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12011 Background: Patients (pts) with high HCT-Comorbidity Index scores (HCT-CI of ≥3), older age (≥65 years), and/or who are frail per gait speed (<0.8 meters/second) have increased morbidity and mortality after allo-HCT compared to younger and healthier counterparts. We report the phase II analysis (PIIA) and interim phase III primary outcome analysis (PIIIA) of a seamless phase II/III prospective, randomized clinical trial conducted at 11 transplant centers to test new approaches to improve quality of life (QOL) in this population. Methods: Phase II compared specialist-administered supportive and palliative care (SPC), patient-administered management of comorbidities (MC, e.g. physical exercise, stress reduction, etc), both (SPC+MC), and usual care (UC) for change in Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT-BMT) QOL scores from baseline to day 90 (D90). Pts deceased prior to D90 were assigned FACT-BMT score=0. The winning phase II arm moved forward versus UC in phase III. Results: PIIA was done after enrolling 35 pts to each of the 4 study arms. Calculating the difference between FACT-BMT scores on D90 minus baseline, excluding missing data, indicated that only SPC resulted in a small improvement in QOL compared to either MC or SPC+MC (Table); hence SPC was the winning phase II arm. The PIIIA was conducted after enrolling 158 SPC pts and 153 UC pts. The SPC and UC arms were well balanced with median age (both 68 years), HCT-CI ≥3 (49% vs 55%), frailty per gait speed (13% vs 12%), female sex (41% vs 34%), non-white race (9.5% vs 11.5%), and Hispanic or unreported ethnicity (7.7% vs 5.7%), respectively. After median follow-up of 362 days, 45 pts had died in each arm. The mean QOL difference between D90 and baseline was 2.83 for SPC and 4.27 for UC (difference of differences, -1.44, 95% CI of difference, -5.03 to 2.14, p=0.43). Fitting a generalized linear model that included baseline, D30, and D90 values and testing the null hypothesis that the slope of scores differs between SPC and UC resulted in p=0.85. Using the Kaplan Meier method, no difference in survival was observed across arms (HR 1.13 [0.75-1.73]). Conclusions: Specialist-administered palliative care showed no meaningful improvement in QOL, nor a survival advantage, compared to usual care in frail, older and comorbid allo-HCT recipients, resulting in the cessation of this Phase II/III trial. Analysis of the whole patient population for primary and secondary outcomes is in progress. Clinical trial information: NCT03870750 . Change in FACT-BMT (D90 value minus baseline value) comparing the 4 arms of phase II. Group Mean difference (sd) Median difference (range) SPC (n=28) -2.93 (28.52) 0.25 (-102 to 38.22) CM (n=18) -18.37 (33.80) -9.50 (-98.33 to 11) SPC+CM (n=27) -15.76 (32.69) -7.67 (-90 to 32)

10587 Background: The American Society of Clinical Oncology (ASCO) and NCCN recommend germline testing for patients (pts) with biliary tract cancers (BTC), particularly those diagnosed at a young age. Prior studies estimate that approximately 15% of pts with BTC harbor pathogenic germline alterations. Germline testing can identify hereditary cancer syndromes, guide targeted therapy, and inform family counseling. This study aimed to further characterize and describe the prevalence of pathogenic germline variants (PGVs) in patients with young-onset BTC (YO-BTC). Methods: We conducted a retrospective review of medical records for pts diagnosed with YO-BTC (ages 18–55) across all Mayo Clinic tri-sites from January 2014 to October 2024. Data collected included results from germline DNA sequencing, tumor genetic testing, demographics, history of other malignancies, and family history of cancer. The primary outcome was the identification of pathogenic germline mutations associated with cancer predisposition. Results: Among 239 pts with YO-BTC, the median age at diagnosis was 43 years (range 19–55), with 62% female and 65.2% identifying as white. Clinical germline testing (e.g., Invitae, Ambry, Myriad) was performed in 123 pts (51.5%), revealing PGVs in 15 pts (12.1%), variants of uncertain significance (VUS) in 30 pts (24.3%), and likely benign variants in 4 pts (3.2%). Among those with PGVs, DNA repair mutations were the most common findings (10/15), including ATM (4), CHEK2 (2), BRCA2 (2), BAP1 (1), and PALB2 (1). One pt had a Lynch syndrome-associated mutation (MSH6), and four had mutations in other cancer-related genes (MUTYH, HOXB13, RMRP, and PIK3CA). Tumor genomic profiling (via CARIS, TEMPUS, or FoundationOne) was performed in 9 pts with PGVs, detecting the variant in 4 (44%), while liquid biopsy (Guardant) identified the PGV in 4 of 6 cases (66.6%).The majority of PGV carriers had advanced BTC (14/15), with intrahepatic cholangiocarcinoma being the most prevalent (11/15), while 4 had extrahepatic cholangiocarcinoma. Additionally, most PGV carriers had a first- or second-degree relative with a prior history of malignancy (14/15), and 3 pts had a second malignancy. Of the 15 pts with PGVs, 4 had BTC associated with primary sclerosing cholangitis. Conclusions: In this large institutional series of YO-BTC, PGVs were identified in 12.1% of pts, demonstrating a significant yield from germline testing in this population. Notably, tissue and liquid biopsies demonstrated different detection rates for PGVs, underscoring the variability in PGVs reporting across platforms. Germline testing through CLIA-approved methods should remain the standard of care. DNA repair pathway mutations, particularly ATM, CHEK2, and BRCA2, were the most frequently identified PGVs, highlighting their role in the pathogenesis of YO-BTC and their potential to guide treatment decisions.

10556 Background: The coexistence of interstitial lung diseases (ILD) and lung cancer (LC) presents a clinical challenge. ILD, including idiopathic pulmonary fibrosis (IPF) and non-IPF entities, is associated with an elevated risk of LC. However, the clinical features, treatment patterns, and survival outcomes of ILD-LC, especially IPF-LC, remain underexplored. We aimed to comprehensively evaluate survival outcomes and risk factors for mortality of ILD-LC patients based on a real-world long-term clinical cohort. Methods: A total of 1,341 eligible patients for this study were drawn from the Epidemiology and Genetics of Lung Cancer research program database (Mayo Clinic) including 96 IPF-LC, 111 Non-IPF ILD-LC, 99 ILD-only, and 1,035 propensity-matched LC-only patients (Controls). Data were collected on demographics, comorbidities, tumor features, treatment, and patient outcomes. Survival analyses used Kaplan-Meier methods; risk factors were assessed via Cox Proportional Hazards models. All comparisons reported below were statistically significant with p-values≤0.001 unless specified. Results: Among the 20,470 primary LC patients who were diagnosed from 1997 through 2016 and followed to 2021, 207 (1.0%) had ILD-LC, of which 96 (46.4%) had IPF. Comparing to Controls, ILD-LC patients were 4 years older at the time of LC diagnosis, 63.8% (vs. 52.8%) male, had a higher rate of former smokers (60.4% vs. 47.3%), a lower proportion of adenocarcinoma (37.7% vs. 57.5%), and a higher proportion of squamous cell (28.0% vs. 20.3%) and small cell carcinoma (13.5% vs. 8.4%). Although no significant differences in either LC stage or grade, ILD-LC patients had a significantly higher mortality rate (90.3% vs. 78.8%), particularly among IPF-LC patients (97.9% vs. 83.8%). ILD-LC patients were less likely to undergo surgery or receiving pharmacological treatments (73.9% vs. 93.5%). The median 5-year overall survival rate (OS, months) were 49.5 for Controls, 35.2 for Non-IPF ILD-LC patients, and 15.9 for IPF-LC patients. Analysis of six most common comorbidities revealed that pulmonary hypertension was associated with worse OS in ILD-LC patients compared to those without it (11.9% vs. 20.1%, P < 0.05); however unexpectedly, hypertension in ILD-LC patients was associated with better OS (21.3% vs. 14.4%) and emphysema in IPF-LC patients with better OS (7.9% vs. 3.4%, P < 0.05) when compared to those without the two comorbidities, respectively. Conclusions: This study highlights the poorer survival outcomes in ILD-LC patients, particularly IPF-LC patients, emphasizing the need for further investigation into optimized therapies and comorbidity management. Our findings also call for attention to two unexpected associations of hypertension and emphysema, warranting in-depth research on the possible biological and physiological mechanisms.

10544 Background: Incorporation of Polygenic Risk Scores (PRS) can refine traditional breast cancer risk assessment models to provide precise estimates of breast cancer risk. However, the impact of such an integrated model on clinical decision-making related to breast cancer surveillance and preventive strategies is not fully understood. Methods: The GENRE-2 is a prospective single-arm multisite clinical trial (NCT04474834) incorporating PRS into standard breast cancer risk assessment models to determine the impact of PRS on clinical decisions on breast cancer prevention and surveillance. Women at high risk of breast cancer due to NCI-BCRAT 5-year risk of ≥ 3%, or IBIS (Tyrer-Cuzik) 10-year breast cancer risk of ≥5%, biopsy-proven high-risk breast lesion, or a pathogenic variant (PV) in ATM , BRCA1, BRCA2, CHEK2 or PALB2 , were enrolled from five sites in the United States. All women were invited to complete surveys on their breast surveillance and cancer prevention decisions based on pre-PRS standard risk models and post-PRS risk estimation, and further annual surveys are planned for 10 years. Results: Among 902 women enrolled in the study, 605 (median age: 52 years) received PRS results and completed a survey to date. Of those who received PRS results,195 (32.2%) were PV carriers. Among non-carriers, the median 10-year and lifetime pre-PRS IBIS-based risk was 10.0% and 28.7%, respectively. Among PV carriers, the CanRisk-based 10-year and lifetime pre-PRS risk estimates were 6.3% and 25.2% for ATM , 22.3% and 77.6% for BRCA1 , 18.5% and 77.7% for BRCA2 , 7.1% and 25.7% for CHEK2 , and 16.8% and 38.0% for PALB2 PV carriers, respectively. After the incorporation of PRS, the lifetime risk of breast cancer increased by at least 10% in 31% of non-carriers and 7.7% of PV carriers and decreased by at least 10% in 10.7% of non-carriers and 7.7% of PV carriers. The proportion of non-carriers with lifetime risk < 20% or > 40% changed from 17.3% and 22.0%, respectively, in the pre-PRS evaluation to 24.4% and 32.9%, in the post-PRS evaluation. A higher lifetime post-PRS score was associated with intent to take preventive action (surgery or endocrine agents). In non-carriers, the proportion of women with a lifetime risk < 20% with intent to take preventive action was 11%, compared to 36.8% of those with a lifetime risk > 40% (p < 0.001). Similarly, in PV carriers, the proportion of women with lifetime risk < 20% with intent to take preventive action was 20.8% compared to 41.1% of those with lifetime risk > 40% (p = 0.015). Conclusions: The GENRE-2 trial demonstrates that the incorporation of PRS into breast cancer risk assessment models in high-risk women is feasible and leads to clinically meaningful changes in breast cancer risk estimates and decision-making regarding preventive strategies. Evaluation of the implementation of breast cancer risk management strategies in study participants is ongoing and will be reported. Clinical trial information: NCT04474834 .

4568 Background: The 2IR immune response score was initially developed using bulk RNA sequencing of pre-treatment tissue from ImVigor 210 and CheckMate 275 trials, however these trials enrolled patients (pts) with pure urothelial carcinoma (pUC) histology. Patients with hsUC often exhibit worse response to immune checkpoint inibitors (ICI) than patients with pUC. Here, we evaluated the 2IR score as a prognostic or predictive biomarker in real-world pts with hsUC. Methods: Specimens from pts with pUC (n = 1677) and hsUC (n = 417) were profiled at Caris Life Sciences (Phoenix, AZ) using next generation sequencing (NGS) of DNA and RNA. HsUC histologies included majority ( > 50%) squamous (n = 340), sarcomatoid (n = 51), neuroendocrine (n = 20), and micropapillary (n = 6) component. 2IR was calculated by comparative RNA expression of 10 adaptive immune genes and 39 pro-tumorigenic genes. Tumors were classified as 2IR-Low (2IR ≤ -0.5), -Mid (-0.5 < 2IR < 0), and -High (2IR ≥ 0), as previously described (Wang et al., 2022). Spearman correlation analysis was utilized to compare 2IR with tumor mutation burden (TMB), interferon score (IFN) and the tumor microenvironment (TME) cell fractions estimated using quanTIseq. Clinical outcomes included real-world overall survival (rwOS) from ICI start to last contact and time on treatment (ToT) with pembrolizumab, obtained via matched insurance claims data and calculated using Kaplan-Meier methods, while Hazard ratio (HR) was calculated by Cox proportional model. Results: For patients with hsUC, distribution of 2IR score was High 5.76%, Mid 33.3%, and Low 60.9%. Median 2IR score was significantly lower in squamous (-0.60, p < 0.0001) and sarcomatoid UC (-0.82, p < 0.0001) compared to pUC (-0.41) and significantly higher in neuroendocrine UC (-0.15, p = 0.003). Among patients with hsUC, median rwOS was significantly longer for patients with high/mid 2IR score compared to low 2IR score (25.3 [10.9-39.3] months vs. 8.7 [6.2-11.3] months; HR 0.52, 95% CI 0.34 – 0.78, p = 0.0017). ToT with pembrolizumab was also significantly longer for high/mid 2IR score compared to low 2IR score (3.0 [1.4-5.5] months vs. 2.1 [1.4-3.3] months; HR 0.68, 95% CI 0.46-1.00, p = 0.0471). Similar to pUC, 2IR score in patients with squamous UC was positively associated with CD8 T cell infiltration (r = 0.39; p < 0.0001), IFN score (r = 0.41, p < 0.0001), and TMB (r = 0.20, p < 0.001) and negatively associated with M1 macrophage infiltration (r = -0.25, p < 0.0001). 2IR scores in hsUC correlated positively but not significantly with mutations in TP53 (Median: -0.59 vs -0.62, p = 0.067) and PIK3CA (Median: -0.56 vs -0.61, p = 0.172) and negatively with mutations in CDKN2A (Median: -0.67 vs -0.59, p = 0.052). Conclusions: In a real-world cohort of patients with hsUC, we show the 2IR score may be prognostic for rwOS and predictive for pembrolizumab ToT. Prospective studies are needed to further validate this biomarker for use in this population.

3011 Background: BMS-986504 selectively binds to the PRMT5-MTA complex, which represents a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP– wild-type cells. In the first-in-human phase 1/2 CA240-0007 study in advanced, unresectable or metastatic solid tumors with homozygous MTAP -del, BMS-986504 was found to be well tolerated and demonstrated antitumor activity in multiple tumors. Here, we report clinical results and the first PK and PD analyses of BMS-986504 from the dose escalation and expansion phases of CA240-0007. Methods: Pts with measurable/evaluable disease and no available treatment (Tx) with curative intent were enrolled; 7 doses were evaluated (50 to 800 mg) in dose escalation. Objective response rate (ORR), disease control rate (DCR), duration of response (DOR), time to response (TTR), safety, PK, PD, including plasma SDMA were assessed. Results: As of 2 Dec 24, 152 heavily pretreated pts were enrolled across all doses: NSCLC (n = 34), PDAC (n = 41), cholangiocarcinoma (n = 12), and mesothelioma (n = 12) were the most common tumor types. With a median f/u of 9.0 mo (95% CI 7.6–9.9), continued durable antitumor activity and deepening tumor regression were seen across tumor types and doses (ORR = 23%, DCR = 70%, median DOR = 10.5 mo, TTR = 4.6 mo). No new safety signals were identified. Most Tx-related adverse events (TRAEs) were grade (Gr) 1 or 2; 13% had Gr ≥ 3 TRAEs (Gr 3 = 12%, Gr 4 = < 1%, Gr 5 = 0). Doses from 50 to 600 mg QD were assessed for PK/PD. The AUC (0-24) after multiple doses was approximately dose proportional at 200 to 600 mg, and the terminal t 1/2 after a single dose was approximately 24 h (table). There were dose-dependent reductions in predicted plasma SDMA, with the 400 and 600 mg doses approaching the plateau. Conclusions: With longer f/u, BMS-986504 continued to show increasingly durable antitumor activity. BMS-986504 demonstrated a favorable PK/PD profile, supporting QD dosing at 400 and 600 mg. These results support further investigation of BMS-986504 at 400 and 600 mg QD as a potential first-in-class synthetic lethal Tx option in pts with advanced solid tumors with MTAP -del. Clinical trial information: NCT05245500 . PK and PD. 50 mg QD 100 mg QD 200 mg QD 400 mg QD 600 mg QD PK after multiple doses t max a (min–max), h 2.0 (2.0–4.0)n = 3 2.0 (1.0–2.0)n = 3 2.0 (0.5–6.0)n = 8 2.0 (0.5–4.0)n = 10 2.0 (1.0–6.0)n = 10 C max , b ng/mL 107n = 3 377n = 3 685n = 8 1240n = 10 2110n = 10 AUC (0-24) , b h∙ng/mL 948 n = 3 3060 n = 3 7150 n = 7 11,800n = 10 26,700n = 9 AUC (0-24) , b,c h∙ng/mL/mg 19.0n = 3 30.6n = 3 35.8n = 7 29.5n = 10 44.6n = 9 Terminal t 1/2 after single dose, d h 21.7 n = 1 80.7 n = 1 21.5 n = 14 21.7 n = 14 24.1 n = 1 PD Translational exposure targets (C avgss ), X 0.08 0.21 0.5 1.1 1.7 Predicted plasma SDMA reduction, a % (90% PI) 30.0 (23.2–37.8) 38.8 (27.1–47.5) 48.3 (42.0–53.0) 55.0 (50.7–57.6) 57.4 (54.3–59.0) a Median. b Geometric mean. c Dose-normalized. d Arithmetic mean.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

Abstract Background Optimal treatment for resectable gastric and gastroesophageal junction (GEJ) adenocarcinoma remains unclear due to limited head-to-head comparisons among chemotherapy and chemoradiation regimens. This network meta-analysis aimed to determine the relative efficacy of available multimodality treatment regimens in these patients. Methods MEDLINE, EMBASE, Scopus, Web of Science, and CENTRAL were searched till September 20, 2024. Phase 3 randomized trials evaluating perioperative/neoadjuvant systemic therapy ± radiation in resectable gastric/GEJ adenocarcinoma were included. Primary outcomes were disease-free survival (DFS) and overall survival (OS). Frequentist network meta-analysis was conducted to compare hazard ratios (HRs) and 95% confidence intervals (CIs). Results Fifteen trials (8072 patients) were analyzed. pFLOT (perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel) ranked highest for DFS in the overall population (P-score 91%), achieving significant improvements compared to surgery alone (HR 0.48, 95% CI, 0.38-0.60) and nCROSS (neoadjuvant paclitaxel, carboplatin, and radiotherapy) (0.67, 0.56-0.81). For OS, nPLF + nCRT(EP) (neoadjuvant cisplatin, leucovorin, and fluorouracil for induction, followed by etoposide, cisplatin, and radiotherapy) (P-score 90%) and pFLOT (P-score 87%) were the top regimens. pFLOT significantly outperformed surgery alone (0.57, 0.45-0.72) and nCROSS (0.73, 0.60-0.89). Based on the limited data available, adding neoadjuvant chemoradiation to pFLOT provided no additional OS (1.14, 0.76-1.72) or DFS (1.22, 0.83-1.82) benefit. Similarly, adding pembrolizumab to perioperative chemotherapy (cisplatin and fluorouracil/capecitabine) was not superior to pFLOT (DFS: 1.10, 0.71-1.69; OS: 1.09, 0.69-1.72). Conclusions pFLOT demonstrated superior efficacy in resectable gastric/GEJ adenocarcinoma, outperforming surgery alone, nCROSS, and alternative perioperative regimens. The additive role of immunotherapy requires further investigation to optimize patient selection and outcomes.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract As the prevalence of hip arthroscopy increases, management of capsular defects as well as capsulotomy closure has increasingly been recognized for their impact on recurrent symptoms in the young athletic hip. Several recent studies have shown that capsular closure at the time of primary hip arthroscopy improves both short‐ and long‐term patient‐reported outcomes, revision rates, and conversion to arthroplasty. Specifically, capsular insufficiency is a source of recurrent pain and microinstability. In this context, far medial labral tears pose a challenge for suture fixation, given the historic need of extending the interportal capsulotomy to obtain adequate trajectory for suture anchors and subsequent passage. Given the suboptimal stability consequences of extending the capsulotomy medially, here we present a novel approach for suture fixation of the medial labrum. This technique provides an effective method for suture fixation of the medial labrum, without necessitating extension of the interportal capsulotomy. Technique Video video See video under supplementary data.