Citations

Abstract Introduction: Metaplastic breast cancer (MpBC) is a rare, aggressive subtype of breast cancer that has limited evidence-based data to guide treatment. Historically, MpBC has had limited response to chemotherapy; however, the response of MpBC to antibody-drug conjugates (ADCs) remains poorly characterized. Methods: We performed a retrospective cohort study of patients (pts) with pathologic diagnosis of MpBC who received ADC therapy as part of standard of care in the metastatic setting across 4 NCI-designated cancer centers. The primary endpoints were objective response rate (ORR) at time of best response to ADC & real world PFS (rwPFS) of ADC compared to non-ADC therapy, defined as time from treatment start to time of progression or death. Results: We identified 48 pts with MpBC who received at least one ADC between 3/2016 and 10/2025. Median age was 54 years (range 31-77); all pts were biological females. Most pts had triple negative disease (n=39, 81%), 5 (10%) had HER2+ disease, 3 (6%) had hormone receptor positive disease & 17 (35%) were confirmed HER2-low (IHC 1+ or 2+, ISH nonamplified). The most common MpBC subtypes were with squamous differentiation (n=17, 35%), chondroid (n=11, 23%), matrix-producing (n=11, 23%) & spindle cell differentiation (n=10, 21%). Ten pts (21%) had de novo metastatic disease & 38 (79%) had recurrent disease. Most common metastatic sites were lung (n=33, 69%) & liver (21, 44%). 37/38 (97%) patients had curative intent anthracycline & taxane, with median disease-free interval of 16 months (range 2-241). 18 pts (38%) received curative intent immune checkpoint inhibitor. Most pts received ADC in the first (n=19, 40%) or second line (n=18, 38%) with Sacituzumab govitecan being the most common (n=38, 79%) ADC, followed by Trastuzumab deruxtecan (n=9, 19%). 7 pts (15%) received a second ADC. ORR at time of best response was 38% (n=18), with 4 pts experiencing complete response (1 patient who received ADC in 1L, 3 in the 2L) & 14 experiencing partial response. 3 pts (6%) experienced stable disease, & 27 pts (56%) experienced progressive disease as best response. Median rwPFS of pts receiving ADC in the first line was 2.3 months, compared to 4.3 months in those receiving non-ADC/chemotherapy (HR 1.34; 95% CI 0.72-2.49, p=0.89). Median rwPFS of pts receiving ADC in the second line was 2.6 months, compared to 2.3 months in those receiving non-ADC/chemotherapy (HR 0.56; 0.28-1.11; p=0.10). Toxicity resulted in dose reductions in 17 pts (35%), dose delays in 14 (29%), & ADC discontinuation in 2 (4%). Conclusion: In this multi-institutional cohort of pts with metastatic MpBC, ADC treatment yielded a 38% ORR, including four complete responses. However, rwPFS was poor overall & similar between ADC & non-ADC therapy. These findings highlight the need to develop new treatment strategies for MpBC, though a subset of pts may experience meaningful response to ADC. Citation Format: S. Jacob, S. Premji, S. Fisch, A. LeVee, S. Marion, D. Schmolze, J. Mortimer, L. Huppert, D. Idossa, A. Nayak, P. Wileyto, A. DeMichele, P. D. Shah. Efficacy of antibody drug conjugates in patients with advanced metaplastic breast cancer: a multi-institutional retrospective cohort study [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 PS1-09-18.

Abstract Introduction: Metaplastic breast cancer (MpBC) represents a rare subtype, constituting <1% of all breast cancer cases. It is pathologically characterized by epithelial and mesenchymal cellular components exhibiting a basal molecular pattern, hormone receptor and HER2-negativity, and high grade. Clinically, MpBC exhibits an aggressive course with early disease progression and poor survival. Antibody-drug conjugates (ADCs) have been shown to penetrate the central nervous system (CNS); however, little is known about the response of ADCs in MpBC, particularly in patients with CNS disease. Here we aimed to describe features of CNS disease in a subset of patients (pts) who received an ADC for MpBC . Methods: We conducted a multi-institutional retrospective observational study of pts with advanced MpBC treated with ADCs at 4 NCI-designated cancer centers (abstract #A-345). This analysis includes a subset of this cohort with CNS metastases, with the aim of examining the incidence, characteristics, and treatment patterns. Clinical outcomes were evaluated for pts with information available, including CNS median progression-free survival (mPFS; defined from initiation of systemic therapy to time of further documented CNS progression or death) and median real world PFS (rwPFS; defined from time of treatment initiation to documented disease progression or death). Results: We identified 48 pts with MpBC who received an ADC. Among them, we identified 15 (31%) who developed CNS metastases. Of these, the majority (n=11, 73%) had triple-negative breast cancer, and 4 (27%) had HER2-positive breast cancer. The median age was 50 years (32-75 years). The median interval from the initial MpBC diagnosis to CNS metastasis was 13 months (0-54 months). Excluding those with de novo CNS disease, the median interval from time of metastatic diagnosis to development of CNS metastasis [mets] was 3 months (0-22 months). 4 (27%) pts had de-novo metastatic disease, of which 2 (50%) presented with CNS disease. 4 (27%) pts had screening CNS imaging prior to their diagnosis of CNS metastatic disease. At the time of CNS disease diagnosis, 9 (60%) pts had oligometastatic intraparenchymal CNS disease (defined as <5 CNS mets), 5 (33%) had diffuse (>5 CNS mets) CNS disease, and 1 (6%) had leptomeningeal and intraparenchymal disease. Most pts 14(93%) with CNS disease were symptomatic at time of diagnosis. One pt underwent resection, 9 (60%) underwent stereotactic radiosurgery (SRS), 6 (40%) underwent whole brain radiation therapy (WBRT), and 1 pt received intrathecal chemotherapy with methotrexate. The median number of lines in the metastatic setting prior to documented CNS disease was 1 (range 0-3). The majority 13 (87%) underwent a change in systemic therapy at time of CNS disease diagnosis, with 60% changing to an ADC at the time of CNS diagnosis or progression. Among pts with progression of CNS disease warranting change in systemic therapy, the median time from first CNS event to further CNS progression was 6.5 months. Median CNS PFS was 3.5 months (range 1 -74 months) and median rwPFS was 4.4 months. For those patients who used ADCs after diagnosis of metastatic CNS diagnosis (12/15), median rwPFS was 4 months. Conclusions: Within this CNS sub-cohort study, we found that 31% of pts with MpBC developed CNS metastasis. The majority of pts had neurological symptoms at diagnosis, but most pts did not undergo routing screening for CNS disease. Given the high rate of CNS mets within a short timeframe from diagnosis with poor outcomes, CNS screening should be considered. The extremely short median CNS PFS and low median rwPFS of this cohort highlight the guarded prognosis associated with MpBC. Given the small sample size of this cohort, larger studies are warranted to validate these findings. Citation Format: S. Premji, S. Jacob, A. LeVee, S. Marion, S. Fisch, L. Huppert, J. Mortimer, D. Schmolze, A. Nayak, A. DeMichele, P. Shah, R. Leon-Ferre, D. Idossa. Central nervous system disease in patients with metaplastic breast cancer receiving antibody drug conjugates: a multi-institutional study [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 PS1-09-07.

Non-muscle-invasive bladder cancer (NMIBC) comprises approximately 75% of new bladder cancer cases and generally carries a favorable prognosis, yet high rates of recurrence and progression necessitate close surveillance with frequent cystoscopies and repeated transurethral resections. Upfront treatment for high-risk disease is typically Bacillus Calmette-Guérin (BCG), although combinations with immune checkpoint inhibitors have reported results. Patients with BCG-unresponsive, intolerant, or refractory disease represent a subset of patients with high risk of progression, with early radical cystectomy being the standard approach for this setting. Global BCG shortages and the substantial impact of cystectomy on quality of life underscore the need for therapeutic alternatives. Over the past decade, investigational trials in immunotherapy have expanded treatment options for BCG-unresponsive NMIBC with CIS, leading to FDA approval of intravesical nadofaragene firadenovec, nogapendekin alfa-inbakicept, and systemic pembrolizumab. This narrative review summarizes developments in intravesical and systemic immunotherapies for NMIBC, highlights ongoing trials, and addresses controversies in trial design, treatment sequencing, comparative efficacy, and safety.

Despite advances in drug and device technology, health care delivery, and research infrastructure, cardiogenic shock (CS) continues to have nearly 50% in‐hospital mortality. In patients with CS, both the initial severity of Society for Cardiovascular Angiography and Intervention CS and its subsequent trajectory predicts the clinical outcomes. Accordingly, delayed initial recognition and failure to escalate or deescalate treatment can significantly affect the outcomes of CS. Traditional assessment methods, with the exception of blood pressure measurement, require a high index of suspicion and frequent reassessment by the clinical team. Electronic medical record‐based detection has been successfully implemented in acute and critical care patients with septic shock and acute kidney injury. In CS, electronic medical record‐based studies have largely focused on using models to predict outcomes in patients with CS, with limited data on electronic medical record‐based tools to assist with either predicting CS or providing real time alerts when escalation or de‐escalation might be indicated. Early detection of CS may be associated with detection of earlier Society for Cardiovascular Angiography and Intervention stages of CS and potentially prevent deterioration to higher stages. In this review, we seek to highlight a blueprint for electronic medical record‐based detection of CS that focuses on reproducibility, convenience, clinical decision support, and research aspects.

ABSTRACT Objectives While maxillary sinus fungal balls (MSFB) can be associated with odontogenic conditions (MSFBO), MSFBO clinical and dental features have not been compared to odontogenic sinusitis (ODS). This multicenter study aimed to compare characteristics of MSFB, MSFBO, and ODS. Methods A multicenter international retrospective cohort study was conducted on adults with MSFBs and ODS who underwent sinus surgery. First in MSFBs, it was determined whether different dental conditions were more likely in FB versus non‐FB sides. Second, clinical features and dental pathologies were compared between MSFBO and ODS. For analyses, dental conditions were considered individually and as two groups: infectious pathologies and dental/oral procedures with indwelling metallic materials. Results After exclusions, there were 203 MSFBs and 163 ODS. Among MSFBs, 141 were MSFBOs. FB sides were associated with sinus protrusion of root canal treatment (RCT) materials ( p = 0.040) and dental implants ( p = 0.040). Compared to MSFBO, ODS patients were younger, more likely to have MS purulence (OR = 40.9, p < 0.010), more likely associated with apical periodontitis (OR = 2.59, p = 0.010) and oroantral fistulas (OR = 6.94, p = 0.020), and less likely associated with extruded RCT materials (OR = 0.01, p = 0.010) and protruded midface screws (OR < 0.01, p = 0.010). Comparing purulent MSFBO and ODS, ODS was more associated with infectious dental pathologies ( p < 0.009). Conclusion Compared to MSFBs, MSFBOs were associated with RCT extrusion and implant protrusion. Compared to MSFBOs, ODS was more likely purulent and associated with infectious dental pathologies. While ODS is often distinct from MSFBO, the two conditions can coexist, and surgeons must determine whether patients have infectious dental pathology requiring treatment with both conditions. Level of Evidence 4.

BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Abstract Background/Introduction Optimal mean arterial pressure (MAP) in patients with acute myocardial infarction related out-of-hospital cardiac arrest (AMI-OHCA) and cardiogenic shock (AMI-CS) remains unclear. Randomized controlled trials (RCTs) comparing MAP targets have been performed in OHCA patients with presumed cardiac cause, but did not provide answers to the important question what MAP target would be optimal for the AMI-OHCA population. To our knowledge, no RCTs comparing MAP targets in AMI-CS patients have been performed. Purpose This comprehensive systematic review and meta-analysis aimed to evaluate the effect of low- and high-MAP levels on short-term mortality in AMI-OHCA and AMI-CS patients. Methods We conducted a systematic search of MEDLINE (OVID), EMBASE (OVID), CINAHL (Ebsco) and Cochrane CENTRAL databases. Eligible studies reported outcomes for AMI-OHCA or AMI-CS patients for at least two groups of different average MAP levels. Both RCTs and observational studies were eligible to ensure comprehensive data collection. Authors were proactively contacted for supplementary AMI data. Random-effects models were used to pool data. Results Of 7,728 screened studies, 57 were assessed for eligibility, and 11 were included in the final analysis (4 RCTs and 7 observational studies), encompassing 3,846 patients. The primary analysis included 1,251 AMI-OHCA patients. In the AMI-OHCA patients, no significant difference in short-term mortality was observed between low- and high-MAP groups in RCT (34.9% vs. 39.4%, RR 0.88, 95%-CI 0.70-1.10), observational-, and combined data. As only one of the 11 included studies reported on separate AMI-CS data, no meta-analyses of solely AMI-CS patients could be performed. Conclusions Our meta-analysis showed no significant difference in short-term mortality between low- and high-MAP levels in AMI-OHCA patients. Only one study in selected AMI-CS patients without OHCA patients was available. This highlights the importance of identifying tailored MAP strategies in both AMI-OHCA and AMI-CS patients.Flow chart of the selection of studies Short term mortality – AMI-OHCA patients

Abstract Background Left ventricular ejection fraction (LVEF) and diastolic dysfunction (DD) are key prognostic factors in patients with ST-segment elevation myocardial infarction (STEMI). AI-enabled ECG (AI-ECG) has been shown to have excellent agreement with transthoracic echocardiography (TTE) assessment and incremental prognostic value to LVEF. Methods We retrospectively analyzed 1,005 adult acute STEMI patients referred for echocardiography (10/2007–01/2025) who had ECGs within seven days before and after the reference echocardiogram. The ECG closest to the TTE date was designated as the pre-STEMI and post-STEMI ECG, respectively. AI-ECG was used to classify diastolic function grades and grades 2 and 3 were considered as DD. Patients were stratified by LVEF (≤50% vs. &gt;50%) at the time of TTE and the association between AI-ECG-determined DD and 10-year mortality was assessed using Cox regression and Kaplan-Meier curves. Results Among 1,005 patients (mean age 66.4 ± 13.4 years, 29.9% females), AI-ECG-determined DD prior to STEMI was present in 47.9% of patients with LVEF ≤50% and 30.3% of those with preserved LVEF (&gt;50%). DD status remained unchanged post-STEMI in 79.3% of cases, while 10.2% showed worsening diastolic function. Regardless of LVEF, AI-ECG-determined DD prior to STEMI was associated with higher mortality risk (LVEF ≤50%: HR 3.03, 95% CI 2.16–4.24, p &lt; 0.001; LVEF &gt;50%: HR 2.32, 95% CI 1.58–3.41, p &lt; 0.001). Post STEMI AI-ECG-determined DD remained a significant predictor of mortality (LVEF ≤50%: HR 2.54, 95% CI 1.82–3.53, p &lt; 0.001; LVEF &gt;50%: HR 2.43, 95% CI 1.66–3.58, p &lt; 0.001). Echocardiographically determined DD also correlated with higher mortality (LVEF ≤50%: HR 4.91, 95% CI 2.95–8.15, p &lt; 0.001; LVEF &gt;50%: HR 2.72, 95% CI 1.68–4.41, p &lt; 0.001). In patients with LVEF ≤50%, AI-ECG-determined DD remained associated with higher mortality even after adjusting for echocardiographically determined DD (pre-STEMI: HR 1.85, 95% CI 1.23–2.80, p &lt; 0.001; post-STEMI: HR 1.90, 95% CI 1.23–2.91, p &lt; 0.001). Conclusion AI-ECG-determined DD is a significant predictor of mortality in STEMI, independent of LVEF. The presence of normal filling pressure may indicate a better clinical outcome in patients with reduced LVEF patients. These findings underscore the clinical utility of AI-ECG in refining risk stratification beyond conventional LVEF assessment.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.