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; p_interaction = 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; p_interaction = 0.02). These results indicate that tissue site may be a relevant confounder in biomarker analyses.

中文翻译：

---

样本位点影响肾细胞癌的 RNA 生物标志物


免疫疗法 （ICI） 仍然是治疗晚期透明细胞肾细胞癌 （ccRCC） 的主要药物。生物标志物分析表明，基因表达谱与方案特异性结果相关。这些转录组学分析使用了混合样本队列 （原发性和转移性肿瘤标本），目前尚不清楚转录组学特征的临床相关性是否受组织部位的影响。我们评估了先前研究 （IMmotion151 和 CheckMate-009 、 -010 和 -025） 中 1132 例接受 ICI 治疗的转移性 ccRCC 患者的数据。我们确定了组织部位基因表达的显着且可重复的差异。我们按组织部位 （MTC1-原发性和 MTC1-转移） 测试了先前描述的分子组织簇 （MTC） 与无进展生存期 （PFS） 和对全身治疗的客观反应之间的关联。在 IMmotion151 中，MTC2 转移与舒尼替尼治疗组更好的 PFS 显著相关（风险比 [HR] 3.39,95% 置信区间 [CI] 1.32-8.69;p = 0.01） 与 MTC2 初级 （HR 0.95,95% CI 0.65-1.38;p = 0.80;p_交互作用 = 0.02）。CheckMate 试验中已知 RNA 特征的评估显示，标枪转移与 ICI 上更好的 PFS 相关 （HR 0.77,95% CI 0.62-0.97;p = 0.03） 与 JAVELIN 初级 （HR 1.04,95% CI 0.91-1.19;p = 0.56;p_交互作用 = 0.02）。这些结果表明，组织部位可能是生物标志物分析中的相关混杂因素。