UCSF Helen Diller Family Comprehensive Cancer Center

To evaluate the effects of ambient air pollution on rheumatoid arthritis (RA) incidence in a racially and ethnically diverse population. This analysis included 42,152 California Multiethnic Cohort participants, aged ≥65 years (>70% African American and Latino adults) who were enrolled in the Fee For Service component of Medicare (2001-2018). We employed multivariable Cox proportional hazards regression to examine the associations of time-varying air pollutants based on spatiotemporal models with RA incidence (n=2,027) after adjusting for demographics, neighborhood socioeconomic status, smoking, work, and other exposures. RA incidence increased with exposure to fine particulate matter (PM) with diameter ≤2.5 μm (PM2.5) (hazard ratio [HR] per 2 μg/m3=1.20 [95% confidence interval (CI) 1.16-1.23]) and nitrogen dioxide (NO2) (HR per 10 μg/m3=1.44 [95% CI 1.35-1.52]). Air pollutant levels and risk associations were higher in African American and Latino than in Japanese American and White adults (Pheterogeneity < 0.05). The RA-PM2.5 association was higher in men (HR 1.23 [95% CI 1.15-1.32]) than in women (HR 1.17 [95% CI 1.12-1.21]; Pheterogeneity=0.06). RA associations with PM2.5 (and NO2) did not differ by demographics, smoking, or other lifestyle factors, but the HR associated with PM2.5 was higher among those with high-risk work (longest occupation in labor/craftsman work and exposed to ≥10 years in one or more of 13 industries; HR 1.29 [95% CI 1.18-1.41]) than those without high-risk work exposures (HR 1.16 [95% CI 1.12-1.21]; Pheterogeneity=0.04). Exposure to PM and gaseous pollution associates with increased RA incidence after age 65 years, particularly among African American and Latino adults. Further characterization of air pollution's contribution to racial and ethnic disparities in RA risk is warranted.

Liver cancer is a leading cause of cancer-related death due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult-to-treat subset of patients. Given MYC's ability to reprogram cancer metabolism and the liver's role in coordinating systemic metabolism, we hypothesized that MYC induces metabolic dependencies that could be targeted to attenuate tumor growth. We discovered that MYC-driven liver cancers catabolize alanine in a GPT2-dependent manner. GPT2 is the predominant alanine-catabolizing enzyme expressed in MYC-driven liver tumors and genetic ablation of GPT2 limited liver tumorigenesis. In vivo isotope tracing identified alanine as a substrate for a repertoire of pathways including the tricarboxylic acid cycle and biosynthesis. Finally, treating a MYC-driven liver tumor model with L-cycloserine diminished the frequency of mouse tumor formation and attenuated the growth of established human liver tumors. Thus, we identify a targetable metabolic dependency that MYC-driven liver tumors usurp to ensure their survival.

Immune checkpoint inhibition (ICI) and anti-angiogenic therapies are active in hepatocellular carcinoma (HCC), although patients with impaired hepatic function have worse outcomes. We conducted an open-label phase II clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with nivolumab, in patients with advanced HCC and varying liver function. In a Part 1 safety lead-in, we investigated the maximum-tolerated dose (MTD) of the combination in patients with Child-Pugh A or B7. In Part 2, we enrolled patients with Child-Pugh B7-9 HCC with the primary endpoint of grade ≥3 treatment-related adverse event (TRAE) incidence. Exploratory endpoints included immunological biomarkers. Overall, 25 patients were consented and 16 eligible patients enrolled. In Part 1, dose-limiting toxicity occurred in one of six patients in Dose Level -1, and two of five patients in Dose Level 1; Dose Level -1 was determined to be the MTD. In total, 69% of patients experienced a grade ≥3 TRAE, with similar distribution for patients with Child-Pugh A and B (70%, 95% CI: 0.35-0.93 vs. 66.7%, 95% CI: 0.22-0.96). The objective response rate was 6% and median overall survival was 12.99 months (Child-Pugh A: 15.26 and Child-Pugh B: 10.41). We found that patients with Child-Pugh B liver disease harbored more circulating suppressive CD14+ monocytes at baseline compared with those with Child-Pugh A disease. Although combination sorafenib and nivolumab demonstrated acceptable safety at the MTD in both Child-Pugh subgroups, the objective response rate was below the prespecified threshold to be declared worthy of further exploration. A distinct immune cell profile in patients with Child-Pugh B disease might define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need. This study addresses the crucial need for effective therapies for patients with advanced HCC and compromised liver function, a population historically excluded from many clinical trials. The findings suggest that, although the combination of sorafenib and nivolumab demonstrated acceptable safety across different liver function subgroups, there was a low response rate overall. Importantly, the discovery of distinct immune profiles, particularly an increase in suppressive immune cells in patients with worse liver function, provides insights into potential mechanisms of resistance to immunotherapy. These results are crucial for understanding how we can improve the treatment of advanced HCC, especially in patients with impaired liver function. NCT03439891.

818 Background: The current treatment landscape of metastatic urothelial cancer has recently expanded beyond platinum-based chemotherapy to include antibody-drug conjugates such as enfortumab vedotin and immune checkpoint inhibitors such as pembrolizumab. Nevertheless, treatment resistance and disease progression remain major challenges. Here, we apply single-cell spatial transcriptomics to characterize the locally advanced and metastatic urothelial carcinoma microenvironment and identify immune neighborhoods predictive of response to enfortumab vedotin ± pembrolizumab. Methods: Thirty-one formalin-fixed paraffin embedded (FFPE) bladder and metastatic site samples were obtained from ten patients with metastatic urothelial cancer and analyzed using the 10X Genomics Xenium In Situ Single-Cell Spatial Transcriptomics platform. The cohort included both primary bladder tumors and metastatic sites, totaling 27 tumor specimens and 4 matched benign samples. Patients received either singe-agent enfortumab vedotin (n = 9) or combination enfortumab vedotin plus pembrolizumab (n = 1). Three patients achieved a complete clinical response and contributed only pre-treatment samples. Five patients experienced disease progression and contributed both pre- and post-treatment samples. Two additional patients who progressed provided only two post-treatment samples. Data processing and downstream analysis were performed using Seurat v5.0. Results: In total, 419,644 single cells from ten patients passed quality control. In the pretreatment setting, CD4+ FOXP3+ regulatory T cells and CD8+ T cells were detected in significantly higher proportions among immune cells from patients who achieved a complete clinical response compared to nonresponders (p &lt; 0.05). Spatial analysis revealed a distinct immune-enriched niche that was consistently present in responders (p &lt; 0.05). This niche was predominantly composed of CD4+ T cells, CD4+ FOXP3+ regulatory T cells, CD8+ T cells, macrophages and dendritic cells. Ligand-receptor analysis demonstrated that this niche was highly enriched for antigen-presenting, costimulatory, and chemokine signaling pathways, indicative of active immune engagement. Cell-cell communication analysis further showed that CD8+ T cells served as the dominant signal senders, whereas dendritic cells and macrophages acted as the primary signal receivers, together defining a myeloid-T cell interactive microenvironment associated with therapeutic response. Conclusions: Spatial single cell-profiling revealed that patients responding to enfortumab vedotin ± pembrolizumab possess a pre-existing immune activated niche enriched in antigen presentation and T-cell co-stimulation.

87 Background: Treatment-emergent neuroendocrine prostate cancer (tNEPC) arises as a phenotype of metastatic castration-resistant prostate cancer (mCRPC) under therapeutic pressure. Despite its poor prognosis, no consensus diagnostic criteria exist for tNEPC. Its clinical and molecular features remain unclear due to the rarity of disease. This study assessed clinical characteristics, biomarkers and outcomes of tNEPC as compared to adenocarcinoma (ACPC) in the mCRPC setting. Methods: This was a retrospective study of adult patients with tNEPC and a matched ACPC cohort (up to 1:2 ratio based on the biopsy date) diagnosed with mCRPC from 01/01/2013 to 12 months before data collection (04/15/2024-11/30/2024) at two US academic institutions. Biopsies obtained after mCRPC diagnosis (index biopsy) were reviewed by two central pathologists to confirm histological diagnosis, using pre-specified standardized definition and pathology criteria. Patients’ characteristics, immunohistochemistry (IHC) markers, treatments and outcomes were compared between tNEPC and ACPC. Results: This study included 79 patients (28 site-defined tNEPC and 51 matched ACPC). The majority were &gt;65 years (mean age: 73 vs 72 years) and white (84% vs 83%), with comparable baseline clinical characteristics between groups. Median follow-up was 13.3 months (tNEPC 6.3; ACPC 15.6). The central pathologists confirmed site diagnoses in 76 patients (κ agreement= 0.91), leaving 71 matched patients (25 tNEPC [24 small cell carcinoma]; 46 ACPC) in the final analysis. All biopsies were metastatic and most came from the liver (tNEPC 44.0% vs ACPC 35.2%). For IHC markers, tNEPC patients had higher positivity of synaptophysin (92% vs 35%) and chromogranin (79% vs 33%), while NKX3.1 positivity was higher in ACPC (24% vs 97%). The most common first lines of therapy (1L) after index were platinum-based chemotherapy (50%) for tNEPC, and androgen receptor pathway inhibitors (53%) for ACPC, but 20% of tNEPC and 22% of ACPC had no record of mCRPC-specific treatments constituting a 1L. While PSA response (≥50% decline) in the post-index period was similar between tNEPC and ACPC (41% vs 42%), tNEPC patients had significantly worse overall survival (OS) after index than ACPC (median OS: 6.3 vs 14.7 months; HR=1.99, 95% CI 1.14–3.42). In tNEPC patients, NKX3.1 positivity appeared associated with better OS (HR=0.29; 95% CI: 0.1-0.9). Conclusions: tNEPC shows distinct histological and IHC profiles, treatment patterns, and worse OS compared with ACPC. These findings highlight important unmet medical need in tNEPC. While the high concordance between central review and site pathologists’ review could be due to expertise in genitourinary/prostate pathology at the academic institutions, our results suggest standardized histopathologic criteria for tNEPC, along with IHC markers, help improve disease classification and diagnostic accuracy in clinical practice.

685 Background: EV plus P has become the standard-of-care first-line therapy for most pts with advanced UC in the United States, based on results of the EV-302 study. However, primary progressive disease was noted in 8.7% of pts and median PFS was 12.5 months (mos) in the EV plus P treated pts on EV-302. Pts who fail to respond to EV plus P therapy or quickly lose response have a poor prognosis, highlighting the need for early identification of this pt cohort. Methods: This is a retrospective analysis of advanced UC pts, who initiated EV plus P at 5 academic institutions from 8/13/2018 to 7/21/2025. All pts had somatic next generation sequencing of their tumor tissue performed using a commercially available assay. Pts also needed to have at least 1 whole body scan to assess for treatment response, which was interpreted using RECIST criteria by the treating physician. Pts who had primary progressive disease or lost response to EV plus P within 6 mos of starting therapy were selected for this analysis. Extracted data included demographic, clinical, treatment, and genomic variables. Data was analyzed using descriptive statistics and Kaplan-Meier estimation. Results: A total of 29 were included, with 69% being male, 79.0% identifying as Caucasian, and a median age of 67 years [range, 27 to 92]. 76% had a primary bladder tumor, 20.6% had a primary upper tract tumor, and 3.4% had primary urethral tumor. At EV plus P start,14% had liver metastasis and 7.8% had peritoneal metastasis. Median duration of P therapy was 3.0 mos [range, 1.0 to 33.0], while median duration of EV therapy was 2.4 mos [range, 0.3 to 5.1]. Median progression free survival (mPFS) was 3.4 mos [IQR, 2.1 to 7.8], while median overall survival (mOS) was 12.0 mos [IQR, 8.3 to 24.0]. Median time to next therapy from EV plus P start, available in 25 pts, was 5.4 mos [range, 2.5 to 24.2]. Median tumor mutational burden (TMB) was 8 m/MB [range, 1 to 71] (available for 25/29 pts). Microsatellite instability (MSI) high status was 3.4% (available for 29/29 pts). HER2 immunohistochemistry (IHC) expression of 1+ or higher was noted in 86% tumor samples (available for 14/29 pts). HER2 positivity by fluorescence in situ hybridization (FISH) was positive in 21% of samples (available for 17/29 pts). Selected genomic alterations for all pts are listed in Table 1. Conclusions: This small retrospective dataset demonstrated a poor mPFS and mOS in pts with advanced UC who have primary progressive disease or loss of response within 6 mos to first-line EV plus P therapy. Low TMB/MSI-high status as well as frequent TERT variant promoter and FGFR2/3 alterations were noted. Further investigation into the genomic landscape of these tumors is needed. Selected genomic alterations of pts who fail EV plus P therapy. Genomic mutation % of pts FGFR 2/3 41 MTAP 6.7 TERT variant promoter 62 ERBB2 17 CDKN2A/2B 11