Therapy-relevant gene signatures in the high risk localized renal cell carcinoma setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).
Authors: Rappold Phillip M. , Silagy Andrew W. , Kuo Fengshen , Marker Mahtab , Reising Albert , Millholland John , Russo Paul , Coleman Jonathan , Voss Martin H. , Chan Timothy A. , Motzer Robert J. , Hakimi A. Ari 
Published: March 2021

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Background: Transcriptomic profiling of the renal cell carcinoma (RCC) tumor microenvironment (TME) has revealed gene signatures predictive of response to therapies in the metastatic setting. High expression of angiogenesis genes correlate with responses to tyrosine kinase inhibitors. Adenosine in the TME exerts immunosuppressive effects that can facilitate tumor growth. Adenosinergic agonism has revealed gene signatures, comprised of inflammatory myeloid mediators, that correlated with response to adenosine pathway inhibition on a previously reported cohort of patients. Given these promising data from the metastatic space, we sought to interrogate prognostic gene expression in the TME from patients with localized disease. Methods: Clinicopathologic and whole-gene microarray data were acquired from 202 patients in the placebo arm of the PROTECT trial (NCT01235962). Transcriptomic scores assessing angiogenesis and adenosine signaling with individual annotations above/below median categorized patients into four groups (angiogenesis high vs. low; adenosine high vs. low). Categorical association with disease free (DFS) and overall survival (OS) was tested with logrank testing and assessed interdependence with the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Overall, 37% of the cohort developed recurrence and 81% were alive at last follow up. Kaplan-Meier analysis showed Adenohi and Angiolo signatures were individually associated with decreased DFS and OS, compared to Adenolo and Angiohi, respectively. Upon integrating these signatures, we found the AdenohiAngiolo group exhibited the worst and the AdenoloAngiohi group had the best DFS and OS. These associations were validated in the TCGA cohort. Multivariate Cox regression models showed AdenohiAngiohi (HR 3.75; 95% CI, 1.72-8.21; p = 0.0009) and AdenohiAngiolo (HR 6.44; 95% CI, 3.06-13.54; p < 0.0001) groups (AdenoloAngiohi as reference group) and pathologic T4 (HR 8.69; 95% CI, 2.66-28.36; p = 0.0003) were significantly associated with worse DFS, but not UISS score (HR 0.56; 95% CI, 0.24-1.31; p = 0.18) and T3 tumors (HR 1.54; 95% CI, 0.8-2.94; p = 0.2; T2 as reference group). Conclusions: RCC TME subgroups stratified into adenosinergic and angiogenic expression profiles carry independent prognostic significance in patients with localized RCC. On multivariate analysis, these gene signatures enhanced conventional clinicopathologic risk stratification variables in predicting DFS after nephrectomy. Given the early data fueling interest in developing the prognostic capacity of these gene signatures in the metastatic space, and their ability to predict outcomes in the post-nephrectomy setting, these biologically relevant subgroups should be explored as a guide for future biomarker-driven adjuvant therapy trials.