6th International Kidney Cancer Association Symposium,6—7 May, 2011, Warsaw

The role of biomarkers in kidney cancer treatment

Professor Brian Rini (University of Cleveland, Ohio, USA)

So biomarkers is a very interesting field in kidney cancer now; we finally have some drugs that work and we’re trying to figure out how to most optimally apply them to patients because there are so many  choices right now we just give them empirically in a sequence. It would be nice to be able to predict benefit either before or early on in treatment.

There are several different areas of biomarkers, some of the early biomarkers looked at circulating levels of growth factors like VEGF, vascular endothelial growth factor, soluble VEGF receptor. And that work really showed that they do change with treatment, that these drugs modulate those drug levels but it hasn’t really panned out that they are allowing us to predict benefit from treatment.

People have looked at Von Hippel-Lindau gene mutation, which is prevalent in kidney cancer, which we think drives the VEGF addiction of the disease and probably because most people have VHL in activation and because it’s an early event, it also hasn’t really been shown to be associated with outcome.

More recently people have looked at single nucleotide polymorphisms, or SNPs as we call them for short, which are a natural DNA variation within a population, and their association with both toxicity and clinical outcome to a particular agent. And there are really just relatively small, usually single institution series at this point. There are tens of thousands of SNPs, so people just look at a small candidate list. People have started to come up with some hypotheses that certain SNPs, meaning certain patients with that genetic variation, may be more prone to toxicity or may be more prone to response. So I think that particular area is promising, it’s a one-time blood draw, it’s DNA, so it’s nothing you have to monitor with treatment, it’s something that the patient has since birth in essence. So more work needs to be done but that’s a particularly hot area.

Lastly clinical biomarkers have been looked at most recently and the main one that has been looked at is hypertension. So these drugs cause hypertension because of their effect on the VEGF receptor and VEGF itself, and it has been shown that treatment induced hypertension identifies patients who will do better with treatment. Again, all retrospective data, all hypothesis generating, but a very strong biologic signal that hopefully we can build on.

Is polymorphisms a field you are investigating?

Some of the large scale clinical trials, phase III clinical trials are now collecting blood samples in appropriately consenting patients so that we can do more prospective large scale assessment. Again, the initial large trials didn’t collect blood on there so there are just no samples available, so it was institutional samples that were used. Now I think it’s moving into the larger data sets.

The idea is to see if certain polymorphisms, and they may be frequent or infrequent, are associated with outcome or toxicity. So could you test this panel of polymorphisms and predict that a patient would have this, that or the other toxicity, or predict they won’t do well with drug X but they would do well with drug Y. Those are difficult things to show and those take a lot of samples and a lot of time and resources, but I think that’s where we’re heading.

What about immunotherapy?

There is a select subset of patients who still can and should get high dose interleukin-2, which is curative for a very small subset. There is a new wave of immunotherapy that is developing vaccine based therapy. Now that we have some drugs that can actually control disease, immunotherapy may have a chance, that is the time to work. By itself, immunotherapy wasn’t really enough to control the tumour so most patients didn’t do well but immunotherapy keeps coming back in kidney cancer and I think we’re about to have another wave of immunotherapy.

There are a couple of vaccines that are entering late stage clinical testing. One is a patient tumour derived RNA vaccine, another is just another off the shelf peptide-based vaccine. Then there is an antibody to a molecule called PD-1, which has shown some very interesting results, albeit in phase I studies for what it’s worth but it’s entering phase II testing. So there is, again, another wave of interesting drugs or approaches and we’ll see if we can’t get some more mileage out of immunotherapy. All these trials may be negative and then we’ll be back to square one in immunotherapy, but it’s always been a disease considered immunoresponsive. I think part of that was because it wasn’t responsive to anything else but part of it is because there are 5-10% of patients who really do well with that therapy. It’s not a big percentage but it’s a signal that maybe that can be expanded.