1478P Clearseq1-4 classifier in localized and metastatic clear-cell renal cell carcinoma (ccRCC)

Abstract

The ccrcc1-4 transcriptomic subtypes that we have previously identified on fresh frozen ccRCC through unsupervised clustering, have prognostic value post-nephrectomy/metastasectomy and predictive value for 1L VEGFR-TKI. We aimed to develop a classifier for FFPE samples. RNA sequencing of tumoral FFPE tissue was performed in ccRCC patients. The classifier assigns subtypes through relative proportions of 8 gene signatures with strong discriminative value for the molecular subtypes (ccrcc3_upregulated, ccrcc3_downregulated, ccrcc2_upregulated, cell cycle, T effector, ccrcc1-4_upregulated, ccrcc4_upregulated, ccrcc1_upregulated). 214 tumors were classified. Sarcomatoid features and IMDC poor risk were enriched in ccrcc4 tumors. The favorable prognostic impact of the ccrcc2 subtype was validated after nephrectomy in localized setting, after cytoreductive nephrectomy (CN) and upon metastasectomy with curative intent (MWCI). The angiogenic ccrcc2 subtype was correlated with improved outcome on 1L VEGFR-TKI and the highly inflamed ccrcc4 subtype with improved outcome on 1L IO/IO. ccrcc2 tumors had the longest PFS on 1L VEGFR-TKI and the longest OS, as long as patients did not access to IO in later lines. In patients who could access IO in later line, OS was similar between subgroups, indicating that the ccrcc4 subtype has the largest OS benefit on IO therapy. On IO treatment in any line, ccrcc4 tumors had superior PFS. IO counteracted the poor prognosis of this subtype, resulting in OS outcomes comparable to those of less aggressive subtypes.Table: 1478Pnccrcc2ccrcc3ccrcc1ccrcc4pPrognostic impact post surgeryAfter nephrectomy in localized settingDFS110433019120.002After CNSTFS9263420.009Upon MWCIDFS6631211340.0006STFS732540160.007OS1165193320.01Impact on outcome on systemic therapyOn 1L VEGFR-TKIPFS145146940.003OS in patients without access to IO in later lines7423251150.002OS in patients with access to IO in later lines7139NR56790.21On 1L IO/IOPFS2011NA4470.04OS45NA23NR0.005On IO in any linePFS934130.048OS31300.37DFS: disease free survival. STFS: systemic therapy free survival. Open table in a new tab DFS: disease free survival. STFS: systemic therapy free survival. The Clearseq1-4 classifier allows reliable ccrcc molecular subtype determination on FFPE tissues and validates previous biomarker findings for both surgical and systemic treatment approaches.