Roy Elias

Due to increasing evidence that socioeconomic deprivation influences cancer outcomes through biological effects and care disparities, this single-institution retrospective study estimated associations between neighborhood-level socioeconomic deprivation, measured by the area deprivation index (ADI), and clinical outcomes among patients with metastatic solid tumors treated with immune checkpoint inhibitors (ICIs). Eligible patients included adults with metastatic solid tumors who received ICI between 2013 and 2024 and had a response assessment. Exclusions included adjuvant ICI receipt and missing ADI. Survival outcomes were estimated using the Kaplan-Meier method, and Cox regression models were used to measure associations between ADI and survival in the full cohort and stratified by tumor type. In a cohort of 691 patients with multiple solid tumor types and a median follow-up of 56.1 months, there was a trend toward shorter overall survival (OS) with increasing ADI quartile (HR=1.60 for the most vs. least deprived quartile), although not statistically significant ( P =0.143). There was no significant association between ADI and progression-free survival ( P =0.215). Exploratory analyses of tumor type subsets also revealed no statistically significant association between ADI and OS. In conclusion, there was no significant association between survival and ADI in this cohort. Further study in larger and more diverse cohorts is needed to elucidate the relationship between neighborhood-level socioeconomic deprivation and survival among patients with metastatic solid tumors receiving ICI.

PURPOSE: Enfortumab vedotin and pembrolizumab (EVP) is the standard first-line treatment for locally advanced and metastatic urothelial cancer (la/mUC) although response biomarkers remain an unmet need. Tumor-informed circulating tumor DNA (ctDNA) has proven to be useful as a marker of response in a variety of cancers. We sought to explore whether ctDNA dynamics is associated with survival outcomes. METHODS: This retrospective study included patients with la/mUC receiving first-line EVP, who had plasma ctDNA collected using the Signatera assay within 3 months after treatment initiation. Associations between ctDNA clearance and overall survival (OS) and progression-free survival (PFS) were assessed using multivariable time-dependent Cox proportional hazard (CPH) models and landmark analyses at 1, 2, and 3 months after EVP initiation. Longitudinal ctDNA trends were examined in a subpopulation with baseline ctDNA values collected. RESULTS: Fifty-eight patients were included. In multivariable time-dependent CPH models, ctDNA clearance was associated with both OS (hazard ratio [HR], 0.04 [95% CI, 0.01 to 0.24], P < .001) and PFS (HR, 0.09 [95% CI, 0.02 to 0.32], P < .001). In landmark analyses, ctDNA clearance was associated with longer OS and PFS at 2 months (log-rank test P = .003, P < .001, respectively). Among patients with baseline ctDNA (n = 42), 69% achieved ctDNA clearance after EVP initiation, whereas just 14% (n = 6) never had a decrease in ctDNA. The median time to clearance of ctDNA was 1.41 months (IQR, 0.85-1.94). CONCLUSION: While primarily hypothesis-generating, this study suggests that patients with la/mUC treated with first-line EVP frequently and rapidly clear ctDNA. Clearance of ctDNA in this population is associated with longer survival and merits further study.

Renal well-differentiated neuroendocrine tumors (RenNETs) are rare primary renal neoplasms with enigmatic histogenesis. To define the molecular features of RenNETs and clarify their relationship to neuroendocrine tumors (NETs) from other sites, we performed whole-exome DNA sequencing and transcriptomic profiling on six RenNETs. In one case, adjacent non-neuroendocrine cystic epithelium and a regional lymph node metastasis were independently analyzed. RenNETs demonstrated a low-to-intermediate tumor mutational burden and recurrent copy number alterations, including losses involving chromosomes 3, 11, and 18 and gains involving chromosomes 1, 2, 8, and 14, partially overlapping those reported in gastroenteropancreatic NETs, in the absence of alterations in canonical NET-associated driver genes. RNA sequencing revealed marked upregulation of genes involved in neuroendocrine differentiation, peptide processing, and pancreatic beta cell function, accompanied by loss of renal lineage markers, indicating a neuroendocrine transcriptional program distinct from other primary renal neoplasms. RenNETs showed heterogeneous activation of hormone related transcriptional programs, rather than conforming to a discrete EC-cell or L-cell signature. Immunohistochemistry confirmed strong membranous expression of somatostatin receptor 2A (SSTR2A) in all cases, supporting established imaging and therapeutic paradigms used for NETs. Notably, two RenNETs were associated with adjacent CDX2-positive epithelial-lined cysts with intestinal differentiation. In one case, a shared somatic mutation was identified across the epithelial cyst, the adjacent RenNET, and a nodal metastasis, providing genetic evidence of a common clonal origin and implicating gastrointestinal-type epithelium as a potential precursor lesion in a subset of cases. Features supporting teratomatous origin, such as chromosome 12p gains or other germ cell tumor elements, were not identified. Together, these findings demonstrate that RenNETs exhibit convergent transcriptomic and phenotypic neuroendocrine programs, along with partial copy number overlap, with well-differentiated gastroenteropancreatic NETs, and support a model in which RenNETs may arise from developmentally displaced or aberrantly differentiated epithelial precursors with gastrointestinal-type differentiation, although this hypothesis requires validation in larger cohorts.

Clear cell renal cell carcinoma (ccRCC) is characterized by a branching genomic trajectory in which early biallelic VHL inactivation splits into PBRM1- and BAP1-mutant lineages. However, driver mutations alone do not account for the molecular and phenotypic heterogeneity. To dissect this heterogeneity, we developed a non-negative matrix factorization (NMF)-based gene expression analytical framework for identifying recurrent transcriptional programs across factorization dimensionalities and across datasets. We applied it to three curated datasets (IMmotion151, n = 823; JAVELIN Renal 101, n = 726; TCGA, n = 614) to define 17 consensus transcriptomic programs (CTPs). Mapping CTPs onto single-cell RNAseq (scRNAseq) of human ccRCC tumors and patient-derived tumorgraft models linked these programs to their cellular sources, distinguishing RCC-intrinsic, tumor-cell-extrinsic, and mixed programs. RCC-intrinsic CTPs associated with canonical drivers, including VHL (R1), PBRM1 (R2), BAP1 (R4), PTEN/TSC1 (R3), TFE3/TFEB fusions (R5), NF2 (R6), and CDKN2A/TP53 (MP-Prolif). Additional CTPs captured tumor microenvironment (TME) composition (TME-Tcell, TME-Myelo, TME-Endo, TME-Stroma) and biological processes active across multiple cellular compartments, including proliferation, Y-chromosome-linked expression in male tumors, ciliary biology, and translation. Trajectory inference methods revealed PBRM1-like and BAP1-like branches that converged on a shared aggressive late transcriptomic stage (TS) associated with higher nuclear grade, additional driver alterations, myeloid/stromal infiltration, and poor clinical outcomes. Spatial transcriptomics (and multiregional sequencing) of paired conventional ccRCC and sarcomatoid regions linked TS advancement with morphological progression and clonal evolution. After adjusting for stage, grade, and BAP1/PBRM1 status, TS remained independently prognostic. Furthermore, our data suggest that immune checkpoint inhibitor combinations are particularly beneficial for MP-Prolif and not R1 utilizing specimens. In summary, we present an atlas of recurring transcriptomic programs in RCC and an ontological framework bridging genotype, tumor-cell-intrinsic gene expression, and microenvironment remodeling, with implications for risk stratification and treatment selection in ccRCC.

WES QC 66 Patients (B = 34, W = 32) 123 Samples (57 T/N, 9T) RNAseq QC Avg.

Supplementary Tables from Clear-Cell Renal Cell Carcinoma Molecular Subtypes Differ by African and European Genetic Similarity

Supplementary Tables from Clear-Cell Renal Cell Carcinoma Molecular Subtypes Differ by African and European Genetic Similarity

WES QC 66 Patients (B = 34, W = 32) 123 Samples (57 T/N, 9T) RNAseq QC Avg.

Self-reported Black (B) individuals remain underrepresented in molecular studies of clear-cell renal cell carcinoma (ccRCC) relative to White (W) individuals. We performed whole-exome and transcriptome sequencing on paired tumor and normal samples from 59 matched B and W patients undergoing nephrectomy for localized ccRCC, comparing molecular differences by estimated genetic similarity to African (AFR) and European (EUR) 1000 Genomes groups. We validated our findings with a propensity-matched subset of The Cancer Genome Atlas, yielding a final cohort of 254 patients (79 AFR and 175 EUR) with similar baseline clinical variables. Significant differences emerged in VHL mutation frequency (AFR: 23.4%, EUR: 57.5%; FDR = 0.0029) and chromosome 3p deletions (AFR: 59.2%, EUR: 82.6%; FDR = 0.086). Transcriptomic analyses identified 34 genes associated with genetic similarity, and gene set enrichment revealed inflammatory (IFN-γ/IFN-α, allograft rejection), proliferative (E2F targets, G2–M checkpoint), and metabolic (bile acid, fatty acid, glycolysis, MTORC1, peroxisome) pathway enrichment in EUR. We also observed differences in ccRCC molecular subtype distribution, with “Proliferative” and “Angio/Stromal” subtypes being more common in AFR (P = 0.018). Importantly, differential subtype membership explained most group-level differences. These results link EUR and AFR genetic similarity to distinct ccRCC molecular subtypes, underscoring the importance of molecular classifiers in disease stratification and the need to include diverse populations in molecular studies to improve our understanding and treatment of ccRCC.Significance:Our study shows that AFR genetic similarity correlates with distinct ccRCC molecular subtypes. Further research is needed to disentangle environmental and genetic influences. Identifying these differences underscores the critical importance of including racially and ethnically diverse populations in cancer research to ensure more equitable and sustainable outcomes worldwide for all patients.

AFR and EUR groups are associated with a distinct tumor microenvironment composition. A, Heatmap of xCell results performed on the pooled analytic cohort (n = 78 AFR and n = 175 EUR). Values are row-scaled xCell enrichment scores for lymphoid, myeloid, and stromal cell types (n = 38 cell types). B, Box plots depict xCell enrichment scores for differentially enriched cell types. Box plot borders depict the median, upper quartile, and lower quartile. P values were determined by the Kruskal–Wallis test with multiple hypothesis correction. Statistical significance is as follows: *, P <0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001. aDC, activated dendritic cell; cDC, conventional dendritic cell; DC, dendritic cell; ES, enrichment score; iDC, immature dendritic cell; NKT, NK T cell; pDC, plasmacytoid dendritic cell; Tcm, central memory; Tem, effector memory; Tgd, gamma–delta T cell; Treg, regulatory T cell.