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4562 Background: Approximately 50-80% of patients (pts) with la/mUC have tumors with HER2 protein expression. As HER2-directed therapies enter development, a robust understanding of HER2 prevalence and real-world outcomes with standard-of-care (SOC) therapies across HER2 expression subgroups is needed. SGNDV-003 (NCT05902494) is a global retrospective chart review study in which HER2 status was assessed via central lab testing and outcomes were analyzed by HER2 status in pts with la/mUC. Methods: SGNDV-003, conducted 6/2023-7/2025, included pts with la/mUC who received ≥1 prior treatment (tx) (incl. 1 line of platinum-based chemotherapy [chemo]). HER2 status was centrally tested using a UC-specific investigational immunohistochemistry [IHC] and in situ hybridization (ISH) assays. HER2 status was defined as: HER2-positive (IHC3+ or IHC2+/ISH+), HER2-low (IHC2+/ISH- or IHC1+), HER2-expressing (IHC3+, 2+, 1+), and HER2-zero (IHC0). Index line of therapy (LOT) was defined as the first LOT received after platinum-based chemo. Outcomes included real-world objective response rate (rwORR) (per RECIST 1.1 or physician-assessed response) to index LOT, real-world progression-free survival (rwPFS), and overall survival (OS) from start of index LOT. Data was analyzed via descriptive statistics. Results: A total of 353 pts with la/mUC and available HER2 status were analyzed (male, 76%; median age, 70 years). 70% of pts were HER2 expressing (19% HER2-positive, 51% HER2-low); 30% were HER2-zero. Disease characteristics were well balanced by HER2 status. Index LOT tx and real-world outcomes are shown in the Table. Immuno-oncology therapies (IO) and enfortumab vedotin (EV) were the most common index LOTs. For IO, rwORRs were 21% for HER2-expressing and 17% for HER2-zero. For EV mono, rwORRs were 36% (HER2-expressing) and 38% (HER2-zero), respectively. Conclusions: This global study provides a robust estimate of HER2 distribution in la/mUC based on standardized central lab testing, showing high prevalence of HER2 expression. Real-world outcomes with current SOC therapies were broadly consistent across HER2 subgroups, establishing an important benchmark for the clinical development of HER2-directed therapies in this setting. HER2-positive (n=67) HER2-low (n=181) HER2-expressing (n=248) HER2-zero (n=105) Total (n=353) Real-world Outcomes rwORR, n (%)[95% CI] 17 (25.4)[15.5, 37.5] 50 (27.6)[21.3, 34.7] 67 (27.0)[21.6, 33.0] 22 (21.0)[13.6, 30.0] 89 (25.2)[20.8, 30.1] Median rwPFS (95% CI), mo 2.8(2.0, 4.1) 3.7(2.7, 5.1) 3.0(2.7, 4.5) 2.6(2.1, 3.4) 2.9 (2.6, 3.5) Median OS(95% CI), mo 12.2(9.3, 16.5) 11.5(9.5, 13.5) 11.9(10.3, 13.4) 7.7(5.9, 9.9) 10.8(9.1, 12.3) Index LOT, n% IO EV monoChemoOther tx 37 (55)17 (25)10 (15)3 (5) 94 (52)51 (28)24 (13)14 (8) 131 (53)68 (27)34 (14)17 (7) 65 (62)21 (20)12 (11)7 (7) 196 (56)89 (25)46 (13)24 (7)

4515 Background: Adenocarcinomas of the urinary tract are rare malignancies with limited prospective data. Outcomes of triplet chemotherapy remain poorly defined. Methods: This was a prospective, single-arm, phase II study (NCT00082706) conducted at MD Anderson. Between 2005 and 2010, patients (pts) aged ≥18 years with ECOG 0–2 and metastatic or unresectable urachal (UA) or non-urachal adenocarcinoma (NUA) received frontline GemFLP (5-fluorouracil 200 mg/m² continuous infusion ×5 days with leucovorin 23 mg IV daily ×5; cisplatin 20 mg/m² IV daily ×5; gemcitabine 200 mg/m² IV on days 1 and 5). Best overall response (BOR) was assessed by imaging. Primary endpoints were objective response rate (ORR) and overall survival (OS); secondary endpoint was toxicity. PFS was calculated from treatment initiation and duration of response (DoR) from first CR/PR to progression or death; time-to-event endpoints were estimated by Kaplan–Meier (KM). Post hoc analyses evaluated baseline tumor markers (CEA, CA19-9, CA125, β-hCG) Treatment-related adverse events (TRAEs) were graded per CTCAE v5. Results: Forty-six pts were enrolled (28 UA, 18 NUA). Median age was 58 years; 41% were de novo metastatic, and 78% had visceral metastases. ORR was 44% (20/46). Among responders, median DoR was 8.6 months (95% CI 4.6–30.8). median PFS was 3.3 months (95% CI 2.3–8.4) and median OS (mOS) was 21.0 months (95% CI 15.9–35.3) There was no difference in PFS (p=0.39) or OS (p=0.99) between UA and NUA. Baseline CEA, CA19-9, CA125, and β-hCG were not associated with ORR or PFS. Higher baseline CA125 was associated with inferior OS (HR 1.33, 95% CI: 1.12–1.58; p =0.001) Subsequent systemic therapy was administered to 28 pts (60.9%); median number of subsequent treatment lines was 2 (range 1–5). The most common hematologic TRAEs were anemia (28.1%; grade ≥3 [G3] 12.5%), thrombocytopenia (21.9%; G3 12.5%), and neutropenia (12.5%; G3 9.4%). The most frequent non-hematologic TRAEs were dehydration (21.9%; G3: 6.2%), diarrhea (9.4%; G3 6.2%) and catheter-related thrombosis (9.4%; G3 9.4%). No grade 5 events occurred. Conclusions: In this prospective phase II study, frontline GemFLP achieved a 44% ORR with durable responses (mDoR 8.6 mo) and 21 mo mOS in advanced UA and NUA. Survival did not differ between UA and NUA subtypes. Baseline CA125 was associated with OS. Toxicity was manageable. These data provide a prospective benchmark for this rare disease. Clinical trial information: NCT00082706 . Variable UA (n=28) NUA (n=18) Characteristics Age, median [ICR] 58 [54– 62] 58 [54– 62] 67 [ 62-72] Race, n (%) White 22 (79) 11 61) Black 6 (21) 6 (33) Other 0 1 (6) Prior surgery for localized disease, n (%) 18 (64) 5 (28) Mets at baseline Any 24 (86) 7 (39) Lung 6 (21) 4 (22) Liver 3 (11) 0 Peritoneum 17 (61) 0 Bone 3 (11) 3 (17) Nodal-only mets 1 (3) 2 (10) Outcomes ORR (%) 43.5 35.7 55.6 BOR n (%) CR 4 (14) 2 (11) PR 6 (21) 8 (44) SD 11 (39) 4 (22) PD 6 (21) 3 (17) NE 1 (4) 1 (6)

1617 Background: Large language models (LLMs) are increasingly evaluated for oncology decision support, yet guideline concordance and hallucinations remain variable across cancer types and tasks. Retrieval-augmented generation (RAG) may improve safety by constraining the evidence base used during generation. Prior oncology LLM studies report discordance with guideline-based care, but few describe a reproducible health-system “vetting mechanism” that couples guideline-only retrieval with clinician-scored safety rubrics across multiple oncology domains. Methods: We assembled 316 de-identified oncology cases in a tumor-board template: medical oncology (breast, GI, GU, leukemia; n=216), gynecologic oncology (n=50), and neuro-oncology/CNS metastatic cancer (n=50). Each case was run on three systems: baseline GPT-4 (O1), NCCN-guideline anchored RAG (O2; guideline-constrained retrieval), and a literature-anchored system (OpenEvidence; O3). Oncologists independently scored outputs using a modified Generative Performance Score (mGPS; −1 to +1) combining guideline concordance with hallucination penalties; readability/rationality was scored on a 1–5 Likert scale. Inter-rater reliability was assessed (κ =.63). This workflow was designed as a pre-deployment model credentialing step for health-system governance (source policy → case bank → clinician-scored acceptance criteria). Results: Across all 316 cases (case-averaged), O2 achieved the highest mean total mGPS (0.75) compared with O1 (0.43) and O3 (0.59). In the medical oncology cohort (n=216), O2 outperformed O1 and O3 (mean mGPS 0.72 vs 0.35 and 0.54), with higher guideline concordance (0.85 vs 0.68 and 0.75) and lower hallucination penalties (−0.09 vs −0.25 and −0.19); readability was also highest for O2 (4.17 vs 3.22 and 3.86). In gynecologic oncology (n=50), O2 again performed best (mGPS 0.827) relative to O3 (0.697) and O1 (0.647). In the CNS cohort (n=50), mean composite mGPS favored O2 (0.82) over O3 (0.68) and O1 (0.55), while readability remained stable across models (3.55–3.73). Severe hallucination/unsafe recommendation rate: O1 [26%], O2 [5%], O3 [17%] (pre-specified definition; e.g., major fabricated citation or guideline-discordant harmful recommendation). Conclusions: In a 316-case, multi-domain clinician-scored evaluation, limiting retrieval to oncology guideline sources improved safety-aligned performance relative to unconstrained generation or literature-only anchoring. A guideline-constrained RAG configuration paired with clinician-scored rubrics and tail-risk reporting can serve as a practical health-system vetting mechanism for governance, re-validation, and change control of LLM decision support, including in resource-limited settings where reliable guideline-consistent recommendations are essential.

11177 Background: Early detection of recurrence after curative-intent treatment is a critical priority, traditional imaging often detects relapse when disease burden is high, potentially limiting treatment efficacy. ctDNA has emerged as an established prognostic biomarker for molecular residual disease (MRD) detection and early relapse. We performed a real-world meta-analysis on published datasets that utilized personalized, tumor-informed ctDNA testing to assess its performance across tumor types and clinical management approaches. Methods: Real-world studies published from December 2022 to December 2025 using the personalized, tumor-informed Signatera ctDNA assay (Natera, Inc.) were included. Eligibility required ctDNA assessment in the MRD (2–16 weeks post-surgery (histology dependent)/pre adjuvant therapy (ACT)) and/or surveillance (post-ACT/end of the MRD window if no ACT was given) settings, with outcomes stratified by ctDNA status and hazard ratios (HR) reported from univariable or time-dependent Cox regression analysis. Exclusions included: clinical trials, biobanks, metastatic disease treated with palliative intent, case reports, reviews, editorials, or commentaries. Clinical outcomes were harmonized into a composite event-free survival (EFS) endpoint (time to recurrence, progression, or death). Pooled HRs and 95% CIs were estimated using random and fixed effects models and heterogeneity between studies was assessed using the I 2 and Cochran’s Q test. Median lead time from ctDNA-positivity to radiographic or clinical recurrence was summarized when available. Results: We identified 18 eligible publications comprising 3,004 unique patients across 15 solid tumor types. During the MRD window, ctDNA positivity was associated with a significantly increased risk of an EFS event compared with ctDNA negativity (pooled HR: 8.15; 95% CI: 6.12–10.85, I 2 = 0.00%, P = 0.844, n = 13). During the surveillance window, inclusive of post-definitive treatment, ctDNA positivity conferred an even greater EFS risk (pooled HR: 18.30; 95% CI: 14.17–23.65, I 2 = 0%, P = 0.911 for heterogeneity, n = 16). Across studies, ctDNA detection during surveillance preceded radiographic or clinical recurrence by a median of 3.20 months (95% CI: 2.50-4.10, P < 0.0001, n = 10), although this varied substantially by study/tumor type (I 2 = 80.9%). Conclusions: In this pan-cancer real-world meta-analysis, ctDNA positivity assessed using a tumor-informed assay was highly prognostic following curative-intent therapy at all timepoints evaluated with low heterogeneity between studies. These findings support the broad clinical utility of tumor-informed ctDNA testing for post-treatment risk stratification and longitudinal disease monitoring across solid tumors.

10610 Background: The role for genetic testing (GT) for prostate cancer (PCa) patients (pts) has expanded to find pts with germline pathogenic variants (PV) for therapeutic opportunities given FDA-approvals for PARP inhibitors in metastatic PCa as well as understanding familial cancer risk and opportunities for tailored screening and risk reduction. The PROMISE Registry (NCT04995198) was set up as a genetic registry to partner with PCa pts for rapid access to a new standard of care given insurance coverage and clinical implementation were initially major barriers. A second goal is to characterize disease features and treatment outcomes to inform management and provide updates about novel therapeutic clinical trials, both of which remain important to rare genetic variant carriers. Methods: PROMISE is a US decentralized prospective PCa genetic registry initiated in 2021 with initial phase to enroll and provide clinical-grade germline genetic testing (30 gene cancer-specific panel) to 5,000 PCa pts to identify ~500 PCa pts with variants of interest (pathogenic variants, PV, and variants of uncertain significance, VUS) in DNA repair genes for long-term clinical follow-up of 15 years (LTFU). Here, we report the initial phase testing results and identification of the LTFU cohort. Study design and enrollment strategy have been reported separately. Results: Between 2021-2026, 7,275 pts with any stage PCa across 50 US states self-consented to PROMISE, of which 5,674 (78%) of pts completed genetic testing, indicating feasibility of patient-directed, decentralized enrollment. We have identified 495 (8.7%) pts for LTFU. Baseline data is reported for n=367 (Table 1, will be updated at time of presentation). The most frequently observed PV/LPV variants being in CHEK2 (25%) , BRCA2 (23%) , ATM (12%) , and BRCA1 (4.6%). At the time of PCa diagnosis, the majority of LTFU pts had non-metastatic disease, with 47% of pts with Gleason>7, median PSA of 5 ng/mL, and median time from diagnosis to PROMISE GT of 25 months. Conclusions: PROMISE is a nationwide decentralized PCa genetic registry that has completed initial goal to recruit 5,000 PCa pts to offer germline genetic testing and recruit a cohort of 500 for LTFU. Data about diagnosis characteristics are reported, and analysis of ongoing disease course, treatment response/outcomes and overall survival is being collected. Clinical trial information: NCT04995198 . Long-term follow-up participant demographics. Characteristic Overall, N = 367 Age at Diagnosis (yrs) 63 (57, 69) Race N = 361 (6, nr) Asian, American Indian or Alaska Native, Multiracial, Other 22 (6.0%) Black or African American 22 (6.0%) White 317 (86%) Disease State at Diagnosis N = 348 (19, nr) Metastatic 46 (13%) Non-metastatic 302 (87%) Time from Diagnosis to PROMISE GT (months) 25 (4, 82) Gleason Score N = 280 (87, nr) </= 7 148 (53%) >7 132 (47%) PSA At Diagnosis (ng/mL) 5 (0, 10) (88, nr) Subjects with baseline data entered. nr=not reported. Median (Q1, Q3); n (%).

10513 Background: Prior reports of high frequency of BRCA1 and BRCA2 ( BRCA1/2 ) PVs among South Asian women from Bangladesh, India, Nepal, and Pakistan with breast or ovarian cancer require validation in large prospective unselected cohorts. Methods: Individual-level anonymized patient data from two prospective cohorts were pooled to evaluate the prevalence of germline PVs among South Asian women: the South Asian Regional Alliance for Hereditary Cancers (SARAH Consortium) in Bangladesh, Nepal, and Pakistan, and the previously reported Nurse-led Genetic Counseling and Awareness (NuGenA) expansion cohort in India. Both studies enrolled consecutive cases of histologically confirmed newly diagnosed breast or epithelial ovarian cancer irrespective of age at diagnosis or family history. In both studies, participants completed questionnaires on personal and family history (first-, second- or third-degree) and provided blood for germline genetic testing after written consent. PVs in cancer predisposition genes including ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, PALB2, RAD51C, RAD51D, and TP53 were identified as part of the studies utilizing a multigene panel and the results were returned to ordering clinicians. The data cutoff date for this analysis was November 30, 2025. Results: The analysis included 1,711 South Asian women with breast (n=1,210) or ovarian (n=501) cancer. A family history of breast or ovarian cancer was noted in 177 (10.3%). Among breast cancers, 94% were invasive, 84% were ductal, 35% were triple-negative and over two-thirds presented with nodal involvement. Germline PVs across 13 predisposition genes were observed in 17.7% of breast and 35.9% of ovarian cancers. Notably, BRCA1/2 PVs accounted for most of these PV (13.6% of breast and 28.3% of ovarian cancer cases) with PVs in all genes except BRCA1/2 under 1%. The frequency of BRCA1/2 PVs was 24.4% in triple-negative breast cancer and 8.0% in ER+/HER2-. BRCA1/2 PV carriers were diagnosed with breast cancer at a younger age than non-carriers (Median age: 42 vs 46 years, P<0.001), with no age difference observed in ovarian cancer (50 vs. 51 years, P=0.79). Notably, among the 306 BRCA1/2 PV carriers identified, 229 (74.2%) did not report a family history of breast or ovarian cancer. Conclusions: We confirm a high prevalence of BRCA1/2 PVs among unselected South Asian women with either breast or ovarian cancer. The observations of younger age at cancer diagnosis, and low rates of family history support the need for population-specific germline genetic testing and risk management strategies in South Asia.

Background: Asymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized entity for which vascular risk-factor optimization is the primary management strategy, with no current indication for routine antiplatelet therapy or endovascular intervention for primary stroke prevention. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their association with outcomes in asymptomatic ICAS is yet to be evaluated. The present study aims to evaluate the association between GLP-1RA use and cerebrovascular outcomes in adults with asymptomatic ICAS. Materials and Methods: We used the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with ICAS between 1 January 2016 and 31 December 2025, and excluded patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) during the 6 months before or on the date of index ICAS diagnosis. Outcomes were assessed at 1 year, and included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed, including demographics, vascular risk factors, comorbidities, antithrombotics, lipid/diabetes therapies, and cardiometabolic laboratory/physiologic measures. Results: Before matching, 1746 GLP-1RA users and 71,792 non-users met inclusion criteria; after matching, 1728 patients remained in each cohort. GLP-1RA use was associated with lower 1-year risk of ischemic stroke (4.40% vs. 6.10%; hazard ratio [HR] 0.70, 95% CI 0.52–0.95; p = 0.044), lower all-cause mortality (3.40% vs. 9.40%; HR 0.35, 95% CI 0.26–0.47; p < 0.001), and lower composite outcome risk (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39–0.59; p < 0.001). Notably, these associations were observed despite matching for HbA1c, LDL cholesterol, BMI, and systolic blood pressure, suggesting potential effects beyond measured cardiometabolic risk profiles. Conclusions: In this large, propensity-matched cohort of adults with a-ICAS, GLP-1RA use was associated with lower ischemic stroke, all-cause mortality, and composite outcome at 1 year. These findings are hypothesis-generating and require further prospective studies to confirm this observation.

Introduction Obesity and related cardiometabolic comorbidities, including hypertension, dyslipidaemia, diabetes, metabolic dysfunction-associated steatotic liver disease and atherosclerotic cardiovascular disease, are increasingly prevalent among individuals with inflammatory bowel disease (IBD). These conditions influence disease activity, therapeutic response, surgical outcomes and overall quality of life, yet evidence remains fragmented. The M odulate O besity and relate D metabolic compl I cations F or Y ielding improvements in IBD outcomes (MODIFY-IBD) initiative aims to synthesise evidence and generate consensus recommendations to guide practice and future research in this area. This study describes a protocol for a structured evidence synthesis and Research ANd Development/University of California, Los Angeles (RAND/UCLA) Appropriateness Method (RUAM) consensus process. Methods and analysis We will conduct three systematic reviews and a structured evidence synthesis organised into three domains: (1) the impact of obesity on IBD outcomes, (2) the burden of cardiometabolic complications in IBD and (3) the management of overweight, obesity and cardiometabolic comorbidities in IBD. A multidisciplinary international panel of gastroenterologists, surgeons, endocrinologists, hepatologists, cardiologists and dietitians will assess each statement using the RAND/UCLA appropriateness method. Panellists will rate the appropriateness of each statement (only those that fall within their area of expertise) on a 1–9 scale (1–3=inappropriate, 4–6=uncertain and 7–9=appropriate), with medians rounded up (eg, 6.5=appropriate). Agreement will be assessed using the RAND Disagreement Index (DI<1.0=agreement). Ethics and dissemination This study will not involve direct patient participation, as it is based on evidence synthesis and expert consensus; therefore, formal research ethics committee approval will not be required. Patient representatives will contribute to the consensus process to provide contextual perspectives but no identifiable data will be collected. Findings will be disseminated through publication in peer-reviewed journals, presentation at major gastroenterology and IBD conferences and communication with professional societies. A lay summary and patient-friendly infographic will also be developed to facilitate translation of recommendations into clinical practice. PROSPERO registration numbers CRD420251178843: a systematic review of the impact of obesity on inflammatory bowel disease outcomes. CRD420251178799: a systematic review of cardiometabolic complications in inflammatory bowel disease. CRD420251174653: management of overweight, obesity and cardiometabolic comorbidities in inflammatory bowel disease: a systematic review.

Introduction Geriatric distal femur fractures are associated with mortality rates exceeding 20%, comparable to hip fractures. Traditional single implant fixation often requires weight-bearing restrictions that delay recovery. This pilot study aims to assess the feasibility of conducting a multicentre randomised controlled trial comparing dual vs single implant fixation for geriatric distal femur fractures. Methods and analysis This multicentre, prospective, randomised controlled pilot trial will enrol 80 participants aged 60 years or older with displaced distal femur fractures at five US level 1 trauma centres. Patients will be randomly allocated 1:1 to receive either single implant (lateral plate or retrograde nail) or dual implant (nail-plate or dual plate) fixation. All patients will be permitted immediate weight-bearing. The primary outcome is feasibility assessed through enrolment rate (80 patients in 12 months), protocol adherence (≥90%) and follow-up retention (≥85% at 12 months). Secondary outcomes include post-surgical mobility (AM-PAC, TUG), patient-reported outcomes (PROMIS-PF, PROMIS-29), mortality (90-day and 1 year) and complication rates. Analyses will be on an intention-to-treat basis. Ethics and dissemination The protocol was approved by the University of Utah Institutional Review Board (IRB_00149119) and IRBs at all participating centres. Written informed consent will be obtained from participants or legally authorised representatives. Findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration number NCT05292313 .