Transcriptomic insights into the prognostic role of mean platelet volume and ferroptosis in immunotherapy-treated metastatic clear cell renal cell carcinoma.

e16506 Background: Immune checkpoint inhibitor (ICI)-based treatments have revolutionized the management of clear cell renal cell carcinoma (ccRCC), but many patients (pts) derive limited benefit, highlighting the urgent need for reliable biomarkers. Ferroptosis, a form of programmed cell death driven by iron-dependent phospholipid peroxidation, involves the generation of reactive oxygen species, with platelets playing critical role in this process. While high platelet count predicts poor cancer outcomes, the role of mean platelet volume (MPV) is understudied. This study aims to explore the prognostic significance of MPV and its transcriptomic associations in metastatic ccRCC. Methods: This study included 77 pts with metastatic ccRCC treated with ICI-based therapy at the Ohio State University, with Bulk RNA sequencing available for 74 pts. Clinical data were obtained from electronic medical records. Survival and hazard ratios (HRs) were estimated using Kaplan-Meier and Cox proportional hazards models. Transcriptomic differences between pts with high ( > median) and low (≤ median) MPV were assessed using GSEA and KEGG pathway analysis. Results: The median age of the cohort was 62.2 years (interquartile range [IQR]: 56.1–66.4), with 22 (28.6%) female pts. ICI-based therapy was administered as first-line treatment in 31 (40.3%) pts, second-line in 27 (35.1%), and third-line or beyond in 19 (24.6%). The median MPV at treatment initiation was 8.8 fL (IQR: 7.7–9.8). Patients with high MPV had a progression-free survival (PFS) of 16.6 months compared to 7.1 months for those with low MPV (HR: 0.59, 95% CI: 0.355–0.972, p = 0.038). The median overall survival (OS) was 51.5 months (95% CI: not estimable) for pts with high MPV compared to 21.6 months (95% CI: 12.5–30.7) for low MPV (HR: 0.47, 95% CI: 0.27–0.83, p = 0.009). In multivariate analysis, MPV remained a significant prognostic factor for OS, irrespective of therapy line and age. In the KEGG pathway analysis, ferroptosis and NF-kappa B signaling pathways were significantly enriched in pts with high MPV, with respective adjusted p value (Padj) 0.040 and 0.041. Subsequent analysis using GSEA revealed that pts with high MPV demonstrated significant enrichment in the platelet activation pathway (normalized enrichment score [NES] = 2.2, Padj < 0.001), Class I MHC-mediated antigen presentation (NES = 2.2, Padj < 0.001), and ubiquitination and proteasome degradation pathways (NES = 2.1, Padj < 0.001). Conclusions: High MPV was associated with improved PFS and OS in pts receiving ICI-based treatments for metastatic ccRCC. High MPV was correlated with increased ferroptosis, platelet activity, and antigen presentation. These findings suggested that MPV holds potential as a prognostic biomarker for immunotherapy outcomes, warranting further investigation into its underlying mechanism and clinical utility.