Comprehensive Genomic and Transcriptomic Characterization of Matched Primary and Recurrent Tumors in High-risk Localized Renal Cell Carcinoma.

Abstract

Recurrence after nephrectomy in high-risk localized renal cell carcinoma is common, but the genomic and transcriptomic differences between primary and recurrent tumors are not well understood. In the IMmotion010 trial, patients were randomized to receive adjuvant atezolizumab versus placebo. Tumor tissue was collected at pre-treatment baseline (n = 754) and subsequently at the time of recurrence (n = 80). We performed matched transcriptomic (n = 80) and genomic (n = 52) analyses on primary versus recurrent samples. Using previously described transcriptomic classifications, resected primary tumors had a higher proportion of angiogenic and small nucleolar RNA transcriptomic signatures and lower proportion of T-effector/proliferative and stromal/proliferative signatures compared with published metastatic cohorts. Sites of recurrence exhibited upregulation of signatures related to cell proliferation, fatty acid synthesis, and stromal biology, including matrix and fibroblasts. Comparing treatment arms, tumors that recurred in placebo-treated patients demonstrated increased B cell and macrophage signatures, while tumors that recurred despite adjuvant atezolizumab showed downregulation of major histocompatibility complex (MHC)-I. Although requiring further clinical validation, the latter finding may substantiate scientifically a potential rationale for transitioning to vascular endothelial growth factor (VEGF)-inhibition after adjuvant checkpoint inhibition.