ASCO GU 2021: 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)

( Up to 40% of patients with localized renal cell carcinoma (RCC) will develop metastatic disease and unfortunately, adjuvant therapy trials to date have failed to demonstrate an overall survival benefit. Transcriptomic profiling of the RCC tumor microenvironment has revealed gene signatures predictive of response to therapies in the metastatic setting, as high expression of angiogenesis genes correlate with responses to tyrosine kinase inhibitors. Additionally, adenosine in the tumor microenvironment 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, Dr. Phillip Rappold and colleagues sought to interrogate prognostic gene expression in the tumor microenvironment from patients with localized disease, results of which were presented at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU).


Clinicopathologic and whole-gene microarray data were acquired from 236 patients in the placebo arm of the PROTECT trial (NCT01235962).1 Transcriptomic scores assessing angiogenesis and adenosine signaling with individual annotations above and below the median categorized patients into four groups: angiogenesis high versus low; adenosine high versus low. Categorical association with disease free and overall survival was tested with log-rank testing and assessed interdependence with the UCLA Integrated Staging System (UISS) in a Cox regression model.

The median patient age in this cohort was 58 years (IQR 52-65) and the majority of patients underwent radical nephrectomy (94.5%) 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 disease-free survival and overall survival, compared to Adenolo and Angiohi, respectively. Upon integrating these signatures, Dr. Rappold and colleagues found the AdenohiAngiolo group exhibited the worst and the AdenoloAngiohi group had the best disease-free survival and overall survival. These associations were then validated in the TCGA cohort:


Multivariate Cox regression models showed AdenohiAngiohi (vs AdenoloAngiohi: HR 3.75, 95% CI 1.72-8.21) and AdenohiAngiolo (vs AdenoloAngiohi: HR 6.44, 95% CI 3.06-13.54) groups, as well as pathologic T4 tumors (HR 8.69, 95% CI 2.66-28.36) were significantly associated with worse disease-free survival, but UISS score (HR 0.56, 95% CI 0.24-1.31) and T3 tumors (vs T2: HR 1.54, 95% CI 0.8-2.94) were not associated with disease-free survival.

Dr. Rappold concludes this presentation with the following summary points:

  • The RCC tumor microenvironment 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 disease-free survival 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

Presenter: Phillip Rappold, MD, PhD, Urologic Oncology Fellow at Memorial Sloan Kettering Cancer Center, New York, NY

Co-Authors: Andrew W. Silagy, Fengshen Kuo, Mahtab Marker, Albert Resing, John Millholand, Paul Russo, Jonathan Coleman, Martin H. Voss, Timothy A. Chan, Robert J. Motzer, A. Ari Hakimi

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021


  1. Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). J Clin Oncol 2017;35(35):3916-3923.
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