Expert Discusses Molecular Diagnosis of Renal Cell Carcinoma

There is still work to do in the field of molecular diagnosis for renal cell carcinoma, according to David I. Quinn, MBBS, Ph.D., FRACP, FACP.
BY Brielle Benyon
PUBLISHED March 25, 2019
While there are some exciting advances coming down the pipeline, there is still much work to do when it comes to the molecular diagnosis of patients with renal cell carcinoma (RCC), explained David I. Quinn, MBBS, Ph.D., FRACP, FACP.

Quinn, the medical director at the USC Norris Cancer Hospital and Clinic and associate professor of medicine at the Keck School of Medicine at USC, recently sat down with OncLive, a sister publication of CURE, to discuss these advances in kidney cancer.  
 
OncLive: Can you give an overview on the molecular diagnosis of RCC? 
Quinn: It's important for us to understand that the modern therapeutics of renal cell cancer are predicated on what we've learned about the molecular makeup of the cancer, particularly driven by pathways such as angiogenesis and also the MTOR pathway and then an altered immune system in most renal cell cancers that is targetable. Those three factors are very important when it comes to understanding the therapy of RCC. They are also important when it comes to understanding some underlying principals of treatment. 
 
Where that becomes important is when we're looking at a diagnosis of someone with RCC, they might have an underlying germline mutation. That's important that we distinguish the behavior of the cancer and also some of the treatment. There are particular clinical characteristics that help us there. But then we have to get the patient testing and followed up. 
 
The other issue is this: Do markers in renal cancer tissue help us with treatment at the moment? And the answer is, they don't. But there are some very important proofs of principle related to different therapies that are starting to emerge. 
 
What are some of the pathways and targets that are showing the most promise when it comes to treatment decisions? 
We've looked for a long time at the VEGF targeted agents, mainly the VEGF receptor tyrosine kinase inhibitors (TKIs). First, we had Nexavar (sorafenib) and Sutent (sunitinib) approved for RCC, and then we had a subsequent plethora of other agents that target either relatively specific pathways, particularly VEGF receptor 2, or some other pathways. There’s Cabometyx (cabozantinib), a more recently approved agent, that also targets VEGF, as well.
 
We've been looking to tie those molecular alterations up with the things that they target. We've had limited success over about 20 years. We've looked, for example, at hypoxia inducible factor 2 in patients treated with Sutent. Initial results from a small study suggested that would help us, but an actual fact is that it doesn't really. 
 
The truth is that in the totality of the assessment, it's probably not an individual molecular (biomarker), but more likely patterns and signatures that might help us. 
 
How does this all tie in to the precision medicine approach that we're hearing about in multiple types of cancer? 
At the moment, not very well. We may end up in a situation where to give certain therapies we need to have a marker to do that, such as PD-L1 expression or elevation in the tumor or tumor infiltrating immune cells. That's not certain as of yet. If an oncologist is given the opportunity to give a marker or not, they'll generally not, unless there's a big advantage to doing that marker assessment. From that perspective, at the moment, the markers are not in common use. 

What we have from a series of studies looking at different combinations of immune and VEGF-targeted therapies, compared with VEGF and immune therapies is an emergence that there are perhaps signatures for patients who will do well with VEGF therapy or who will do well with single-agent immune therapy, and then the tantalizing effect of combination of these drugs that may overcome intrinsic resistance that's present in renal cell. But that's just postulated at this stage and needs to be proven.
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