The genomic architecture and evolution of clear cell renal cell carcinomas (RCC) depicted on the cover of this issue represent more than just branches of what a consortium calls “phylogenetic trees for RCC.” These spoke-like directions might be a metaphor for investigations into the biology of the disease itself, branching out into myriad avenues as we seek to define and redefine biomarkers and gain more of a foothold on the heterogeneity of the gene sequence in RCC.
We have known for many years that the most common histological subtype, clear cell RCC, is associated with abnormalities in the Von Hippel-Lindau tumor suppressor gene (VHL) in almost all cases. Drugs able to inhibit the vascular endothelial growth factor (VEGF) pathway such as bevacizumab, sunitinib, pazopanib and axitinib are active in clear cell RCC. However, no drugs have been developed to date able to target the loss of tumor suppressor genes, as is the case of VHL in RCC, and VEGF inhibitors do not directly target tumor cells but the tumor microenvironment. No predictive biomarkers in clear cell RCC have been identified yet and around 30% of patients will not benefit from treatment.
This is why the work of the PREDICT Consortium, as reviewed by investigators in this issue of the Kidney Cancer Journal should be of interest to all caregivers hoping for additional clues to identifying predictive biomarkers. Unlike the therapeutic arena, where breakthroughs or at least milestones in targeted therapies occasionally appear, the progress in defining biomarkers is glacial and we only obtain advances in small increments as investigations proceed over the years. Yet, much like peeling away the layers of an onion, more of the intratumor heterogeneity of renal tumors is being revealed. The goal of course would be to devise a pre-treatment test able to predict with some reliability the efficacy of cytokines, VEGF therapies and mammalian target of rapamycin (mTOR) inhibitors. The challenge of doing so remains daunting because the responsiveness to treatment can differ significantly between patients even when their tumors have been classified within the same histological subtype, grade and/or stage.
Much progress has been made, for example, in identifying predictive markers for the use of high-dose interleukin-2 (IL-2). Efforts in this area have led to much improved identification of patients more likely to respond to IL-2. Similarly, additional work is focusing on the extent to which predictive markers can be identified for other treatment strategies.
The nature and extent of that challenge becomes real through the image on the cover. The image is somewhat haunting because within it lies much of the enigma of the disease still to be revealed. But slowly, like the layers of an onion being peeled away, the essence of the disease, or at least glimmers of it, will be delineated.
Janice P. Dutcher, MD