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Long-term ctDNA reassessment (LTctDNA) in NSCLC immunotherapy responders.

e20539 Background: Immune checkpoint inhibitors (ICI) with or without chemotherapy are standard frontline therapy for metastatic non–small cell lung cancer (mNSCLC). However, the optimal duration of immunotherapy remains undefined. ctDNA monitoring at a long-term timepoint may have the potential to identify patients at risk of progression. Methods: Patients with mNSCLC who started frontline ICI-based treatment and had an ongoing durable response for at least 18 months were included. All patients had ctDNA analysis at diagnosis and at an 18+ month time point (long-term ctDNA reassessment, LTctDNA) utilizing Guardant360 Liquid to assess genomic alterations (single nucleotide variants, indels, fusions, and copy number variants) and Guardant Reveal to evaluate methylation-based tumor fraction (mTF). Demographics, cancer and treatment information, and subsequent progression/death events were collected. Subsequent progression free survival (PFS) was calculated from time of LTctDNA draw. Molecular response was assessed using (1) change in mTF and (2) change in mean variant allele frequency (VAF) of genomic alterations between baseline and LTctDNA timepoints. Associations between ctDNA response metrics and PFS were evaluated using via log-rank analyses. Results: Our cohort included 30 eligible patients with paired samples. Median age was 64.9 years, 27 (90.0%) had a smoking history, and 17 (56.7%) were white. The majority had adenocarcinoma (76.7%); 36.7% were treated with ICI monotherapy vs chemoimmunotherapy; and 53.3% were still on treatment at time of LTctDNA draw. The median time from ICI start to LTctDNA draw was 27.1 months (range, 17.9 to 75.2). The majority of patients (23/30) had LTctDNA clearance by mTF (-100% mTF change), only 1 of whom had subsequent progression of disease (CNS-only, 10.3 months after LTctDNA draw). Of the 7 patients who did not have LTctDNA clearance, 4 experienced progression of their original cancer, and 2 died of their cancer. mPFS from LTctDNA draw was 22.6 months for the overall cohort and was longer in patients with LTctDNA clearance vs. non cleared (NR vs 9.8 months; log rank p<0.001). Compared to the methylation-based assay (mTF change), molecular response by genomic assay (VAF change) was much less reliable in predicting subsequent progression (75% vs 80% sensitivity; 59% vs 88% specificity). Conclusions: In our study, LTctDNA clearance using a commercially available methylation-based assay correlated with improved mPFS and had a 100% negative predictive value for systemic progression. These findings suggest that LTctDNA assessment at a clinically meaningful decision point, such as the 18–24 month landmark when discontinuation of ICI is often considered, could provide valuable prognostic information and guide individualized treatment decisions.

Progression-free survival as a surrogate endpoint for overall survival in metastatic triple-negative breast cancer: A systematic review and meta-analysis.

1131 Background: Overall survival (OS) remains the gold standard endpoint in metastatic triple negative breast cancer (mTNBC), but its assessment is confounded by post progression therapies and prolonged follow up. Progression-free survival (PFS) is frequently used as a primary endpoint; however, its validity as a surrogate for OS in mTNBC remains uncertain. We conducted an updated systematic review and meta analysis to evaluate the strength and reliability of PFS as a surrogate endpoint for OS across contemporary RCTs. Methods: We searched PubMed, Embase, Cochrane Library, and major oncology conference proceedings through January 2026 for randomized controlled trials evaluating systemic therapies in metastatic or unresectable TNBC. Eligible trials reported hazard ratios (HRs) for both PFS and OS. Trial level correlations between log(HR_PFS) and log(HR_OS) were assessed using weighted Spearman correlation and weighted linear regression, with sample size based weights. Certainty of evidence was assessed using a modified GRADE framework. Results: Twenty-seven treatment comparisons from 29 trials (8,527 patients) met inclusion criteria. Across all comparisons, PFS demonstrated a strong correlation with OS (weighted Spearman ρ = 0.80; 95% CI, 0.55-0.91), with a moderate surrogate relationship (R² = 0.64). The regression slope (0.66; 95% CI, 0.46-0.87) indicated attenuation of OS benefit relative to PFS. The surrogate threshold effect corresponded to an HR PFS of 0.96. Eight trials (30%) showed concordant PFS and OS benefit, while 44% demonstrated PFS improvement without significant OS gain. Surrogacy was strongest in phase III trials (R² = 0.71). Treatment class analyses revealed strong surrogacy for immune checkpoint inhibitors (R² = 0.95) and platinum based chemotherapy (R² = 0.87), but weak correlation for AKT pathway inhibitors (R² = 0.31). Overall certainty of evidence was moderate. Risk of bias assessment using the Cochrane RoB 2.0 tool showed 30% of comparisons at low risk, 56% with some concerns (primarily due to open label design), and 15% at high risk, mainly related to crossover and outcome assessment. Conclusions: PFS is a moderate and clinically acceptable surrogate for OS in metastatic TNBC, particularly for immune checkpoint inhibitors and platinum based regimens. However, surrogate validity varies substantially by treatment class, underscoring the need for confirmatory OS data especially for targeted therapies with novel mechanisms.

Metal exposure and Ki67 response to neoadjuvant aromatase inhibitor therapy in estrogen receptor-positive (ER+) breast cancer: The NAOMI trial.

e12632 Background: Prior studies suggest that exposure to metals, including arsenic, may be elevated in patients with breast cancer. This is particularly relevant in New Hampshire, where higher metal exposure has been attributed to widespread private well use (approximately 46% of households) and granite bedrock. Neoadjuvant endocrine therapy (NET) with the aromatase inhibitor (AI) letrozole is clinically effective in ER+ breast cancer. Through the NAOMI trial, we evaluate whether metal exposure influences clinical outcomes in ER + breast cancer treated with AI and its association with changes in Ki67, a marker of tumor proliferation. Methods: NAOMI is a phase II, single-arm, open-label trial of NET with letrozole in postmenopausal women with stage III ER+ breast cancer. The trial began in 2021 with projected completion in 2029. Participants received letrozole for 4-12 weeks prior to surgical resection. Preoperative urine samples were collected, and urinary metal concentrations were measured. Tumor tissue was obtained at baseline (diagnostic biopsy) and at surgery. Ki67 expression in the tissues were assessed by immunohistochemistry. Linear regression evaluated associations between Ki67 change and urinary metal concentrations along with BMI, tumor size, and age. Urinary metal levels in our patients were compared with NHANES 2017-2018 (US representative) and NH TRACE 2019(regional) reference data. Results: Urine samples were analyzed from 121 patients (93% White). Twenty-seven metals were measured, including speciated arsenic and its metabolites monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as cadmium, tin, lead, and uranium. Mean age was 68 years, mean BMI was 31, and mean tumor size was 2 cm. Higher BMI and larger tumor size were significantly associated with greater decreases in Ki67 (BMI: t = −2.5, p = 0.01; tumor size: t = −2.3, p = 0.02). An increase of BMI by 10 led to a decrease of KI67 by 4.3, assuming that the tumor size did not change. A twofold increase in tumor size led to a 2.4 decrease in KI67. Speciated arsenic, MMA, DMA, and other metals showed no significant association with Ki67 change. Median urinary concentrations of arsenic, cadmium, tin, lead, and uranium were 6.0, 0.28, 0.44, 0.39, and 0.009 µg/L, respectively. Between 4-15% of participants exceeded NHANES 95 th percentile values, and 3-15% exceeded NH TRACE 95 th percentile reference values. Conclusions: This study identified BMI and tumor size as the primary predictors of change in Ki67, whereas urinary metal concentrations were not predictive. Urinary metal levels were comparable to national and regional reference populations. Speciated arsenic subtypes related to seafood intake were excluded. Limitations include variability in urinary metal half-lives. Future studies should incorporate blood, nail, and tissue measurements to better characterize metal exposure. Clinical trial information: NCT04568616 .

Inhaled delivery of KB707, a novel HSV-based immunotherapy, in combination with pembrolizumab in advanced non–small cell lung cancer: A phase 1/2 study.

8564 Background: Though immune checkpoint inhibitors (ICIs) have significantly improved the treatment for lung cancers, resistance invariably develops and novel approaches are needed to overcome such resistance and enhance anti-tumor immunity. KB707 is a replication-defective herpes simplex virus type 1 (HSV-1)-based vector engineered to deliver human interleukin (IL)-12 and IL-2 to induce both innate and adaptive antitumor immunity. Inhaled KB707 monotherapy was previously shown to be well tolerated with encouraging efficacy in pts with advanced non-small cell lung cancer (aNSCLC): 4 of 11 pts achieved partial response (PR). Delivery of IL-12/IL-2 by inhaled KB707 may significantly increase the anti-tumor efficacy of ICI (pembro) in pts with aNSCLC who are relapsed or refractory to standard therapy. Extending from the monotherapy results, the safety and efficacy of adding inhaled KB707 to pembro in pts with aNSCLC is presented. Methods: KB707-02 is a Phase 1/2, open-label, multicenter study of inhaled KB707 (NCT06228326). Eligible pts with at least one measurable lung lesion at screening and histological confirmation of stage 3 or 4 NSCLC received nebulized KB707 (10 9 PFU) every 2 weeks and pembro (400 mg) every 6 weeks. Pts must have previously received one line of prior ICI, with or without platinum-based chemotherapy. The primary objective is to assess safety and tolerability per CTCAE v5.0, with a secondary objective to evaluate preliminary efficacy per RECIST 1.1. Results: As of 01 Jan 2026, a total of 21 pts (11 female) were enrolled and received at least one dose of inhaled KB707 plus pembro. The majority of treatment-related adverse events (TRAE) have been mild to moderate in severity and transient. Consistent with known adverse event profiles of IL-2 and IL-12, the most common TRAE were flu-like symptoms (fever, chills, vomiting, fatigue) and dyspnea. The efficacy population (n=16) received at least one treatment cycle and had at least one evaluation per RECIST 1.1. The 16 pts were of advanced age (median 72 [50-88] years old) and heavily treated (3 median lines of prior therapies). The ORR was 31.3% (5/16) and DCR was 75% (12/16) with 5 pts achieving confirmed PR and 7 with stable disease (SD). Median treatment duration was 24.1 weeks (6.1-71.9) with 5 out of 16 pts remaining on study. Median overall survival and progression free survival were not reached. Conclusions: Delivery of IL-12/IL-2 by inhaled KB707 in combination with pembro was well tolerated and encouraging antitumor effects were observed in heavily treated aNSCLC, as evidenced by 31.3% ORR and 75% DCR. The study is proceeding with enrollment of an additional cohort to further evaluate inhaled KB707 in combination with docetaxel in aNSCLC. Clinical trial information: NCT06228326 .

Dedicated multidisciplinary oligometastatic breast cancer clinic (OMBCC) as a platform for standardized decision-making and real-world evidence generation.

e13614 Background: Management of de novo oligometastatic breast cancer remains controversial, where randomized trials are limited by feasibility, heterogeneity, and patient selection. While aggressive locoregional and metastasis-directed therapy may benefit select patients, variability in practice and lack of standardized multidisciplinary evaluation limit consistent care. To address this gap, our centre established a dedicated multidisciplinary OMBCC with the intent to standardize decision-making, optimize patient selection, and serve as a platform for prospective data collection and clinical trial facilitation. Methods: The OMBCC is a central monthly clinic led by a multidisciplinary team of breast cancer specialists, including surgical, medical, and radiation oncologists. Referral criteria include patients with de novo MBC with < / = 5 metastases. Each case undergoes multidisciplinary review with consensus recommendations for investigations, optimal systemic therapy, locoregional management, metastasis-directed therapy, and potential enrolment on relevant clinical trials. Prospective data collection includes clinicopathological characteristics, imaging, and metabolic response to therapy with serial PET scans. Results: The OMBCC clinic was launched in July 2025 with 14 patients evaluated to date. Clinic feasibility was demonstrated through consistent operation, multidisciplinary attendance, and standardized documentation of recommendations. Key patient demographics, disease characteristics and management recommendations are summarized in Table 1. The clinic provides centralized expert consensus to enable coordinated and consistent decision-making across disciplines. Ongoing data collection will support evaluation of treatment patterns, changes in management, and enrollment into clinical trials. Conclusions: Establishment of a dedicated multidisciplinary OMBCC is feasible and provides a structured platform for standardized decision-making in a clinically controversial area where randomized evidence is limited. This care delivery model supports consistent evaluation, screening for clinical trials, and prospective real-world data generation to optimize management for carefully selected patients with de novo oligometastatic breast cancer, with the intent to improve outcomes. Demographic and clinical characteristics, and treatment recommendations. Age at Diagnosis, median (range) 41 (32-57) HR+, HER2-, n (%) 7 (50%) Node positive, n (%) 12 (86%) Number of metastases, median (range) 2 (1-6) On 1 st line systemic therapy, n (%) 8 (57%) Recommended surgery for locoregional disease, n (%) 10 (71%) Recommend consolidative RT after locoregional surgery, n (%) 5 (36%) Recommend primary RT to locoregional disease, n (%) 1 (7%) Recommend metastasis-directed therapy with SABR, n (%) 5 (36%)

Postmastectomy radiotherapy in pN1 breast cancer: Survival outcomes and prognostic factors from a single-institution cohort

Purpose/Objectives The role of postmastectomy radiotherapy (PMRT) in patients with pathologic N1 (pN1) breast cancer, including triple-negative breast cancer (TNBC), remains controversial in the era of modern systemic therapy. We evaluated the association between PMRT and recurrence-free survival (RFS) and overall survival (OS) and identified prognostic factors in a contemporary single-institution pN1 cohort. Materials/Methods We retrospectively reviewed female patients with pT1-2N1M0 breast cancer treated with mastectomy between 1999 and 2023. RFS and OS were estimated using Kaplan-Meier methods and compared by PMRT status with log-rank testing. Univariable Cox proportional hazards models assessed associations between clinical factors—including tumor laterality, receptor subtype (TNBC vs non-TNBC), nodal burden, and adjuvant therapies—and survival outcomes, with subgroup analyses by PMRT status and receptor subtype. Results Fifty-seven patients were included; 22 (38.6%) received PMRT. With a median follow-up of 85 months, PMRT was not associated with improved RFS (median 133 vs 120 months; p = 0.256) or OS (not reached vs 195 months; p = 0.154). Hormone therapy was significantly associated with improved RFS (HR 0.43; p = 0.026) and OS (HR 0.13; p = 0.003), while having 2–3 positive lymph nodes predicted worse RFS (HR 2.86; p = 0.007). No significant differential benefit from PMRT was observed in patients with TNBC or non-TNBC disease. Conclusions PMRT was not associated with a survival benefit in this pN1 cohort, including patients with TNBC. Interpretation is limited by modest sample size and statistical power. Outcomes appeared driven by tumor biology, nodal burden, and systemic therapy, supporting individualized PMRT decision-making.

Stimulation of surface ionization waves by pulsed laser irradiation

The inclusion of a semiconducting material within a composite barrier enables the uniform propagation of surface ionization waves (SIWs) in air at atmospheric pressure regardless of the polarity of the applied electric field, unlike surface discharges generated using purely dielectric barriers. We exploit the photonic properties of silicon to perturb the SIW using external irradiation by a 2 ns pulsed laser at 532 nm, with a fluence of 1.3 mJ/cm2 per pulse at the surface. No effect is observed when irradiation occurs more than 3 μs before plasma generation. This timescale is attributed to the ambipolar diffusion of photoexcited carriers away from the Si–SiO2 interface. When this delay shortens to less than 3 μs, the SIW propagates farther and with more intense optical emission. Furthermore, the energy of the discharge increases by up to 7%. The sensitivity to the laser-plasma delay demonstrates that the observed stimulation of the SIW cannot be due to the desorption of surface charge by irradiation.

Synergistic nanocomposites of gold nanorods and reduced graphene oxide for optical and electrochemical sensing of hydrogen peroxide

Supramolecular Mismatch Elevates the Flow Transition Temperature of Ionogels

ABSTRACT Ionogels, formed by integrating polymer networks with ionic liquids (ILs), are promising for flexible electronics and ionotronic devices, yet their practical application is often limited by poor high‐temperature stability arising from low flow transition temperatures ( T f ), which are commonly reduced upon incorporation of ILs. Here, we report a supramolecular mismatch strategy that fundamentally elevates the T f of polyurethane‐based ionogels, effectively suppressing thermal softening under heating. By introducing mismatched supramolecular chain extenders into the polymer backbone, the resulting ionogels exhibit a markedly increased T f of up to 151°C and a substantially expanded operating temperature window approaching 200°C. Rheological measurements reveal a markedly higher loss modulus for the mismatched ionogel at elevated temperatures, indicating enhanced internal friction that stabilizes the network against thermal flow. Importantly, this strategy mitigates the disruptive effect of ILs on polymer–polymer interactions while maintaining high ionic conductivity and optical transparency. Beyond thermal stability, the ionogels also display good elasticity, self‐healing capability, and stable sensing performance at elevated temperatures. This work establishes supramolecular mismatch as a powerful design principle for overcoming the intrinsic thermal limitations of ionogels, enabling their use in wide‐temperature‐range soft electronic and sensing applications.

Resurrection of chromosomes from frozen animals by single chromosome transfer into mouse oocytes

Correction: Balanced production of ribosome components is required for proper G1/S transition in Saccharomyces cerevisiae

Updated overall survival results from a randomized phase III trial of non–cross-resistant adjuvant chemotherapy plus endocrine therapy versus endocrine therapy alone in HR+/HER2−/lymph node–positive breast cancer with residual disease following neoadjuvant chemotherapy (NCT01019616).

506 Background: Patients with HR+/HER2−, node-positive breast cancer and residual disease after neoadjuvant chemotherapy (NAC) represent a high-risk population yet substantial recurrence risk. Whether additional non-cross-resistant chemotherapy after surgery provides long-term survival benefit beyond endocrine therapy remains uncertain. Our previous analysis of this phase III trial (NCT01019616) with shorter follow-up (median, 72.4 months) did not show a statistically significant survival benefit. Here we report updated survival outcomes with extended follow-up. Methods: Women aged < 65 years with invasive HR+/HER2−, node-positive breast cancer who completed anthracycline-containing NAC and had residual disease (Miller–Payne grade 1–3 and/or residual nodal involvement) were randomized 1:1 to receive either 4 cycles of non-cross-resistant adjuvant chemotherapy plus endocrine therapy (CT+ET) or endocrine therapy alone (ET). The primary endpoint was distant disease-free survival (DDFS); overall survival (OS) was a secondary endpoint. Hazard ratios (HRs) were estimated using Cox proportional hazards models with multivariable adjustment. Results: A total of 379 patients were randomized (CT+ET, n = 187; ET, n = 192) with balanced baseline characteristics. At median follow-up of 135.0 months, 52 deaths occurred: 18 (9.6%) in CT+ET versus 34 (17.7%) in ET. OS was significantly improved with CT+ET (log-rank P = 0.023). Ten-year OS rates were 89.9% versus 82.9% (adjusted HR, 0.56; 95% CI, 0.32–0.99; P = 0.048). DDFS showed a favorable trend ( P = 0.059) with 10-year rates of 85.5% versus 78.3% (adjusted HR, 0.67; 95% CI, 0.41–1.09). Greatest benefit was observed in patients with residual node-positive disease (OS HR, 0.47) and Miller–Payne grade 3 response (OS HR, 0.31). Conclusions: This randomized phase III trial demonstrates long-term overall survival benefit from the addition of non-cross-resistant chemotherapy to endocrine therapy for HR+/HER2−, node-positive patients with residual disease after NAC. Clinical trial information: NCT01019616 .

Multi-modal AI foundation models approach for diagnosis of myelodysplastic syndromes across whole bone marrow aspirate and biopsy slides.

6571 Background: Morphologic diagnosis of myelodysplastic syndromes (MDS) from bone marrow aspirates and biopsies is subjective and error prone. Compared to narrow/specific predictive AI methods used in the literature, recently developed pathology foundation models pretrained on large, diverse histopathology corpora have the potential to improve generalizability while reducing task-specific annotation requirements. Here, we evaluate and compare multiple pretrained foundation models across bone marrow aspirate and biopsy whole-slide images (WSI), incorporate a cell-level bag-of-cells (BoC) foundation model, and assess tri-modal ensemble strategies. Methods: Digitized bone marrow aspirate (Asp) and biopsy (Bx) WSIs from patients with MDS and non-MDS cytopenias were analyzed using four pretrained pathology foundation models (GigaPath, H-Optimus-0, Virchow2-CLS, MUSK) for tile-level feature extraction. Cell-level features from aspirate-derived BoCs were extracted using DinoBloom-B, a foundation model pretrained for hematologic cell representations. Tile- or cell-level features were aggregated using attention-based multiple instance learning (ABMIL). Models were evaluated on 645 patients (319 MDS, 326 non-MDS) from the NHLBI MDS Natural History Study (NCT02775383) using 5-fold cross-validation (CV) and a held-out test set (n=129). For each modality, the best-performing model was selected based on test performance. Predictions were evaluated individually and combined using soft-probability ensembles. An oracle ensemble estimated the upper bound of multimodal complementarity. Results: Performance of the foundation models is summarized in Table 1. A soft-vote tri-modal ensemble of the selected models improved performance beyond any single modality (AUC 0.83; accuracy 0.73). Error analysis demonstrated partially non-overlapping failure modes across modalities, and an oracle ensemble achieved substantially higher accuracy (0.94), indicating unrealized multimodal complementarity. Conclusions: Foundation models enable robust AI-based diagnosis of MDS across bone marrow specimen types. Tri-modal ensembling improves diagnostic performance, while oracle analysis motivates TriPath, a unified framework for joint modeling of aspirate, biopsy, and cellular morphology to support standardized and generalizable MDS diagnosis. Performance summary. Model Bx WSI​ CV AUC Bx WSI​ Test AUC Asp WSI CV AUC Asp WSI Test AUC Asp-derived BoC CV AUC​ Asp-derived BoC Test AUC​ GigaPath+ABMIL​ 0.80+/-0.05 ​ 0.82 ​ 0.77+/-0.06​ 0.66​ ​ H-Optimus-0+ABMIL​ 0.82+/-0.04​ 0.79​ 0.77+/-0.07​ 0.68​ Virchow2-CLS+ABMIL​ 0.81+/-0.04​ 0.76​ 0.78+/-0.05 ​ 0.74 ​ MUSK+ABMIL​ 0.77+/-0.05​ 0.81​ 0.76+/-0.04​ 0.72​ DinoBloom-B+ABMIL​ ​ 0.83+/-0.05 ​ 0.78 ​ Tri-modal Soft Ensemble Test AUC 0.83 Oracle ensemble (upper bound) Test Accuracy 0.94

Tumor-agnostic ctDNA methylation profiling as an enabler of preoperative risk stratification and pathological response assessment in hepatocellular carcinoma.

e16291 Background: Clinical management of hepatocellular carcinoma (HCC) is becoming increasingly complex, encompassing curative resection for early-stage disease and multimodal treatment strategies across disease stages. However, preoperative risk stratification and timely evaluation of treatment response remain challenging due to the lack of reliable blood-based tools. Tumor-agnostic circulating tumor DNA (ctDNA) methylation profiling may help address these unmet clinical needs by enabling real-time, noninvasive assessment of tumor biology and therapeutic efficacy. Methods: We prospectively enrolled 174 HCC patients undergoing curative hepatectomy and collected plasma samples within 24 hours prior to surgery (Ts). In parallel, an independent neoadjuvant therapy cohort of 27 HCC patients treated with immune checkpoint inhibitor-based systemic therapy was included, in which plasma samples were obtained at baseline before treatment initiation (Tb) and prior to surgery (Ts). All plasma samples were assayed using the GutSeer. A tumor-agnostic machine learning model was developed based on 342 HCC patients and 1,415 healthy subjects to generate a methylation-based cancer score (MCS) for prognostic stratification and pathological response assessment. Results: The hepatectomy cohort was followed for a median of 26.3 months with 47 recurrences. Preoperative Ts MCS was significantly associated with advanced tumor stage, larger tumor size, and vascular invasion, indicating its ability to reflect tumor burden and underlying biological aggressiveness. Based on Ts MCS, patients were stratified into low-risk (n = 45) and high-risk (n = 129) groups, yielding a hazard ratio (HR) of 9.36 (95%CI: 2.27–38.59; p < 0.001) and a negative predictive value of 95.6%. Multivariate analysis confirmed Ts MCS as an independent predictor of recurrence (HR = 5.09, 95%CI: 1.18-21.92; p < 0.05). In the neoadjuvant therapy cohort, MCS decreased significantly from Tb to Ts (p < 0.001). The change of MCS (Tb-Ts) was strongly negatively correlated with the proportion of residual viable tumor (R = -0.70, p < 0.001), indicating MCS changes closely mirror pathological response. Consistently, MCS change accurately discriminated major pathological response (MPR, ≤50% viable tumor cells) from non-MPR (AUC = 0.859), outperforming changes of alpha-fetoprotein (AUC = 0.731) and des-gamma-carboxy prothrombin (AUC = 0.686). Conclusions: This study demonstrates that tumor-agnostic ctDNA methylation profiling enables effective preoperative risk stratification in resectable HCC. Furthermore, dynamic changes in MCS provide a precise, noninvasive biomarker for assessing pathological response to systemic therapy. These findings highlight the broad clinical utility of methylation-based liquid biopsy approaches across surgical and systemic treatment settings in HCC. Clinical trial information: NCT06178809 .

Incidence of arterial and venous vascular complications after radiotherapy for head and neck cancer: A systematic review and meta-analysis.

e18104 Background: Advances in radiotherapy (RT) have improved locoregional control and survival in head and neck cancer (HNC). Long-term vascular toxicity is a clinically important yet underrecognized late effect. This is the first meta-analysis to systematically quantify the incidence of radiation-associated vascular toxicity using only primary studies, stratified by mode of detection and duration of follow-up. Methods: We searched MEDLINE, Embase, and Cochrane (inception-Jan 2025) databases. A meta-analysis of proportions using random-effects models was performed, stratified by detection method (screening vs. clinical) and follow-up (≤5 years, >5 years). Only primary observational studies were included in the quantitative synthesis. Results: A meta-analysis of 12 observational studies (n=2,682) was performed using a random-effects model. The pooled incidence of screening-detected carotid stenosis (≥50%) was 28.3% (95% CI: 21.5–35.7), significantly higher than the 9.4% (95% CI: 6.2–13.3) incidence of clinically-detected stroke/TIA—a 3.0-fold difference. Subgroup analysis revealed a strong time-dependent relationship: incidence was 7.5% within 5 years post-RT but escalated to 32.1% beyond 5 years. Venous complications (jugular thrombosis/stenosis) were sparsely reported (2-5% incidence in 2 studies). Statistical heterogeneity was high across all analyses (I² > 80%). Meta-analysis revealed a 28.3% incidence of screening-detected carotid stenosis (≥50%) versus 9.4% for clinical stroke/TIA—a 3.0-fold disparity. Incidence rose progressively from 7.5% (<5 years) to 32.1% (>5 years) post-RT. Conclusions: Based on primary data, vascular complications represent a substantial under-recognized survivorship burden. Screening-detected disease is three times more prevalent than clinically apparent disease. The marked escalation in risk beyond 5 years post-RT justifies consideration of targeted surveillance for high-risk, long-term survivors.

Burden of renal cell carcinoma: A population-based real-world study of incidence, prevalence, and demographic disparities.

e16530 Background: Renal cell carcinoma (RCC) is the most common primary malignancy of the kidney and contributes substantially to the global cancer burden. However, contemporary real-world data describing longitudinal trends in RCC incidence and prevalence across demographic groups remain limited. Methods: We conducted a population-based incidence and prevalence analysis using the TriNetX Global Collaborative Network, a federated electronic health record platform comprising 168 healthcare organizations worldwide. Adults aged 18 to 89 years with at least one clinical encounter were included. RCC was defined using the ICD-10-CM code C64 (malignant neoplasm of kidney, except renal pelvis). Two time windows were evaluated: January 1, 2010, to December 31, 2015, and January 1, 2016, to December 31, 2025. A lookback period extending from database inception to one day before each time window was applied to distinguish incident from prevalent cases. Outcomes included incidence proportion, prevalence, and incidence rate (cases per person-day), stratified by age, sex, race, and ethnicity. Results: Among 133,787,756 eligible individuals, RCC incidence increased from 0.11% in 2010–2015 to 0.18% in 2016–2025, representing a relative increase of approximately 60%. Prevalence rose from 0.14% to 0.23% over the same periods. Incidence rates increased from 0.000000947 to 0.00000140 cases per person-day. RCC incidence showed a strong age-dependent gradient, peaking in individuals aged 65 to 74 years. Males had consistently higher incidence than females across both decades. Racial disparities were observed, with the highest incidence among White and American Indian or Alaska Native populations. Non-Hispanic individuals had higher RCC incidence and prevalence compared with Hispanic individuals. Conclusions: In this large real-world analysis, RCC incidence and prevalence increased substantially over the past decade, with persistent age-, sex-, race-, and ethnicity-based disparities. These findings highlight the growing population-level burden of RCC and underscore the need for targeted prevention and early detection strategies.

Yield and clinical utility of peritoneal cytology in patients with locally advanced gallbladder carcinoma undergoing staging laparoscopy.

e16225 Background: Gallbladder cancer (GBC) is an aggressive malignancy with a high incidence in India, where most patients present with advanced disease. Accurate exclusion of metastatic spread is critical before initiating neoadjuvant chemotherapy (NACT) in patients with locally advanced gallbladder cancer (LAGBC). Peritoneal metastases are frequently missed on imaging, and the incremental value of peritoneal cytology (PC) during staging laparoscopy (SL) in this setting remains underdefined. Methods: This ambispective observational study was conducted at a tertiary cancer center in India. Patients with LAGBC planned for neoadjuvant therapy and without radiologic evidence of distant metastasis underwent staging laparoscopy with peritoneal cytology. The primary outcome was the yield of peritoneal cytology in detecting occult metastatic disease. Associations between cytology, laparoscopic findings, imaging, and tumor markers were analyzed. Results: Fifty patients with LAGBC were evaluated (mean age 55 years; 56% female). Overall, peritoneal cytology was positive in 18% (9/50). Among patients with no visible metastatic disease on laparoscopy (M0, n = 37), 8.1% (3/37) had positive cytology, representing occult metastatic disease undetected by visual inspection. In patients with gross metastases (M1, n = 9), cytology was positive in 55.6%. Notably, 14.6% of patients staged as M0 on PET-CT demonstrated positive cytology. Elevated CA19-9 levels were associated with a higher cytology positivity rate (25.8% vs. 5.3%), though this did not reach statistical significance. Conclusions: Peritoneal cytology provides an incremental diagnostic value during staging laparoscopy in patients with LAGBC. Routine incorporation of peritoneal cytology into staging protocols for LAGBC should be strongly considered prior to initiation of neoadjuvant chemotherapy.

Exercise and cardiovascular risk among breast cancer patients.

12022 Background: Breast cancer is the most common cancer among U.S. females, accounting for 15% of new diagnoses. As survivorship increases, cardiovascular disease (CVD) has become a major cause of long-term morbidity and mortality. Survivors remain at elevated risk for CVD due to treatment-related cardiotoxicity and underlying risk factors. Despite this growing burden, evidence on whether exercise mitigates cardiac dysfunction remains limited and inconsistent. This study examines the association between physical activity and subsequent CVD and mortality outcomes among breast cancer patients with documented Exercise Vital Sign (EVS) data. Methods: A retrospective cohort study was conducted within the Kaiser Permanente Southern California (KPSC) health system. Adult members (≥18 years) with primary breast cancer diagnosed from 2011–2019 were identified through the KPSC cancer registry. Eligible patients had ≥12 months of continuous enrollment and at least two encounters (separated by ≥1 month) with EVS data in the year prior to diagnosis. Physical activity was defined using median exercise volume: completely inactive (0 min/week; reference), insufficiently active (IA; > 0– < 149 min/week), and sufficiently active (SA; ≥150 min/week). Outcomes included all-cause, cancer-specific, and CVD mortality; congestive heart failure (CHF); cardiomyopathy; and major adverse cardiovascular events (MACE). Cox proportional hazards models adjusted for demographic factors, lifestyle characteristics, tumor features, insurance type, and pre-existing cardiovascular comorbidities. Results: Among the cohort (N = 12,481), compared with the completely inactive group, SA was associated with lower risk of CHF (HR 0.74; 95% CI 0.59–0.89). For MACE, both IA (HR 0.78; 95% CI 0.71–0.86) and SA (HR 0.66; 95% CI 0.59–0.74) demonstrated decreased risk. Similar reductions were observed for all-cause mortality (IA HR 0.75; 95% CI 0.68–0.83; SA HR 0.62; 95% CI 0.54–0.70), cancer-specific mortality (IA HR 0.82; 95% CI 0.71–0.96; SA HR 0.69; 95% CI 0.57–0.83), and CVD mortality (IA HR 0.68; 95% CI 0.58–0.79; SA HR 0.53; 95% CI 0.43–0.65). Physical activity was not associated with reduced cardiomyopathy risk. Conclusions: Physical activity appears to reduce cardiovascular and mortality risk among breast cancer survivors in a dose-responsive manner, with SA patients experiencing the greatest benefit. Even insufficient activity was associated with improved prognosis compared with complete inactivity, supporting the incorporation of exercise promotion into survivorship care. Regular physical activity may reduce CVD and mortality risk among breast cancer survivors, supporting routine EVS screening and referral to exercise or cardio-oncology programs in survivorship care. These findings also reinforce the need for institutional and payer policies that prioritize exercise assessment and counseling as standard components of cancer survivorship care.

Phase 1/2 study of YL201, an anti-B7H3 antibody–drug conjugate (ADC), in patients with relapsed or refractory (R/R) Ewing sarcoma and chondrosarcoma.

11510 Background: The prognosis for R/R sarcoma remains dismal with limited effective treatment options. YL201 is a B7H3-targeting ADC with promising activity in multiple advanced solid tumors. Here, we report the safety and preliminary efficacy of YL201 monotherapy in patients with Ewing sarcoma (EWS) and chondrosarcoma (CHS) from a phase 1/2 study. Methods: Patients with histologically confirmed sarcoma who had an ECOG PS of 0 or 1 and progressed on ≥1 prior line of systemic therapies were enrolled and treated with YL201 intravenously Q3W at 2.0 mg/kg or 2.4 mg/kg until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty-two patients with sarcoma were enrolled, including EWS (n=20), CHS (n=10), osteosarcoma (n=1), and soft tissue sarcoma (n=1). The overall population had a median age of 34.0 years (range: 19–69), with 81.3% male and 46.9% having an ECOG PS of 1. Patients had a median of 1 prior line of therapy (range: 1–6), with 96.9% having received prior chemotherapy and 37.5% having received targeted therapy. As of December 12, 2025, the median follow-up was 11.4 months (95% CI: 9.1–13.2). In EWS sub-cohort, the confirmed ORR was 50.0% (95% CI: 27.2–72.8) with a median DoR of 6.5 months (95% CI: 2.8–NR), and DCR was 95.0% (95% CI: 75.1–99.9). Median PFS was 5.5 months (95% CI: 2.8–7.9), while OS data remained immature. In CHS sub-cohort, antitumor activity was observed with a confirmed ORR of 10.0% (95% CI: 0.3–44.5) and a DCR of 90.0% (95% CI: 55.5–99.7). The median PFS was 11.7 months (95% CI: 3.9–NR), and median OS was not reached. Membrane B7H3 expression was detected by immunohistochemistry in 42.1% of EWS and 44.4% of CHS patients, whereas the remainder exhibited no membrane B7H3 expression. However, no association was observed between tumor response and B7H3 expression level in either sub-cohort. Among all 32 patients enrolled, the treatment-related adverse events (TRAEs) of any grade and grade ≥3 occurred in 100.0% and 34.4% of patients, respectively. The most common grade ≥3 TRAEs included lymphopenia (15.6%), neutropenia (9.4%), thrombocytopenia (9.4%), leukopenia (6.3%), and anemia (6.3%). No interstitial lung disease or pneumonitis was observed. The rate of treatment discontinuation due to TRAEs was low at 3.1%, and no treatment-related deaths were reported. Conclusions: YL201 showed promising antitumor activity and manageable safety profile in patients with R/R EWS and CHS, with a particularly encouraging ORR in EWS. Given the high incidence of Ewing sarcoma in adolescents, these findings support further evaluation of YL201 in pediatric populations. Clinical trial information: NCT06057922 .

Evidence of clonal stability in a 5-year longitudinal prospective cohort of cancer survivors with serial NGS analysis.

10562 Background: Hematopoietic stem and progenitor cells with preleukemic mutations (mut n s), collectively termed clonal hematopoiesis (CHIP) serve as the cellular origin of myeloid neoplasms (MN). While risk of MN development varies, its natural history and transformation potential remain poorly defined. We present findings from our ongoing 10-year CHIP protocol using serial NGS to monitor clonal evolution and MN in cancer survivors. Methods: Retrospective analysis of 210 prospective pts from March 2020 to June 2024. Mut n s were classified CHIP+ if they had a variant allele frequency (VAF) ≥2% (or ≥1% for IDH1, IDH2 , and JAK2 ). Clonal evolution was evaluated by annual VAF changes adjusted for age-related increases (e.g. DNMT3A increases by ~2%/yr based on published data). Mut n s were classified as slow (≤5%/yr: DNMT3A, TET2, ASXL1 ), intermediate (5-10%/yr: TP53, PPM1D, IDH1/2, KRAS, NRAS, SF3B1 ), or fast-growing ( > 10%/yr: JAK2, SRSF2 ). BPearson's Chi-squared, Fisher’s exact, and Wilcoxon rank-sum tests were used. Results: Of 210 pts, 42 (20%) had at least one CHIP+ mut n . Median age was higher in CHIP+ vs. CHIP- pts (66 vs. 59 years, p < 0.001). CHIP+ was not significantly associated with sex, race, family history, smoking, alcohol use, prior cancer types (e.g., breast, head and neck) or treatment (chemo, radiation, surgery). Of 487 samples, 56 had detectable somatic mut n s. The most frequent mut n were DNMT3A (n = 27), PPM1D (n = 10), and TET2 (n = 9). By expected growth kinetics, 37 (66%) mut n were slow-growing, 12 (21.4%) intermediate, 2 (3.5%) fast-growing, and 4 (7.14%) of unknown kinetic category.Beyond VAF-kinetics-based progression, 12 pts developed new mut n in subsequent years - DNMT3A (n = 8), PPM1D (n = 2). Some later became undetectable, suggesting transient clones. In total, 12 pts (1 by VAF kinetics, 11 by new mut n acquisition) clonally progressed over 5 years of this study (5.7%).6 pts regressed by year 2, with gene mut n VAFs becoming undetectable. These included mut n in PPM1D (n = 2), CBL (n = 2), TP53 (n = 1), and DNMT3A (n = 1). Three more pts regressed in year 3, and 1 in year 4. In all, 10 pts showed regression over 5 years (17.8%). Notably, 5 of 10 had received interventions for cardiac comorbidities. Overall, ~94% pts had clonal stability/regression. Slow-growing mut n s - DNMT3A and TET2 had median rates of 0.83% and 2.11%, (historical rates ≤5%). Intermediate mut n s like TP53 and PPM1D had median rates of 1.64% and -0.625%, below the expected 5-10% annual rise. JAK2 , a fast-growing mut n , also showed a lower rate of 0.19%. Conclusions: Despite being a high-risk population due to prior solid malignancy and exposure to chemo/radiation, most pts in our five-year longitudinal study showed clonal stability. Even among those who progressed, VAF kinetics remained stable post-detection. CHIP’s inflammatory link to cardiovascular disease suggests preventive cardiology may impact clonal behavior.