Citations

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy‐related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy‐related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood‐derived immune cell subsets and 103 circulating immunological proteins. Meta‐analysis revealed a genome‐wide significant association between the ULK4 rs6599175C allele and increased MGUS risk ( p = 3.35 × 10 −8 ). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B‐cell differentiation. Additionally, the CDKN2A rs2811710 variant showed a suggestive association with MGUS risk ( p = 2.17 × 10 −4 ), affecting transcription factor binding involved in B‐cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome‐wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B‐cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.

Abstract Background: We have identified two potentially predictive signatures of palbociclib resistance: the RBsig, composed of E2F1/E2F2 dependent genes, which is associated with genetic loss of RB1, and the ratio between the gene expression levels of CCNE1 to RB1 (CCNE1/RB1). Both signatures have been previously analyzed in vitro and in neoadjuvant and metastatic studies with palbociclib. The present analysis aims to explore the role of RBsig and CCNE1/RB1 in the phase III adjuvant PALLAS trial, which randomized patients to palbociclib plus endocrine therapy, versus endocrine therapy alone. Materials and methods: Gene expression data from PALLAS were generated using the HTG EdgeSeq Oncology BM Panel. Of the 87 genes composing RBsig, 46 were available within the EdgeSeq dataset and were used for the analyses; CCNE1 and RB1 were both available. RBsig was calculated as the mean of the Z-score scaled gene expression (log) of the 46 genes; CCNE1/RB1 was computed as the log ratio between the mRNA expression of CCNE1 and RB1. The prognostic/predictive effect of the continuous signatures in terms of invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), and overall survival (OS) was evaluated using Cox proportional hazard models. Results: HTG data were available from 2,587 of 5,748 patients from the entire PALLAS intention-to-treat (ITT) cohort. As RBsig and CCNE1/RB1 levels are affected by pre-surgical treatments, we limited the analyses to 1612 pre-treatment samples (530 core biopsies and 1082 surgical specimens) (analysis population). Compared with the entire PALLAS ITT cohort, the analysis population was significantly enriched for patients with low clinical risk (41.3% vs 59.4%) who did not receive prior chemotherapy (17.5% vs 55.9%). In keeping with the PALLAS ITT cohort, no significant benefit from the addition of palbociclib was observed in the analysis population. Higher baseline RBsig or CCNE/RB1 values were significantly and independently associated with worse IDFS (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.3-2.0; HR 1.22, 95%CI 1.1-1.3, respectively), DRFS (HR 1.94, 95%CI 1.5-2.5; HR 1.26, 95%CI 1.1-1.4, respectively) and OS (HR 1.79, 95% CI 1.3-2.4; HR 1.26, 95%CI 1.1-1.4, respectively) in the analysis population. No predictive effect of palbociclib benefit was observed for either signature in the analysis population, nor according to clinical risk or chemotherapy receipt. Interestingly, higher RBsig was strongly prognostic in patients who did not receive adjuvant chemotherapy (HR 1.83, 95%CI 1.4-2.3) but not in those who received it (HR 1.01, 95%CI 0.6-1.6) (interaction p=0.02) suggesting a potential predictive role of RBsig for chemotherapy benefit. Conclusions: In the PALLAS trial, higher baseline RBsig or CCNE1/RB1 values are associated with worse prognosis, but are not predictive of benefit from palbociclib in the adjuvant setting. RBsig might be associated with differential benefit from chemotherapy. Further study of these biomarkers may strengthen their role in risk stratification.https://acknowledgments.alliancefound.org Citation Format: L. Malorni, D. Hlauschek, E. Mayer, M. Benelli, L. Biganzoli, I. Migliaccio, A. Kermanidis, G. Pfeiler, E. P. Mamounas, A. M. Brufsky, M. Bellet-Ezquerra, K. Clifton, G. Rubovszky, T. Foukakis, M. Goetz, S. Lee, M. Ruiz-Borrego, W. Symmans, K. V. Ballman, F. Liu, J. Machacek-Link, C. Denkert, A. DeMichele, M. Gnant. Prognostic and predictive role of RBsig and CCNE1/RB1 gene-expression signatures for patients with early breast cancer treated with endocrine therapy with or without palbociclib in the PALLAS trial (ABCSG-42, AFT-05, BIG 14-03) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-13.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

Abstract Background The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. Purpose This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across all LVEF categories. Methods Patients with severe isolated TR from the TRIGISTRY, a multicenter international registry, were categorized based on LVEF (preserved EF-pEF:≥50%, mildly reduced EF-mrEF:41–49%, and reduced EF-rEF:≤40%). We assessed the impact of treatment modality and procedural success, defined as residual TR ≤mild-to-moderate, on two-year survival within each LVEF category. Results Among 2,384 patients, 1,383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (P<0.0005) and TTVI (P<0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (P=0.28 for both), nor in those with rEF (P=0.76 and P=0.22 respectively). Similar results were obtained when surgical and transcatheter interventions were grouped together (P<0.0001, P=0.17 and P=0.29 in patients with pEF, mrEF and rEF respectively). Patients with significant residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (P=0.47, P=0.33, and P=0.008 respectively)(Figure 1). Conclusion Tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with preserved LVEF but not in those with mildly reduced or reduced LVEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering tricuspid interventions in individuals with reduced LVEF.Figure 1

Abstract Background While tricuspid regurgitation (TR) is predominantly functional, it can arise from various cardiac conditions. This study aimed to evaluate whether the benefits of tricuspid valve intervention, compared to conservative management, differ based on the underlying etiology. Methods In the TRIGISTRY international cohort, which includes consecutive patients with severe isolated functional TR across 33 centers in 10 countries, we compared mortality rates at 2 years between patients who underwent a tricuspid valve intervention (surgical or transcatheter) versus conservative management according to TR etiology. Patients were classified into three groups: (1) Isolated TR (ITR), defined as left ventricular ejection fraction (LVEF) >60%, systolic pulmonary artery pressure (sPAP) <50 mmHg, and no prior left-heart intervention (LHI); (2) LHI-TR, comprising patients with a history of LHI; and (3) Undetermined TR (UTR), which included those who did not meet the criteria for ITR or LHI, as well as those with missing sPAP data. Given previous findings indicating that intervention provided no survival benefit for patients with a high TRI-SCORE, the present analysis was restricted to individuals with low to intermediate TRI-SCORE (≤5). Survival outcomes between groups were compared using restricted mean survival time (RMST). Results A total of 1,552 patients (72±13 years; 56% female) with severe functional TR and a low (48%) or intermediate (52%) TRI-SCORE were included. Of these, 772 (50%) underwent an intervention, while 780 (50%) were conservatively managed. TR was classified as ITR in 201 patients (13%), LHI in 395 (25%), and UTR in 956 (62%). Overall, patients with ITR exhibited the lowest comorbidity burden, whereas those with UTR had the highest. After adjusting for comorbidities and TRI-SCORE, a survival benefit of a tricuspid valve intervention was observed in patients with ITR (survival estimate: 0.17, 95% CI [0.009, 0.32], P=0.039) and, to a lesser extent, in patients with UTR (survival estimate: 0.09, 95% CI [0.0, 0.184], P=0.048), but not in those with prior LHI (survival estimate: 0.06, 95% CI [-0.08, 0.2], P=0.4). Similar results were found when excluding patients with moderate or greater residual TR after intervention. Conclusion In TRIGISTRY, patients with ITR appeared to derive the greatest benefit from tricuspid valve intervention, followed to a lesser extent by those with UTR, while no benefit was observed in patients with prior LHI. However, the potential influence of unaccounted confounders cannot be excluded, and further studies are needed to better identify patients’ subsets that may derive the most benefit from a tricuspid valve intervention.

Abstract Background Fibroblast growth factor-inducible 14 (Fn14) belongs to the TNFR superfamily. Fn14 overexpression can drive receptor-autonomous signaling, increase both cell invasion and tumor-associated macrophages/microglia (TAMMs) recruitment, and correlates with reduced survival in glioblastoma (GBM) patients and rat gliomas. While prior studies report Fn14 expression in non-tumor cells within the GBM tumor microenvironment (TME), their relative contributions to glioma pathobiology remain unclear. Methods Using tumor-host pairings of Fn14-positive and -knockout (-KO) cells and mice, we examined the role of Fn14 in glioma biology. Mouse glioma and human GBM datasets were analyzed at the cellular, protein, and transcriptomic levels to assess Fn14-associated changes in the glioma TME and survival outcomes. Results Fn14 was found to be highly expressed in tumor cells and TAMMs in human GBM and 2 well-characterized murine glioma models. Fn14 KO in both tumor and host cells increased overall survival. Notably, this survival benefit was greater in the glioma model characterized by a more immunologically activated TME. Immunophenotyping revealed that Fn14 loss reshapes the tumor-immune landscape, reducing the presence of immunosuppressive macrophages and exhausted T-cells, suggesting that Fn14 modulates both innate and adaptive immune responses. These findings were supported by analyses of human GBM datasets, where high Fn14 expression correlated with immunosuppressive shifts and poor patient responses to immune checkpoint inhibitor therapy. Conclusions This study provides the first description of the contributions of both tumor- and host-derived Fn14 expression to tumor immunity and survival and identifies Fn14 as an important mediator of innate and adaptive immune responses in gliomas.

Abstract INTRODUCTION: Prostate cancer (PC) shows marked heterogeneity in clinical outcomes, from indolent to highly aggressive disease. Alterations in TP53, PTEN, RB1, and DNA damage repair genes are linked to poor patient outcomes, yet how the interaction and co-occurrence of these alterations impact prognosis remains unclear. We leveraged the AACR Project GENIE prostate cancer cohort to assess the prognostic impact of individual and concomitant gene alterations, focusing on key PC drivers (BRCA2, TP53, PTEN, RB1). METHODS: the study was conducted in two stages: (i) identification of candidate alterations at individual gene level through a systematic literature review, followed by analyzing the prevalence and co-occurrence of genes in the AACR Project GENIE Public Release (PR) dataset. (ii) Prognostic analysis of the pre-selected biomarkers in the AACR Project GENIE Biopharma Collaborative (BPC) cohort. Analyses were performed in three clinical settings (entire BPC cohort, n=1114; subgroup of patients with localized disease at diagnosis, n=837; and subgroup of patients with metastatic PC with a biopsy collected before or at the time of mPC, n=455) using two statistical approaches: univariate analysis (UA) and inverse probability weighting using propensity scores (PS). Cox models were applied to estimate overall survival hazard ratios (HRs). RESULTS: after integrating the findings from the systematic review with the analysis of the GENIE PR (n=5684), 107 individual genes and 122 co-occurring alterations were selected for study. In the GENIE BPC (n=1114 patients) 75% were M0 at diagnosis, and 67% presented metastatic PC at any time. Alteration prevalence was: TP53, 25%; PTEN, 15%; BRCA2, 4%; RB1, 4%; co-alterations included, PTEN-TP53 (6.4%), RB1-TP53 (2.1%), PTEN-RB1 (1.3%), and BRCA2-TP53 (1.2%). All four key genes showed a statistically significant prognostic impact in the entire cohort with UA (BRCA2, HR:1.9; TP53, HR:2.6; PTEN, HR:2.4; RB1, HR:4.1, all p<0.001). Results were consistent in the subgroup analysis and when using PS. Additional genes such as FANCA, PIK3CA, and MYC were also associated with poor outcomes. Among co-alterations, BRCA2-TP53 (HR:2.0, p=0.05), RB1-TP53 (HR:3.6, p<0.001), PTEN-TP53 (HR:2.4, p<0.001); PTEN-RB1 (HR:5.5, p<0.001), and PTEN-TP53-RB1 (HR:9.0, p<0.001) were the strongest predictors of poor survival, with consistent effects across subgroups and analytical methods. Other combinations including MYC-TP53 (HR 2.2, p<0.001) and PIK3CA-TP53 (HR 3.2, p<0.001), also showed independent prognostic value. CONCLUSIONS: Genomic alterations in TP53, PTEN, RB1, and BRCA2, alone and in combination, independently associate with poor prognosis. Co-alteration patterns such as PTEN-TP53-RB1 define aggressive molecular subsets. This evidence supports integrating genomic interaction patterns for enhancing clinical risk models and guiding precision patient management. Furthermore, this study highlights the potential of AACR Project GENIE to enable data-driven development of biomarker-informed patient care strategies. Citation Format: Pablo Cresta Morgado, Victor Navarro, Guillermo Vilacampa, Haitham Alatoom, Manuel Ramos del Rio, Irbaz Riaz, Shawn Sweeney, Nikolaus Schultz, Ken Kehl, Gregory Riely, Wasim Abida, Katherine Panageas, Deborah Schrag, Philippe Bedard, Christine Micheel, Xindi Guo, Chelsea Nayan, Rodrigo Dientsmann, Joaquin Mateo. Genomic prognostic biomarkers in prostate cancer from the AACR GENIE cohort [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A013.

BACKGROUND AND OBJECTIVES: Unruptured intracranial aneurysms (UIAs) are increasingly detected and require careful management to prevent rupture. No externally validated score currently predicts procedural risk to guide treatment decisions. We developed and validated 2 predictive scores for complications after endovascular treatment (EVT) or neurosurgical treatment (NT) of UIA using routinely collected clinical and aneurysmal features. METHODS: We conducted a multicenter retrospective study including patients with UIA treated with EVT or NT across 15 neurovascular centers (2014-2024). Predictive models were built using multivariable logistic regression, with variables derived from Delphi consensus. The primary outcome was a composite safety end point: new neurological deficits, modified Rankin Scale (mRS) worsening (≥1 point or mRS 2-5 within 30 days), or procedural death. Internal validation used bootstrapping, and external validation was performed temporally and institutionally. Model performance was assessed using area under the receiver operating characteristic curve (AUROC) and calibration. Final scores, named Morbidity and Mortality Associated Risk in the Treatment of UIAs (MARTA)-EVT and MARTA-NT, were compared with existing models identified through systematic review. RESULTS: Among 2647 patients (1907 EVT and 740 NT), procedural complications occurred in 6.3% (EVT) and 12.8% (NT). Independent predictors included age, baseline mRS, aneurysm location, size, morphology, and procedural factors. MARTA-EVT (AUROC = 0.68, 95% CI = 0.57-0.78) and MARTA-NT (AUROC = 0.65, 95% CI = 0.54-0.77) showed moderate discrimination and good calibration. MARTA-EVT outperformed existing models; MARTA-NT performed similarly to SAFETEA. Predictive models are available open-source: https://martascoreapp.shinyapps.io/martascoreapp/. CONCLUSION: MARTA-EVT and MARTA-NT are validated tools for predicting procedural risks in UIA treatment and may support patient counseling and clinical decision making.

632 Background: Paltusotine is an oral, nonpeptide, selective somatostatin receptor 2 agonist. In a phase 2 study, treatment with once-daily paltusotine reduced the frequency and severity of carcinoid syndrome (CS) symptoms and was well tolerated. The effect of paltusotine on biomarkers of serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was further explored. Methods: This exploratory study, without formal power calculations, included an 8-week randomized treatment phase (completed) and a 102-week open-label extension phase (currently ongoing). The purpose was to evaluate safety, pharmacokinetics, and exploratory efficacy endpoints, including changes in biomarkers of paltusotine treatment. Enrolled patients were adults with a stable, documented grade 1 or 2 neuroendocrine tumor (NET) and CS. These patients were actively symptomatic and either untreated with somatostatin receptor ligand (SRL) therapy (average of ≥4 bowel movements [BMs] per day or >2 flushing episodes per day in ≥2 days over a 2-week period) or washed out of SRL therapy (symptoms previously controlled on SRL), with demonstrated symptom worsening after washout. Patients were randomized to once-daily paltusotine 40 mg or 80 mg; one optional uptitration (from 40 mg to 80 mg or 80 mg to 120 mg) was permitted. Blood samples for assessment of biomarkers (serum serotonin and plasma 5-HIAA) were collected longitudinally from screening to end of treatment. Upper limit of normal was prespecified as 541 ng/mL for serotonin and 22 ng/mL for 5-HIAA. This analysis focuses on changes in biomarker from baseline to the end of 8-week randomized treatment phase and after approximately one year (48 weeks). Results: Thirty-six patients (n=9 untreated; n=27 SRL washout) were randomized. Mean age was 60.8 years (range 35-83), and 52.8% were female. Nineteen patients had grade 1 NETs, and 17 had grade 2 NETs. As reported previously, treatment with once-daily, oral paltusotine was well tolerated and reduced the frequency and severity of CS symptoms, justifying further clinical development of the 80 mg dose. Mean serum serotonin decreased from 1553.0 ng/mL at baseline to 643.9 ng/mL at Week 8, and mean plasma 5-HIAA decreased from 245.1 ng/mL to 159.7 ng/mL. There was a trend of untreated patients achieving a greater reduction in comparison to washout patients. At 48-week follow-up, mean serum serotonin was stabilized at 791.50 ng/mL (n=20), and mean plasma 5-HIAA was stabilized at 190.45 ng/mL (n=20). Conclusions: Paltusotine significantly reduced serotonin and 5-HIAA levels, with effects maintained at 48 weeks. Biomarker reductions paralleled reductions in BM and flushing frequency. These findings support further investigation in the ongoing phase 3 study (CAREFNDR, NCT07087054). Clinical trial information: NCT05361668 .