Sample Site Impacts RNA Biomarkers for Renal Cell Carcinoma

• Published in: European urology 2025-01, Vol.87 (1), p.79-83
• Main Authors: Eismann, Lennert, Xie, Amy X., Tang, Cerise, Knezevic, Andrea, Ostrovnaya, Irina, Kuo, Fengshen, Ari Hakimi, A., Reznik, Ed, Kotecha, Ritesh R.
• Format: Article
• Language: English
• Subjects: Biomarkers; Biomarkers, Tumor - genetics; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - mortality; Carcinoma, Renal Cell - pathology; Female; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Kidney Neoplasms - pathology; Male; Progression-Free Survival; Renal cell carcinoma; RNA, Neoplasm - analysis; RNA, Neoplasm - genetics; Transcriptomics
• ISSN: 0302-2838; 1873-7560; 1873-7560
• DOI: 10.1016/j.eururo.2024.09.004

The clinical relevance of gene expression profiles and their association with treatment outcomes for patients with kidney cancer are significantly impacted by tumor site. Consideration of tissue site as a variable is needed during RNA biomarker development for renal cell carcinoma. Immunotherapy (ICIs) remains a mainstay for treatment of advanced clear-cell renal cell carcinoma (ccRCC). Biomarker analyses have demonstrated that gene expression profiles are associated with regimen-specific outcomes. These transcriptomic analyses used mixed sample cohorts (primary and metastatic tumor specimens) and it is unknown whether the clinical relevance of transcriptomic signatures is impacted by tissue site. We evaluated data for 1132 patients with metastatic ccRCC treated with ICI in prior studies (IMmotion151 and CheckMate-009, -010, and -025). We identified significant and reproducible differences in gene expression by tissue site. We tested the association between previously described molecular tissue clusters (MTCs) by tissue site (MTC1-primary and MTC1-metastasis) and progression-free survival (PFS) and objective response to systemic therapy. In IMmotion151, MTC2-metastasis was significantly associated with better PFS on sunitinib (hazard ratio [HR] 3.39, 95% confidence interval [CI] 1.32–8.69; p = 0.01) in comparison to MTC2-primary (HR 0.95, 95% CI 0.65–1.38; p = 0.80; pinteraction = 0.02). Evaluation of known RNA signatures in the CheckMate trials revealed that JAVELIN-metastasis was associated with better PFS on ICI (HR 0.77, 95% CI 0.62–0.97; p = 0.03) in comparison to JAVELIN-primary (HR 1.04, 95% CI 0.91–1.19; p = 0.56; pinteraction = 0.02). These results indicate that tissue site may be a relevant confounder in biomarker analyses.