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HER2 discordance in upper gastrointestinal cancers in a US-based analysis.

e16086 Background: HER2 overexpression is present in 20 to 30% of advanced upper gastrointestinal (UGI) cancers and can be targeted in the first-line setting by combining chemotherapy with trastuzumab +/- pembrolizumab. However, the persistence of HER2 overexpression in progressive cases is unknown. Despite this, HER2 overexpression is often targeted in the second-line or more-advanced settings with trastuzumab-deruxtecan based on the initial pathology. Small international series (n = 48 and n = 7) demonstrated that up to 43% of UGI cancer patients lose HER2 overexpression in progressive tissue. We sought to characterize HER2 overexpression loss in subsequent biopsies in a US-based population. Methods: This study queried the US-based, electronic health record-derived, deidentified Flatiron Health Research Database from January 2011 to June 2025, which has longitudinal patient-level data from approximately 280 cancer clinics. Eligible patients had HER2 assessed prior to initiation of first-line therapy and a second assessment at least 7 weeks or later after first biopsy. HER2 positivity was defined by the ASCO/CAP guidelines. Demographics and baseline clinical and laboratory variables were extracted. We describe proportions with 95% confidence intervals (CI) using the Clopper-Pearson method. We used univariate logistic regressions to estimate odds ratios (ORs) for the binary outcome of loss of HER2 overexpression. Subgroup analyses were stratified by baseline HER2 status (IHC 3+ vs IHC 2+ with fluorescence in situ hybridization [FISH] amplification). Results: A total of 17,305 individuals were assessed for inclusion. In total, 696 patients had at least one HER2 assessment at ≥7 weeks from the initial assessment and 333 patients met criteria for inclusion. Of these, 83 patients (25%) were classified as HER2+ at baseline. HER2+ were more frequently male (73%), former or active smokers (70%), and were more likely to receive HER2-directed therapies in the front line (59%). The initial biopsy site was commonly the primary site (88%), as was the site of second biopsy (67%). Overall, HER2 overexpression was lost on subsequent biopsy 36% (95% CI 25.9-47.4%) of the time. Regardless of therapy received, loss of HER2 overexpression occurred in 83% (51.6-97.9%) of patients with baseline IHC2+/FISH amplified compared to 28% (18.1-40.1%) in patients with baseline IHC3+ (OR 12.8, 95% CI 2.6-63.4, p = 0.002). No other clinical or laboratory factors were associated with loss of HER2 overexpression on logistic regression. Conclusions: Loss of HER2 overexpression is a common occurrence in UGI cancers, particularly amongst patients with baseline HER2 IHC2+/FISH amplification. This is possibly due to clonal pressure from targeting HER2, tumoral heterogeneity, or other unknown mechanisms. Greater consideration should be given for repeat biopsies and biomarker assessments in these patients prior to targeting HER2 in the progressive setting.

Tobacco use–driven lung cancer mortality in the United States: A population-based analysis from 2003 to 2023.

e20039 Background: Lung cancer (LC) is the leading cause of cancer death worldwide, with tobacco use as its primary risk factor. Despite advances in detection and treatment, smoking-related disease continues to impose a heavy burden. This study examines LC mortality disparities, trends, and geographic variation among tobacco users in the United States from 2003 to 2023. Methods: Using the CDC WONDER database for adults aged ≥25, we analyzed age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 for LC (ICD-10: C34) among patients with tobacco use (ICD-10: F17) by year, sex, race/ethnicity, and geography. Joinpoint regression estimated average annual percentage change (AAPC) and annual percentage change (APC) with 95% confidence interval (CIs). Results: During the study, an overall burden of 3,148,638 deaths was observed due to LC, among which 1,222,199 cases were attributed to tobacco use as a contributory cause, most occurring at the Decedent's home. The overall AAMR rose from 12.79 in 2003 to 19.25 in 2023 (AAPC: 1.94%; p<0.001), with significant increases in 2003–2005 (APC: 34.15, 95% CI: 22.16 to 47.32) and notable recent declines in 2016–2023 (APC: -4.97, 95% CI: -5.79 to -4.15). Men consistently had higher AAMR than women, nearly double in 2003 (17.33 vs. 9.50), and the disparity persisted in 2023 (23.19 vs. 16.00). Non-Hispanic (NH) Whites had the highest AAMR, rising 2.49% annually (p<0.001), while NH Asians or Pacific islanders had the lowest with a 1.92% annual increase (p=0.05). Regionally, the Midwest experienced the fastest rise in AAMR at 4% annually (p<0.001), while the West had the lowest AAMR. Mortality in rural areas (AAMR 34.14) rose rapidly (4.37%; p<0.001) than in urban populations (23.75; 2.93%). Vermont and Oregon ranked highest in the top 90th percentile. Conclusions: Tobacco use-driven LC mortality has risen overall, with declines in more recent years. However, disparities in outcomes remain prevalent, underscoring the urgent need for health service initiatives, including tobacco cessation education, lung cancer screening, and telehealth platforms, to improve access to care for affected populations. Deaths and AAPC for trends related to LC among tobacco users from 2003 to 2023. Variable Deaths AAPC (2003-2023) with CI Overall 1,222,199 1.95 (0.89 to 3.01) Male 695,442 1.40 (0.38 to 2.43) Female 526,757 2.46 (1.05 to 4.00) NH White 1,064,773 2.46 (1.37 to 3.56) NH Black 10,8178 1.56 (-0.29 to 3.43) NH American Indian or Alaska Native 7,175 0.68 (-2.10 to 3.53) Hispanic 29,258 -1.34 (-2.71 to 0.04) NH Asians 12,815 1.93 (-0.08 to 3.97) Midwest 371,508 4.01 (1.86 to 6.21) West 163,612 -0.52 (-1.70 to 0.67) South 450,020 1.43 (0.48 to 2.40) Northeast 237,059 1.33 (-0.16 to 2.85)

Empowering Reversible Anionic Redox in Sodium Layered Oxide Cathodes via Ionic Impedance Matching Interphase

ABSTRACT Anionic redox reaction (O 2− /O − , ARR) in low‐cost sodium manganese‐based layered oxide cathodes enable high energy density, but often suffer from rapid degradation under high voltages due to interfacial instability. Here, we design an ionic impedance matching interphase to mitigate this challenge by harmonizing mechanical compatibility and ionic transport. The interphase forms as NaTi 2 (PO 4 ) 3 undergoes thermally driven conversion accompanied by ion migration, inducing gradient surface reconstruction on P2‐Na 5/6 Li 1/4 Mn 3/4 O 2 and yielding a composite architecture comprising an outer Na 3 PO 4 and an inner Ti‐rich spinel‐like layer. The spinel‐like layer shows strong lattice compatibility with layered bulk and is anchored to conductive Na 3 PO 4 through robust Ti−O−P linkages, which alleviates internal stress and stabilizes interfacial chemistry, while its intermediate conductivity lowers interfacial resistance. Moreover, this architecture shields electrolyte components from reactive oxygen species, suppresses gas evolution, and introduces lattice‐permeated Ti doping, which reinforces Ti−O covalency to stabilize lattice oxygen and mitigate Jahn−Teller distortion. These synergistic effects yield a stabilized interfacial environment that promotes reversible redox electrochemistry, achieving high discharge capacity (∼ 230 mAh g −1 ) and low voltage decay (<0.05 V) over extended cycling. This work deepens mechanistic insights into interfacial regulation and provides an effective route for stabilizing anionic redox chemistry for high‐energy sodium‐ion batteries.

Nanocomposite of NiFe2O4-loaded biochar as photocatalyst in photo-Fenton degradation of dye

Ultra‐Confinement of Polaritons in Single Atomic Layer Ag Photonic Quantum Dots

ABSTRACT Light scattering by two‐dimensional (2D) van der Waals heterostructures (vdWHs) is immense, especially given their infinitesimal volume, thus enabling strong light‐matter interactions. Surface 2D polariton waves manifest through a large concentration of electromagnetic field in the vertical direction, normal to their propagation. By confining vdWH materials into 2D photonic shapes, one can manipulate and compress light in lateral directions. Scattering‐type scanning near‐field optical microscopy is a perfect tool for direct imaging of the propagating polaritons and studying the properties of confined polaritons in nanostructures. Though, thus far, the quantitative analysis, such as the wavelength extraction, has been challenged for confined polaritons by incapability of mapping of the wave period on a sub‐wavelength scale and the difficulty of identifying an adequate substrate's “background” to subtract. Here, an analytical approach is developed to reveal the local propagation constant of confined polaritons under the above‐mentioned constraints and map it with sub‐wavelength resolution. Applied to the analysis of the SiC/2D‐Ag/EG (epitaxial graphene) photonic nanostructures, the technique uncovered that the polaritons are highly confined in both vertical (∼ λ /50) and lateral directions (∼ λ /40) by 2D metal.

Intrinsic Coordination Architecture Governing Selectivity Divergence Between Extended and Single‐Site Electrocatalysts

ABSTRACT Distinct material architectures, ranging from extended metal surfaces to single‐atom sites, exhibit characteristic and often divergent selectivity patterns in complex electrochemical transformations, such as CO 2 and nitrate reduction. While thermodynamic descriptors effectively rank catalysts within homologous families, they often fail to rationalize why fundamentally different material classes intrinsically favor distinct reaction pathways. Here, we identify local coordination geometry as a key structural factor that shapes this selectivity bifurcation. By establishing a general coordination‐constraint framework, we show that extended surfaces stabilize intermediates through multi‐atom coordination (ensemble effects). This imposes structural constraints on hydrogenation access to carbon or nitrogen centers while oxygen remains bound, thereby biasing reactions toward fully deoxygenated products (e.g., ethylene and ammonia). In contrast, the unilateral coordination of single‐atom and molecular sites leaves the reactive center spatially exposed, enabling hydrogenation pathways to oxygen‐retaining products (e.g., methanol and hydroxylamine) that are rarely accessible on close‐packed surfaces. Importantly, this geometric effect operates in conjunction with electronic structure and interfacial factors. While coordination geometry defines the set of structurally accessible reaction pathways, electronic and electrochemical conditions govern their relative energetics and kinetic competition. This insight provides a transferable principle for the rational design of selective electrocatalysts.

An artificial intelligence model for prediction of hepatocellular carcinoma risk in patients with chronic hepatitis C

Temporal trends and racial disparities in cancer-related mortality among individuals with substance use involvement in the United States, 1999–2023.

e22630 Background: Cancer-related mortality associated with substance use is an increasing public health concern in the United States and disproportionately affects vulnerable populations. However, national temporal trends and demographic disparities remain poorly defined. We evaluated subgroup-specific mortality patterns to inform targeted prevention strategies. Methods: This retrospective observational study utilized CDC WONDER mortality data from 1999–2023. Cancer-related deaths were identified using ICD-10 codes, categorized by substance use involvement based on multiple cause-of-death drug- and alcohol-induced classifications. Annual mortality counts were calculated, and temporal trends were assessed using linear and log-linear regression models to estimate slopes and annual percent change with 95% confidence intervals. Race-stratified analyses were conducted to evaluate disparities in cancer-related mortality associated with substance use involvement. Results: From 1999 to 2023, 2,179,112 cancer-related deaths involving substance use were identified in the United States. Mortality increased significantly over time. Linear regression demonstrated a strong upward trend with a slope of 6,228.8 deaths per year (95% CI: 4,242.6–8,215.1; p = 1.28×10⁻⁶), corresponding to a 1,459% cumulative increase. Log-linear modeling confirmed this rise with an overall APC of 12.8% (p < 0.001). Race-stratified analyses revealed marked disparities. Asian or Pacific Islander individuals experienced the greatest increase in mortality (APC: 15.97%; 95% CI: 11.90–20.18; p < 0.001), followed by White (APC: 12.97%; 95% CI: 8.89–17.19; p < 0.001), American Indian or Alaska Native (APC: 12.59%; 95% CI: 9.19–16.10; p < 0.001), and Black or African American individuals (APC: 12.40%; 95% CI: 8.87–16.04; p < 0.001). In contrast, White-only and Black-only subgroups demonstrated modest but significant declines (APC: −1.69% and −1.66%, respectively). Substance-specific trends differed substantially. Drug-involved cancer mortality increased most rapidly (APC: 12.40%; 95% CI: 8.56–16.38; p < 0.001), followed by alcohol-involved mortality (APC: 5.78%; 95% CI: 4.32–7.27; p < 0.001), while other substances showed smaller but significant increases (APC: 1.78%; 95% CI: 0.54–3.03; p = 0.007). Period-specific analyses demonstrated accelerated growth during 2011–2019, with no significant change from 2020–2023. Conclusions: Cancer-related mortality among individuals with substance use involvement has risen substantially over the past two decades, with pronounced racial disparities. These findings highlight substance use as a critical driver of inequities in cancer outcomes and support the need for enhanced surveillance, targeted prevention efforts, and integration of addiction-informed care within oncology to mitigate gaps.

Features of the content of components of the vascular endothelial growth factor system in the blood of men with recurrent soft tissue sarcomas.

e23550 Background: Soft tissue sarcomas (STS) have been studied to a lesser extent than tumors of epithelial origin. The main problem with STS is its frequent recurrence. The aim of this study was to investigate changes in the blood levels of VEGFA, VEGFC, and sVEGFR3 in men with primary STS and its recurrences, taking into account the degree of tumor differentiation. Methods: The study included 30 men diagnosed with STS of the extremities: 14 men with primary STS (T2bN0M0) and 16 men with relapses after previous combined treatment (surgery and radiation) completed more than a year ago for primary disease or no more than two episodes of STS relapses (T2bN0M0). Histologically, most STS were liposarcomas. The average age of patients was 58.1±5.3 years. Well- and moderately differentiated tumors (G1-2) were present in 7 men with primary STS and in 8 patients with relapses, the rest had poorly differentiated and undifferentiated tumors (G3-4). The control group included 10 age-matched men without cancer. Blood samples collected from patients before treatment were analyzed using ELISA for the levels of VEGFA (eBioscience, Austria), VEGFC (ThermoFisher Scientific, USA), and sVEGFR3 (eBioscience, Austria). The results were statistically processed in accordance with general recommendations for medical research. Results: In all patients with STS, the level of VEGFA in the blood did not depend on G: in the primary process, it increased twofold compared to donors, and in relapses, it decreased threefold and became 6.0 times lower than in the primary process. Serum levels of VEGFC and sVEGFR3 depended on G and the STS episode. In primary STS G1-2, the content of VEGFC in the blood decreased by 1.4 times (p < 0.05), and sVEGFR3 increased by 2.0 times; in STS G3-4, the content of VEGFC in the blood increased twofold, the level of sVEGFR3 did not change. In patients with relapses of STS G1-2, the content of VEGFC in the blood increased by 1.5 times (p<0.05), while with relapses of G3-4 it decreased by 1.5 times (p<0.05) compared with donors, while the level of sVEGFR3 did not change in anyone. Conclusions: The obtained results reflect a complex picture of tissue and systemic restructuring associated with the development of primary and recurrent STS of the extremities, indicate a possible change in the functional status and informative value of the components of the VEGF system during STS recurrence, expand our understanding of the genesis of tumors of mesenchymal origin, and allow us to determine directions for further research.

Neoadjuvant radiotherapy combined with lenvatinib and sintilimab in patients with resectable hepatocellular carcinoma with portal vein tumor thrombus: An open-label, single-arm, multicenter, prospective phase I clinical trial.

4113 Background: Surgical resection remains the potentially curative treatment for resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) in selected patients, but recurrence remains a major challenge. Neoadjuvant therapies have been proposed to reduce tumor burden and the risk of recurrence. This trial aimed to evaluate the safety and efficacy of neoadjuvant RT combined with lenvatinib and sintilimab followed by resection in resectable HCC patients with PVTT. Methods: This open-label, single-arm, multicenter, prospective phase I trial enrolled patients with resectable hepatocellular carcinoma classified as Barcelona Clinic Liver Cancer stage C without extrahepatic metastasis at 2 hospitals in China. Patients received RT (300cGy ×10 fractions) targeting intrahepatic lesions and PVTT, concurrent with two cycles of lenvatinib and sintilimab, followed by surgery 8 weeks post-RT and postoperative adjuvant therapy with lenvatinib and sintilimab for 1 year. Safety, pathological response, and feasibility were assessed. This trial is registered with ClinicalTrials.gov (NCT05225116). Results: From October 2022 to January 2026, 17 patients (VP2:5, VP3:11, VP4:1) were enrolled, 14 patients had completed neoadjuvant therapy, 12 patients had received surgeries (R0 rate: 100%, 10/10), while 1 patient had disease progression, 1 patient postponed surgery due to abnormal liver function. Preoperative imaging (mRECIST criteria) showed stable disease (SD), partial response (PR), and complete response (CR) rates of 16.7%, 75.0%, and 8.3.0% for primary lesions, and 0%, 58.3%, and 41.7% for PVTT. Postoperative pathological complete response (pCR) rates were 25.0% for primary lesions and 75.0% for PVTT. Concordance between imaging and pathology was 66.7% for primary lesions and 50.0% for PVTT. The median recurrence-free survival (mRFS) was 17 months and median overall survival (mOS) was 27 months. No Grade 3 or worse treatment-related adverse events occurred. Conclusions: Neoadjuvant radiotherapy combined with lenvatinib and sintilimab can bring a high tumor response rate in patients with resectable hepatocellular carcinoma with portal vein tumor thrombus with a favorable safety profiles. PVTT demonstrates higher response rate than primary HCC lesions. Discrepancies between imaging and pathological responses highlight the need for improved predictive biomarkers. These interim results support further investigation of this approach in larger cohorts. Clinical trial information: NCT05225116 .

Expression of nectin-4 in germ-cell tumors.

e17009 Background: Nectin-4 is a cell adhesion molecule and therapeutic target in several malignancies, including urothelial carcinoma. However, its expression pattern in germ cell tumors (GCT) remains poorly characterized. Given the limited treatment options for refractory GCTs, and the urgent need for novel therapeutic options, we present a retrospective analysis of Nectin-4 expression on pathology samples from patients with GCT. Methods: Samples from 93 unique patients with GCT from Indiana University Simon Comprehensive Cancer Center from 2010-2022 were identified. Patients with both seminoma and non-seminoma were included. Nectin-4 staining was performed by IQVIA Laboratories using the non-commercially available anti-Nectin-4 antibody (clone M22-312B41.1). Results: Overall, 93 samples were identified, 5 subjects did not have sufficient tissue to complete Nectin 4 testing. Of 88 evaluable samples, 43 (48.8%) demonstrated Nectin-4 expression. Expression varied significantly by histology. Teratoma demonstrated the highest prevalence, with 33 of 38 cases (86.8%) positive, with frequent high levels of expression (17 of 33 exhibiting ≥20% neoplastic cell positivity). Seminoma showed infrequent expression (3 of 29, 10.3%). No expression was observed in pure embryonal carcinoma (0 of 8). Yolk sac tumors demonstrated variable expression (3 of 7, 42.8%). Mixed histology tumors showed expression in 66% (4 of 6). Nectin-4 positivity was observed across multiple anatomic sites, including retroperitoneal lymph nodes (RP LN), lung, mediastinum, kidney, ureter, and other lymph nodes (LN) and metastatic locations. Conclusions: Nectin-4 varies across histology in GCT. Teratoma has the highest expression of Nectin-4 while embryonal carcinoma appears to have the lowest expression. Expression was not site restricted. These findings suggest that Nectin-4 may represent a biologically relevant therapeutic target especially in patients with unresectable teratoma. Nectin-4 expression by histologic subtype and anatomic site in germ cell tumors. Histology Nectin 4 expression (%) Sites All 43/88 (48.8%) Teratoma 33/38 (86.8%) RP LN (22)Lung (5)Mediastinum (3)Neck (1)Pelvic LN (1)Kidney (1) Seminoma 3/29 (10.3%) RP LN (2)Testis (1) Yolk Sac 3/7 (42.8%) RP LN (1)Ureter (1)Mediastinum (1) Embryonal Carcinoma 0/8 (0%) N/A Mixed Histology 4/6 (66.6%) Testis (1)RP LN (1)Mediastinum (2)

Development of a point-of-care clinical decision support system to optimize total cost of care, while preserving quality outcomes: Integration of economic, clinical, pathological, genomic data, and national guidelines.

e23301 Background: Rising cancer care costs challenge patients and policymakers, with approximately 80% of expenditures driven by physician decisions at the point of care. National guidelines (ASCO/NCCN) emphasize clinical efficacy but rarely incorporate economic impact. Prior work demonstrated cost variation exceeding $50,000 among comparable cohorts of breast, colorectal, and lung cancer pts (Pecora; J Prec Med 2020). We developed an artificial intelligence–enabled clinical decision support (CDS) system that integrates clinical, pathological, and genomic data with evidence-based national guidelines and cost estimates. Methods: We conducted a retrospective cost analysis of stage I–III breast cancer using the CDS platform. The tool synthesizes multidimensional patient data and presents NCCN/ASCO-supported treatment pathways with projected, practice-specific costs. The primary endpoint was estimated cost savings, defined as the difference between 1-year total cost of care recommended by the oncologist and by the CDS. Costs reflected medical oncology only (excluding radiation/surgery) and were standardized using Medicare fee schedules, adjusted for temporal bias (2020–2022) and for insurance fee bias. Consecutive stage I–III breast cancer pts treated at a large community practice and an academic cancer center (2020–2022) were identified, with clinical data extracted from the EMR. Only complete cases with 1-year follow-up were analyzed. IRB approval was obtained with waiver of informed consent. Results: Patients were stratified into risk-adjusted cohorts by stage and prognostic/predictive factors, including genomic data. Of 2,434 records reviewed, 1,188 pts had complete data (579 hospital-based). The CDS identified mean potential cost savings of 21.8% ($7,160 per pt). In a pilot intervention displaying guideline-concordant options alongside comparative costs, physician pathway selection shifted, yielding a 15–20% reduction in calculated 1-year total costs. Conclusions: Integrating economic insights into point-of-care oncology decision-making facilitates value-based care without compromising guideline adherence or quality. This approach enables cost-sharing models between payers and providers while maintaining evidence-based treatment. The CDS is currently piloted in a large multicenter oncology practice, with broader implementation underway in partnership with a major healthcare payer. Breast cancer: 1 year estimated total cost of care. Patients Initial Treatment Cost Savings Opportunity % Reduction Stage I 707 $13,795,728.02 $3,636,927.32 26.36% Stage II 391 $18,977,328.88 $3,371,674.01 17.77% Stage III 90 $7,066,640.88 $1,497,921.41 21.20% Total 1188 $39,851,243.58 $8,506,522.74 21.35%

De-escalate surgery of primary lesions after neoadjuvant immune-combination therapy in locally advanced oral squamous cell carcinoma: The 5-year survival results of two single-arm trials.

e18121 Background: Neoadjuvant immune-combination therapy (NAIT) followed by surgery and adjuvant therapy has been widely studied for resectable locally advanced oral squamous cell carcinoma (LAOSCC). Given the excellent short-term tumor shrinkage effect of NAIT, de-escalate surgery has attracted increasing attention. However, there are few long-term prognostic results corresponding to de-escalate surgery after NAIT in LAOSCC. Methods: We conducted a retrospective analysis of two single-arm NAIT trials, including neoadjuvant immunotarget therapy (NAITT) trial (NCT04393506) and neoadjuvant immunochemotherapy (NAICT) trial (NCT04473716) in LAOSCC patients. 5-year survival analysis was performed including overall survival (OS) and disease-free survival (DFS). Primary tumors were assessed for the percentage of residual viable tumor that was identified on HE staining, and tumor with no more than 10% viable tumor cell was considered as major pathological response (MPR). To determine whether NAIT can improve the long-term prognosis of LAOSCC patients, we compared the 5-year OS and DFS with the neoadjuvant chemotherapy (NACT) of TPF group and the conventional standard treatment (CST) group (surgery followed by adjuvant therapy) (from the previous trial of NCT01542931), using propensity score matching (PSM) based on gender, age, clinical T stage to reduce confounding bias. Additionally, we analyzed the proportion of de-escalate surgery of primary lesions with exemption of free flap reconstruction in the NAIT group, and their long-term prognostic outcomes. Results: From April 2020 to April 2021, 40 LAOSCC patients in two trials received NAIT and radical surgery. The MPR rate of NAIT was 50%. In the patients archived MPR, the 5-year OS and DFS rate was 100% and 95%, in the non-MPR patients, the 5-year OS and DFS rate was 80% and 70%. The patients in the NACT group and CST group were collected from the NCT01542931 trial, following a 1:1:1 PSM adjustment, each group consisted of 40 patients. The patients in the NAIT group had improved 5-year OS compared with the NACT and CST groups (85% vs. 67.5% vs. 57.5%, p=0.024) as well as 5-year DFS (75% vs. 65% vs. 55%, p=0.170). In the NAIT group, four patients achieved de-escalate surgery, obviating free flap reconstruction, none of them experienced surgical complications, and other four patients refused adjuvant radiotherapy because of good pathological response to NAIT; during the follow-up period, no local recurrence or distant metastasis occurred in these patients. Conclusions: NAIT followed by radical surgery could improve the long-term prognosis of LAOSCC patients. The reduction of tumor burden induced by NAIT might translate into de-escalate surgery with reducing free flap reconstruction or exemption of adjuvant radiotherapy without compromising their prognosis. Clinical trial information: NCT04393506 , NCT04473716 .

MAIN-CAV: Phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy (PBC) in patients (pts) with locally advanced/metastatic urothelial cancer (la/mUC; Alliance A032001).

4514 Background: Maintenance avelumab is a standard of care in patients (pts) with la/mUC who do not progress after first-line PBC. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM, active in multiple solid tumors. We hypothesized that an avelumab (Av)-CABO combination would improve outcomes in pts with mUC with an acceptable safety profile compared to avelumab maintenance alone. Methods: MAIN-CAV (NCT05092958) is a phase III randomized, multicenter, international trial for la/mUC pts who did not progress after 4-6 cycles of any PBC (gemcitabine-cisplatin, gemcitabine-carboplatin, MVAC, ddMVAC). Pts were randomized 1:1 to Av 800 mg IV every 2 weeks alone or with CABO 40 mg daily for ≤2 years. Stratification factors were response to first-line PBC (complete response [CR] vs partial response [PR] vs stable disease [SD]) and visceral metastases. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), safety and quality of life. The target accrual was 654 pts; the trial closed early after enrollment of 68 pts following adoption of enfortumab vedotin plus pembrolizumab as the new preferred first-line standard in the US. Results: From 3/2022 to 3/2024, 68 pts were randomized (Av n = 33; CABO-Av n = 35). Median OS was 24.8 months (mo) with Av and 23.0 mo with Avb-CABO (Hazard ratio 1.41; 95% CI 0.66–3.01; p = 0.186). Median PFS was 4.6 mo with Av vs 6.0 mo with Av-CABO (p = 0.343). Objective response rate among pts with PR or SD after first-line PBC was 20.8% with Av vs 11.5% with Av-CABO (p = 0.424). Grade ≥3 treatment-related adverse events occurred in 24.2% pts on the Av arm vs 39.4% of pts on the Av-CABO arm and CABO dose reductions occurred in 63% of pts. Conclusions: Addition of CABO to Av did not improve OS or PFS compared with Av alone in this underpowered, prematurely closed phase III trial; safety was consistent with known profiles. U10CA180821,U10CA180882; U24CA196171, U10CA180863. (CCTG);U10CA180888 (SWOG); https://acknowledgments.alliancefound.org. Clinical trial information: NCT05092958 .

Efficacy and safety of disitamab vedotin in patients with HER2-expressing locally advanced or metastatic urothelial carcinoma: A systematic review and meta-analysis.

e16577 Background: Urothelial carcinoma (UC) is the 4th among most commonly diagnosed malignancy, notorious for poor outcomes in advanced stages, particularly in platinum-ineligible or immunotherapy-refractory patients. Disitamab vedotin (RC48-ADC), a HER2-targeted antibody-drug conjugate delivering monomethyl auristatin E, has shown activity in HER2-expressing UC. This meta-analysis synthesizes evidence on its efficacy and safety. Methods: A systematic search of PubMed, the Cochrane Library, and ClinicalTrials.gov was conducted through November 2025. Eligible studies included studies that assessed Disitamab vedotin (2.0 mg/kg IV every 2 weeks) as monotherapy or with PD-1 inhibitors in adults with HER2-expressing (IHC ≥1+) UC, locally advanced or metastatic in nature. Data were pooled using random-effects models for objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Heterogeneity was assessed using I², and risk of bias was assessed using the ROBINS-I tool. GRADE evaluated evidence certainty. Results: Seventeen studies with 880 patients (5 prospective trials, 12 observational cohorts) were included, with a median age of 65 years, 68% male population, and a median follow-up of 14.5 months. Pooled ORR was 54% (95% CI: 49%-59%; I² = 45.1%; n = 559). Pooled DCR was 84% (95% CI: 80%-88%; I² = 24.8%; n = 550), with partial response (44%; 95% CI: 39%-50%) and stable disease (29%; 95% CI: 24%-36%). Pooled median PFS was 7.47 months (95% CI: 6.06-8.87; 8 studies, n = 335; I² = 69.7%). OS data were limited to a pooled mean of 31.77 months. TRAEs included common events such as peripheral neuropathy (43%), fatigue (38%), decreased appetite (39%), and leukopenia (32%). The overall risk of bias for the majority of studies was judged as serious. Evidence certainty was moderate for ORR/DCR and low for PFS/safety. Conclusions: Disitamab vedotin demonstrates a favorable benefit: risk profile for antitumor activity in HER2-expressing advanced UC. Limitations include the non-randomized design and the predominantly Asian population, which limit generalizability. Nevertheless, these findings support the drug's promising role and highlight the need for larger-scale randomized trials.

Sociodemographic variation in intracoronary imaging utilization among patients with active malignancy undergoing percutaneous coronary intervention: A National Inpatient Sample analysis.

e13697 Background: Intracoronary imaging–guided percutaneous coronary intervention (PCI) is associated with improved procedural and clinical outcomes compared with angiography-guided PCI. Patients with active malignancy represent a high-risk population; however, data on racial/ethnic, sex, and socioeconomic disparities in intracoronary imaging utilization in this group are limited. Methods: We analyzed the National Inpatient Sample (2016–2021) to evaluate sociodemographic differences in intracoronary imaging utilization among patients with active malignancy undergoing PCI. Active malignancy was defined using ICD-10-CM codes. Intracoronary imaging included intravascular ultrasound (IVUS) and/or optical coherence tomography (OCT). Survey-weighted multivariable logistic regression was used to estimate adjusted odds ratios (aORs) for imaging utilization, adjusting for demographics, clinical presentation, comorbidities, and hospital characteristics. Feature importance was assessed using SHapley Additive exPlanations (SHAP) with gradient boosting models. Results: Among 54,300 weighted hospitalizations for PCI in patients with active malignancy, 6,260 (11.5%) involved intracoronary imaging. Imaging utilization was lower among Black versus White patients (9.1% vs 11.6%), women versus men (9.9% vs 12.2%), and patients in the lowest versus highest income quartile (10.6% vs 14.0%). In adjusted analyses, Black race (aOR 0.81; 95% CI, 0.73–0.90; P < 0.001), Native American race (aOR 0.23; 95% CI, 0.09–0.56; P = 0.001), female sex (aOR 0.83; 95% CI, 0.78–0.88; P < 0.001), and lower income (Q2 vs Q4: aOR 0.77; 95% CI, 0.71–0.84; P < 0.001) were independently associated with lower odds of intracoronary imaging use. SHAP analysis identified geographic region (South: mean |SHAP| = 0.110), STEMI presentation (0.041), and heart failure (0.038) as major predictors of imaging utilization, while female sex (0.032) and lower income (0.026) contributed to reduced imaging probability. Conclusions: Among patients with active malignancy undergoing PCI, substantial sociodemographic disparities exist in intracoronary imaging utilization. Black and Native American patients, women, and individuals with lower income are significantly less likely to receive imaging-guided PCI, despite a threefold increase in overall imaging use during the study period. Targeted strategies are needed to promote equitable access to advanced coronary imaging technologies in this vulnerable population.

Bridging the gap: Nationwide genetic counsellor’s survey insights to plan a scalable framework for cancer genetic counselling in India.

e13550 Background: Genetic counselling (GC) is central to precision oncology, guiding appropriate genetic testing for treatment, prevention, and risk stratification. India’s rising cancer burden and expanding genomic testing far outpace the capacity of its 316 board-certified genetic counsellors (BGCI, India). GC practice is largely limited to germline risk assessment for hereditary cancer syndromes with minimal integration into somatic oncology care and multidisciplinary tumor boards. To date, oncology readiness and scalability of India’s GC workforce have not been systematically evaluated. Methods: A cross-sectional, anonymous nationwide online survey was conducted via Google Forms (Sept–Oct 2025). The questionnaire assessed practice setting, training, experience, oncology-specific workload, tumor board access, perceived value of cancer GC, practice barriers and openness to tele-genetics or AI-enabled tools. Data were analyzed using descriptive statistics. Results: 147/316 (46.5%) genetic counsellors responded, based in diagnostic laboratories 50/147 (34%), hospitals/clinics non-oncology 33/147 (22.4%) and only oncology 33/147 (22.4%). Genetic Counsellors held a relevant MSc degree 41/147 (27.9%), PhD 41/147 (27.9%) and Diploma 40/147 (27.2%) along with BGCI certification. 56/147 (38.1%) have more than 5 years’ experience. 26/147 (17.7%) reported more than half of their caseload was oncology-related, GC was predominantly germline-focused with breast/ovarian 119/147 (81%) and colorectal/GI cancers 74/147 (50.3%) as the most common indications. Maximum referrals were direct from Oncologist 84/147 (57.1%). Tumor board access was reported by 75/147 (50.3%), yet only 40/147 (27.2%) participated regularly. Key barriers included low awareness 117/147 (79.6%), cost constraints 108/147 (73.5%), limited access to oncology GC training 78/147 (53.1%) and lack of recognition 37/147 (25.2%). 92/147 (62.6%) expressed willingness to adopt tele-genetics and AI-based tools. Priority needs identified as oncology-focused GC training 49/147 (33.3%), recruitment of additional counsellors in oncology centres 41/147 (27.9%) and government recognition 39/147 (26.5%). Conclusions: India’s first nationwide assessment of genetic counsellors identifies a major mismatch between cancer burden and GC capacity, germline-centric practice and limited oncology integration. Readiness to adopt digital and hybrid models supports a scalable framework using digital pre-test education, tele-genetics, AI-assisted risk assessment tools for Indian population and tiered clinician training to optimize workforce, integrate genomics into routine care and expand equitable access to precision oncology. The findings inform workforce planning, implementation science and policy action in India and further other low- and middle-income countries.

Defining outcomes and risk of second primary malignancy (SPM) in patients with multiple myeloma (MM) in a large, integrated health system.

e19560 Background: Despite significant improvements in overall survival over the past 3 decades, MM is still an incurable disease. Most patients will go through multiple lines of therapy and continue treatment for years. With longer time on treatment, there is concern for the development of second primary malignancy (SPM) which is associated with poor outcomes. The present study seeks to characterize the risk of developing SPM for patients with multiple myeloma in a real-world setting. Methods: This retrospective cross-sectional study included adults 18 years and older with multiple myeloma at 21 cancer centers within Kaiser Permanente Northern California between 2011-2023. Demographics, clinical variables, and treatment characteristics were collected for all patients. SPM was defined as any cancer (excluding non-melanoma skin cancer) diagnosed after initial diagnosis of multiple myeloma. Patients were followed for at least 1 year, and SPM was further characterized by type of cancer and time to diagnosis. A Cox proportional hazards model was used to identify demographic and clinical factors associated with the development of SPM. Results: 2,327 patients were diagnosed with multiple myeloma at a median age of 69 years. 42.7% were female.14.5% were Black, 12.0% were Asian/Pacific Islander, 13.5% were Latinx, and 54.8% were White. The majority (57.2%) were never smokers and 15.4% had a cancer diagnosis prior to multiple myeloma diagnosis. 28.2% underwent autologous stem cell transplant (ASCT) and 75.4% received lenalidomide. In total, 8.6% were diagnosed with a SPM. Of those, 24 developed a hematologic malignancy and 181 developed a solid cancer. The median time to diagnosis of SPM from diagnosis of multiple myeloma was 2.4 years. Median overall survival after SPM diagnosis was 1.3 years and only 8 months for those who developed a hematologic malignancy. None of the demographic factors assessed were associated with increased risk of SPMs including age, sex, race, prior cancer history, and smoking history. Notably, lenalidomide use was not associated with increased risk of SPM (HR 0.61; CI 0.24 - 1.58). History of ASCT showed a numerically increased risk of developing a hematologic malignancy, but this was not statistically significant (HR 1.61; CI 0.57 - 4.56). Conclusions: This large, real-world study demonstrates that the development of SPM is a common occurrence for patients with multiple myeloma with poor outcomes. Future studies are needed to better understand how this risk can be mitigated.

Transcriptional correlates of <i>ARNT</i> expression and its impact on survival outcomes in clear-cell renal cell carcinoma (ccRCC).

e16554 Background: Encoded by ARNT , hypoxia-inducible factor-1β (HIF1β) is an obligate heterodimer for HIF1α and HIF2α, enabling their transcriptional activation of HIF-target pathways, such as angiogenesis. Here, we examine the relation of ARNT expression with hypoxia and immune programs, and its impact on survival outcomes in ccRCC. Methods: We included patients (pts) with RNA-seq data from TCGA-KIRC (stages I-IV; n = 529), and 2 first-line clinical trials in metastatic ccRCC involving VEGF-pathway inhibitor alone vs combined with immunotherapy: Javelin Renal-101 (JR: n = 741) and CheckMate-9ER (CM: n = 403). Transcripts per million (TPM) were log2-transformed and scaled per 1 SD change. Buffa Hypoxia Score (BHS) was computed per prior reports (Bhandari et al., 2020): expression for each of BHS’ 50 genes per patient was assigned +1, if ≥ median for this gene, or -1 if &lt; median, then summed. The immune signatures, IMmotion150 Angio, T eff and Myeloid, JAVELIN and Tumor Inflammatory Score (TIS) were calculated as means of their genes’ log2-transformed TPMs. Spearman correlation associated ARNT expression with each signature, and HIF1A and HIF2A expressions. Multivariable (MV) Cox models assessed the association of ARNT expression with progression-free (PFS) and overall (OS) survival per each full cohort, adjusted for age, sex, stage and sarcomatoid features in KIRC, and for age, sex, IMDC risk, treatment arm and sarcomatoid features in the trials. Likelihood ratio test (LRT) assessed interaction between ARNT and treatment arm in predicting survival. Results: Across three cohorts, higher ARNT expression correlated with higher BHS (ρ = 0.23-0.49), Angio signature (ρ = 0.14-0.57) and TIS (ρ = 0.14-0.21) (p &lt; 0.05). Higher ARNT correlated with higher T eff and JAVELIN signatures in KIRC (T eff : ρ = 0.19, p = 8.3×10⁻⁶; JAVELIN: ρ = 0.16, p = 1.8×10⁻⁴) and JR (T eff : ρ = 0.16, p = 1.2×10⁻ 5 ; JAVELIN: ρ = 0.17, p = 1.8×10⁻⁶) but not CM9 (ρ = 0.09 for both, p &gt; 0.05). A positive correlation was identified between Myeloid signature and higher ARNT expression in JR (ρ = 0.17, p = 2.3×10⁻⁶) and CM9 (ρ = 0.12, p = 0.02), but not KIRC (ρ = 0.05, p = 0.24). A consistent correlation was observed between ARNT and HIF1A (ρ = 0.30-0.51) and HIF2A expressions (ρ = 0.19-0.61), across all cohorts (p &lt; 0.05). MV Cox models revealed no significant association between ARNT expression and PFS and OS (Table), independent of treatment arm per trial (LRT p &gt; 0.05). Conclusions: ARNT expression tracks with hypoxia, angiogenic and immune transcriptional states in ccRCC but is not independently prognostic, suggesting biologic relevance without clear predictive value in current VEGF- and immunotherapy-based regimens. MV Cox for PFS and OS. Cohort PFS HR adj , 95% CI PFS p-value OS HR adj , 95% CI OS p-value KIRC 0.94, 0.79-1.10 0.42 0.9, 0.78-1.05 0.18 JR 1.03, 0.94-1.14 0.48 1.02, 0.88-1.18 0.78 CM9 1.01, 0.90-1.14 0.86 0.98, 0.84-1.13 0.75

Training fellows in genomic oncology: A pilot team-based workshop.

9024 Background: Genomic oncology (GO) is central to diagnosis and management of patients with cancer. However, GO training is an unmet need for hematology/oncology (H/O) fellows. The Training Fellows in Genomic (TFIG) Working Group developed a team-based GO workshop, with goals of creating a “train-the-trainer” experience for faculty and improving fellows’ GO knowledge. Methods: Ten North American H/O fellowship programs participated in the TFIG pilot. Cross-disciplinary faculty (H/O fellowship program leaders [PL] with local GO faculty experts) participated in (2) 60-minute virtual “train-the-trainer” sessions on team-based learning (TBL) and GO content. Faculty then led (2) 120-minute case-based TBL workshops for fellows at their home institutions: 1) methodology and selection of cancer gene panels, and 2) result interpretation and clinical utility. Participating faculty and fellows were sent a post-workshop survey. Fellows received an additional follow-up survey seven months after workshop participation. Results: 96 fellows and 24 faculty participated in the TFIG workshop. 68 fellows (71%) and 21 faculty (88%) completed the post-workshop survey; 60 fellows (62%) completed the follow-up survey. In addition to H/O PL, workshop faculty included pathologists (n=2), genetic counselors (n=2), laboratory geneticists (n=2), medical geneticists (n=1), and genomics professors (n=1). Most (90%) felt train-the-trainer sessions were helpful for workshop preparation. All agreed/strongly agreed that the workshop will help fellows as practicing oncologists. All would recommend the workshop to other fellowship programs. While most fellows (88%) reported using GO in their clinics, 97% had no prior training during fellowship. The majority reported that their pre-workshop knowledge of GO was poor (31%) or fair (43%). Almost all (91%) agreed/strongly agreed that the workshop will help their clinical practice, and most (88%) would recommend this workshop to other fellows. At seven months post-workshop, more than half (52%) of fellows reported greater interactions with genetics professionals and increased use of web-based GO resources introduced during the workshop; 32% reported using knowledge gained during the workshop to educate others. Conclusions: Formalized training in GO is required for H/O practice and remains an unmet need for H/O fellows. Our TFIG pilot demonstrated that an interactive GO workshop is feasible through implementation of standardized faculty training and a case-based TBL format. Faculty found the “train-the-trainer” model helpful and noted TFIG content is effective and recommended for fellows. Fellows reported sustained improvements in GO knowledge, increased use of web-based GO tools explored during the workshop, and greater interdisciplinary engagement with GO experts. These findings support the TFIG model as a scalable and effective means to deliver expert-led, team-based GO training for H/O fellows.