Abstract 3357: Identification of outcome-associated tumor perivascular features in renal cell carcinoma

Abstract Background: One third of patients with clear cell renal cell carcinoma (CCRCC) eventually develop metastasis. The introduction of anti-angiogenic therapy and immunotherapy in metastatic CCRCC (mCCRCC) has significantly improved outcomes for many patients. Among vascular endothelial growth factor tyrosine kinase inhibitors (TKIs), sunitinib is the most commonly used first-line drug. However, treatment is administered without specific patient selection criteria and relapse occurs in approximately 40% of cases. Given the lack of clinical stratification of these patients, predictive and prognostic biomarkers are needed to improve their clinical outcome. Methods: This work explored the clinical impact of perivascular (PV) characteristics in RCC by performing multiplex-based tissue profiling in a population-based cohort (N = 70) and a sunitinib-treated mCCRCC cohort (N = 61). Vessel features and tumor PV cell subsets were characterized based on multimarker (CD34, PDGFRα, PDGFRβ, αSMA and pSMAD2) expression combinations. In both cohorts, patients were categorized using a tertile-based dichotomization of the variables, with the upper tertile compared against the combined lower and middle tertiles to explore associations. Results: Two PV cell subsets, PER4 (PDGFRB+/ASMA+/PDGFRA-/pSMASD2-) and PER5 (PDGFRB+/ASMA-/PDGFRA-/pSMASD2-), showed statistically significant survival associations using multiple endpoints in both cohorts. In the sunitinib-treated cohort (OS from treatment), PER4 (log-rank p < 0.001) and PER5 (log-rank p = 0.002) were associated with poor survival. Similarly, in the population-based cohort (OS), PER4 (log-rank p = 0.043) and PER5 (log-rank p = 0.001) were also linked to worse survival. Univariate and multivariate analyses confirmed robust survival associations for the identified PV cell subsets PER4 and PER5. Conclusions: Collectively, this study identified candidate prognostic or TKI predictive response markers in RCC. These data provided in-depth characterization of PV cell subsets associated with clinical outcome in RCC. These data could be further explored to find clinically useful patient selection to improve the accuracy of anti-angiogenic therapy administration in RCC. Citation Format: Alfonso Martín-Bernabé, Víctor Sánchez-Miñarro, Philipp Schmucker, Magnus Lindskog, Ulrika Harmenberg, Martin Johansson, Lars Egevad, Arne Östman. Identification of outcome-associated tumor perivascular features in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3357.