limited PFS (l-PFS) groups (using median PFS of the control cohort as a cut-off) within each cohort, leading to a focus on immune- and EGFR-related pathways. Secondly, using the median immune- and EGFR-related pathway scores in the ICI cohort as a cut-off, samples were classified combining both pathway activities into an immune high -EGFR high group versus a pooled group comprising all the other cases (immune-EGFR others ). Associations with PFS and OS were assessed by treatment cohort. Results: Thirty-four (87%) (23 e-PFS, 11 l-PFS) and 26 (81%) (13 e-PFS, 13 l-PFS) samples were successfully analyzed in the ICI and control cohorts, respectively. In the ICI cohort, l-PFS samples showed lower activity of both immune- and EGFR-related pathways than e-PFS ones, while no significant differences in the activation of the same pathways were observed between PFS groups in the control cohort. Additionally, 29 pts were classified as immune high -EGFR high (13 [45%] and 16 [55%] in the ICI and control cohorts, respectively) and 31 pts as immune-EGFR others (21 [68%] and 10 [32%] in the ICI and control cohorts, respectively). Immune high -EGFR high pts reported longer PFS (HR: 0.57, 95% CI 0.33-0.98, P =0.04) and OS (HR: 0.66, 95% CI 0.36-1.24, P =0.20) than other pts. Borderline significant interaction between treatment and immune/EGFR signature was found in PFS ( P =0.145) with ICI benefit restricted to pts bearing the immune high -EGFR high signature (HR PFS: 0.56, 95% CI 0.25-1.24, versus 1.25, 95% CI 0.60-2.64 in the others). Conclusions: Exploratory transcriptomic profiling may identify a subset of pMMR RAS/BRAF wt mCRC with concurrent immune activation and EGFR dependency that could benefit from combining ICI to an intensified anti-EGFR-based first-line treatment.