Abstract Purpose: Nivolumab plus ipilimumab is a standard first-line therapy for unresectable malignant pleural mesothelioma (MPM), yet biomarkers predicting immune checkpoint inhibitor (ICI) efficacy remain undefined. We aimed to identify genomic and tumor immune microenvironmental features associated with ICI response in MPM. Experimental Design: We analyzed two independent MPM cohorts. The discovery cohort included patients at the National Cancer Center Hospital (2012–2022) with frozen tumor tissues available for whole-genome sequencing (WGS) and RNA sequencing. Genomic alterations, transcriptomic profiles, immune cell composition, and T-cell receptor repertoire were analyzed, and key findings were validated in a nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) cohort. Results: The WGS cohort comprised 52 patients. Among ICI-treated patients, overall response rates were 30% in the WGS cohort and 29.4% in the C-CAT cohort. Genomic analyses identified frequent alterations in BAP1 and NF2, across both cohorts. ICI responders showed higher T-cell receptor diversity, increased CD8⁺ T-cell infiltration, and enrichment of M1 macrophages compared with non-responders. MTAP loss was associated with higher CD8⁺ T-cell infiltration and T-cell receptor diversity, and was linked to a higher ICI response rate in the C-CAT cohort. In contrast, BAP1 and NF2 alterations showed no consistent association with immune features or ICI efficacy. Conclusions: An immune-active tumor microenvironment characterized by high T-cell receptor diversity, CD8⁺ T-cell infiltration, and M1 macrophage enrichment was associated with favorable ICI responses in MPM. MTAP loss was linked to immune-related features and a higher ICI response, supporting further investigation of MTAP loss as a candidate biomarker.
Abstract Purpose: Bladder cancer (BCa), particularly NMIBC, poses a substantial clinical burden due to its high recurrence rates and the need for lifelong surveillance. While large-scale studies have identified systemic metabolic risk signatures, a critical gap remains in understanding the dynamic, pre-diagnostic evolution of the metabolome and how these systemic alterations relate to early tumor metabolic reprogramming. To address this gap, we used a large prospective cohort with multi-omics data to characterize pre-diagnostic metabolic changes and their links to early tumor metabolic alterations in BCa. Experimental Design: Baseline plasma metabolomics from 48,241 controls and 2,158 BCa cases in the UK Biobank were analyzed to characterize metabolic alterations preceding diagnosis. Targeted metabolomics and transcriptomics were performed in an independent clinical cohort of 107 NMIBC patients and 56 controls. An eight-metabolite plasma classification model was developed and internally validated. Multi-omics integration and functional experiments were conducted to investigate the role of butyrate. Results: 64 circulating metabolites were associated with future BCa risk, predominantly involving lipid and lipoprotein metabolism. Targeted metabolomics identified 24 differential metabolites, including elevated butyric acid and maleic acid in NMIBC. An eight-metabolite plasma panel achieved an area under the receiver operating characteristic curve (AUC) of 0.98 in the held-out test and 0.92 in the validation set, with cross-biofluid validation in urine yielding an AUC of 0.75. Mechanistically, butyrate remodeled chromatin accessibility and activated AP-1 associated transcriptional programs linked to urothelial phenotypic plasticity. Conclusions: These findings define lipid dysregulation as a hallmark of the pre-diagnostic metabolic landscape of BCa.
Abstract Purpose: Dosage modifications, including dose interruptions and reductions, are commonly implemented to manage adverse reactions observed with oncology drugs. However, their impact on efficacy is not well understood. Here, we explored the impact of dosage modifications on progression free survival (PFS) and overall survival (OS) for four US FDA-approved tyrosine kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Methods: We collected patient-level data from clinical trials supporting the original FDA approvals of afatinib, dacomitinib, mobocertinib, and osimertinib. We identified the daily dose received (DDR; a measure of the dosage received by a patient each day), dose interruptions and reductions over the treatment period. In this exploratory analysis, we used a time-dependent Cox proportional hazards model to assess the impact of DDR on PFS and landmark time-fixed Cox models at 30, 60, and 90 days from treatment initiation to assess the impact of early dose interruptions and reductions on PFS and OS.Results: While the impact of dose interruptions and reductions on the risk of death varied among the studied drugs, dose interruptions, such as interruptions for four or more consecutive days, were more often associated with a higher risk of progression or death than dose reductions. Conclusion: For the evaluated drugs as monotherapy in NSCLC with EGFR mutations, our analysis suggests that dose reductions might have a lower impact on efficacy than missing or interrupting treatment. Further studies are needed to evaluate other EGFR treatments, drug classes, and cancer types.
Abstract Purpose: Currently, PSMA- and CD70-targeted imaging are the main focuses in the molecular imaging of RCC, but these modalities have not been compared in clinical studies. The primary outcome of this study was to compare the sensitivity of two imaging modalities in diagnosing RCC lesions and explore their diagnostic thresholds. Secondary outcomes included differences in detection rates, variations in tumor uptake, target-to-background ratios, and their practical impact on patient treatment decisions. Experimental Design: Retrospectively, data were collected from patients with pathologically confirmed RCC who underwent PSMA-targeted ([68Ga]Ga-PSMA-11) or CD70-targeted ([68Ga]Ga-NOTA-RCCB6) PET/CT. Tumor uptake, target-to-background ratio, and lesion detection rates were compared. Another independent prospective study enrolled patients with suspected RCC who underwent both imaging modalities, comparing the sensitivity of the two methods in detecting RCC lesions and investigating diagnostic thresholds. Results: The retrospective cohort included 128 patients, while the prospective study finally enrolled 36 patients. [68Ga]Ga-NOTA-RCCB6 exhibited higher sensitivity (88.7% vs. 76.1%; P < 0.001) for ccRCC, particularly for pulmonary and hepatic metastases, and exhibited higher SUVmax and TBR at the primary lesion and in pulmonary metastases. The detection rates of [68Ga]Ga-NOTA-RCCB6 and [⁶⁸Ga]Ga-PSMA-11 were both limited for nccRCC (68.8% and 63.0%, respectively). [68Ga]Ga-NOTA-RCCB6 improved the extent of lesion detection in 35% (9/26) of patients and affected treatment decisions in 15% (4/26) of patients. Conclusions: [68Ga]Ga-NOTA-RCCB6 PET/CT significantly enhanced diagnostic sensitivity for pulmonary and hepatic metastases, facilitating precise staging and treatment decision-making. Therefore, it represents a valuable complement to existing imaging modalities for ccRCC.
