Recent Advances in Renal Cell Carcinoma

Erik P. Castle, MD, presented “Recent Advances in Renal Cell Carcinoma” at the 26th Annual Perspectives in Urology: Point-Counterpoint, November 11, 2017 in Scottsdale, AZ

How to cite: Castle, Erik P. “Recent Advances in Renal Cell Carcinoma” November 11, 2017. Accessed Dec 2024. https://grandroundsinurology.com/recent-advances-in-renal-cell-carcinoma/

Summary:

Erik P. Castle, MD, discusses the most recent advances in renal cell carcinoma treatment, especially in regards to individualized medicine, immunotherapy, robotics, partial nephrectomy, and other surgeries.

Recent Advances in Renal Cell Carcinoma

Transcript:

So we’ll talk a little bit about renal cell carcinoma.  There aren’t, you know, between now and in the last year most of the focus which I’ll touch on is on these PDL1 and PD1 inhibitors, and what I am going to focus on a little bit is some of the work that we’re doping in the lab and that we consider kind of an advancement and a reflection of what is going on in the scientific community mostly.  

Again, no financial disclosures, nothing picked up between yesterday and today unfortunately.  We’ll talk about just an update kind of overall and management of renal cell, and really kind of the hot thing, the words you’re going to hear now is individualized medicine or tailoring medical treatment to patients and of course immunotherapy.  We’ll briefly cover surgery because there’s not a lot going on there.  Probably the biggest thing that we have seen is you’ll see a lot of papers, presentations and videos, and we have kind of a little bit of a – – thing that we’re doing a little bit later.  I was going to put some videos in here, but I think it will make it too long, because we’ll show some of the advancements in robotics and managing things like the vena cava and all that.  I think we have advanced a lot more in partial nephrectomy, radicals and cable thrombectomy, just about any thrombus below the level of the hepatics now we manage robotically, but we still do open surgery.  

Just a couple of days ago, I had a lady who had a 7-cm mass, and it extended up into her atrium, right atrium, you know, was prolapsing across the tricuspid valve, so there you are going to do a sternotomy and put them on full bypass, because there is no way to get that done robotically no matter what anyone says.  We are really trying multi-modal therapy for recurrences, and that involves using essentially radiation oncology where we are using them in cases of pre-op or adjuvant radiotherapy or even intraoperative for radical nephrectomies that then followed up with a local recurrence.  And I think that is underutilized in the community.  

You have seen the debates about partial nephrectomy, and there are people who like to show videos of off-clamp partial nephrectomies trying to preserve function.  The bottom line is that in a two-kidney model you don’t need to worry so much about ischemia like we used to.  It’s almost like you felt guilty if you let any ischemia go on or even if you did a nephrectomy.  The data is pretty clear that in a two kidney model do what you can to preserve function, but don’t go out of your way and do something heroic that is going to result in a problem for the patient because these zero ischemia things that were hot for a few years really had no benefit, and we presented this at the AUA, at the plenary just recently.  We talked about thrombectomy.  

This is probably the debate that you see a lot, and this would be a great debate.  I don’t know, in the future because this is  debated depending on which camp, how many people here biopsy renal masses?  Okay, how many do not biopsy renal masses?  I would say that still the vast majority of renal masses are not biopsied, and I think if you are a believer in ablation, then biopsy is kind of in your repertoire.  

I’m not so much a believer in ablation.  I have yet to have a biopsy change what I do.  I use a biopsy to make a decision on whether not to operate, so a patient that I’m considering that it’s a metastasis or some sort of lymphoma or hematologic issue that would encourage me not to do a nephrectomy or partial nephrectomy, I think the concern from seeding of the tract is pretty much gone.  But we’re not very consistent with all of the different centers and pathologic departments of how big the biopsy, what kind of core you take, is it more of an aspirate, like a cytology, and you can’t really trust oncocytoma because you are going to have oncytic renal neoplasms I mean there’s, or renal cell carcinoma with oncocytic features, and all of those things have caused problems for us, so we really just use biopsy if we have someone who say they are going to give systemic therapy to and I want to know they are clear cell, or mostly clear cell but even recently Dr. Bryce and my colleagues, we had a patient that was sent to use for a cyto-reductive nephrectomy, the biopsy was clear cell carcinoma, and we did a radical and it was a 41-year-old man, and it was sarcomatoid, and he died within a few weeks because it is such a rapidly progressing disease.  It is just hard to trust biopsy, and any mass that is so small that I would biopsy and survey, I would probably survey whether I biopsied it or not, and if they are too sick to have surgery, they are probably not going to die from the renal cell carcinoma, so I’m probably not going to treat it with ablation, so that is kind of our conventional wisdom, but there is a lot of support in the urologic community to biopsy.  I think if you have a reliable method, you have the right people in pathology and it really does impact the decision making you are doing, feel free to do it.  Keep in mind it does make partial nephrectomy slightly harder if you are going to do a procedure.  

Multi-modal therapy, for recurrences, like I said, I am seeing that we get patients referred to us for recurrent—say someone had a radical and then they have a recurrence right at the staple line or at the hilum, and they don’t have any other metastasis, as we know renal cell carcinoma is unique in that metastasectomy has been well-established to be effective in decreasing tumor volume and curative in quite a few patients, because they kind of select themselves out.  They don’t show up with mets to the lung and intra-abdominal mets with retroperitoneal lymphadenopathy, they are kind of a localized recurrent, so what we do is they go to our radiation oncology colleagues, and they give them preop external beam, we then take them to the OR, we resect it, and we do intra-operative radiotherapy for just kind of gross negative margins.  Why is that?  Because we don’t use a lot of radiation in renal cell.  Well, we know that radiation actually works quite well for metastasis for renal cell carcinoma, particular brain mets, it’s in the primary that radiation does not work very well.  Now, I think if you don’t have access to IORT, you can do external beam, so patients who first example, their insurance doesn’t cover the intraoperative radio therapy at our institution we go ahead and give them external beam in the community, and then we will resect them.  But here you also want to—this is the one case where a biopsy is very useful because if it is clear cell you might even incorporate systemic therapy, pizopanib or sunitinib in these cases, but I think that you should be aggressive for these patients.  

All right.  Let’s get to the kind of cool part that is a little bit more complex, which is individualizing medicine.  So genetics and immunotherapy, we’ll talk briefly on sequencing, camels, which are these circulating we can measure, not circulating tumor cells but macrophages that are response to the tumor environment, and CAR T-cell therapy.  You may have heard of that, kimeric antigen receptor, T-cell therapy where you can create T-cells from the patients themselves and target their own tumor directly or target something specific, and I’ll show you a project that we have going on, and of course the PDL1/PD1 thing, which you will hear ad nauseum nowadays at just about every meeting that you go to.  It’s important to know that all cancer is genetic, and I’m going to move a little quickly because there are a lot of slides here and I know I have limited time.  Cancer results from a variety of different mutations, and that happens over time.  And it is almost like you are trying to get that perfect Powerball combination, all the numbers plus that last one that will end up leading to malignancy.  Most cancer is not hereditary, and the vast majority of renal cell carcinoma falls in this environment, which is the somatic mutation, which is some sort of mutation, quite often in the VHL genome, or excuse me part of the genome, and then we are looking at it.  Then of course as we know, it is loss of VHL that results in this increased tumor growth and all of the drugs that we’re using target some pathway, whether VEGF or some sort of pathway that leads to increased vascularization, and that is why we see these tumors that are just trying to suck up blood left and right and go up into the vascular system.  

So this was one of the prominent mutations identified in the renal cell carcinoma population.  It led to all of the drugs that you see that came out in the early 2000s and had to do with inactivation of the second VHL gene, that led to renal cell carcinoma, particularly clear cell.  

But just loss of VHL function is insufficient.  You still need additional mutations that will play a role in the development of this malignancy.  We do know that epigenetic modifications will play a role, which is basically these modifications to the histone, and we have a project, and a nice, one of my colleagues, Dr. Hoe. who has presented here before has a nice RO1 on this particular thing called SETV2 which we will briefly talk about, but modifications in hypermethylation of a particular area such as the VHL promoter can result in altering the biology of renal cell carcinoma making it either more aggressive or less aggressive, so basically think of it as the genome isn’t just altered specifically in the gene, like losing the gene specifically, but it’s just actually an alteration of how that gene is going to be used, promoted, transcribed throughout the process.  

We have demonstrated this.  This is SET-D2, this is wild type renal cell, mutant clear cell carcinoma, you can see the differences, and this is the SET-D2 that we are looking at.  These are some other areas that have been identified, and you will hear about BAP1 also.  

So these secondary mutations are part of the process that leads to renal cell, and you will see this.  You will get your loss of heterozygosity and then you get your SET-D2, your BAP1, – – one, this is the one that we focus on in the lab here.  

And there are—can they be predictive, can they be prognostic?  A prognostic factor is a characteristic that provides information on the likely outcome of disease and predictive will tell you it provides information on the likely benefit from treatment and that is what is important to us especially with all of these new drugs that are available.  The question is are they predictive of response to systemic therapy.  We know that certain drugs can target the micro environment and targeted therapies are going to inhibit some of these pathways that are turned on or off by these mutations, and particularly these secondary epigenetic mutations.  So for example, if I order molecular genotyping of clear cell, what can we find?  Sometimes we don’t find mutations.  Sometimes we find mutations but we can’t target therapy at it.  Sometimes mutations with targeted therapies aren’t even approved, or going to be paid for, and we know these drugs are very, very expensive, so the ones we are really looking for are mutations associated with hereditary cancer syndromes, and we’ll talk about where we’re going to go with that patient population, particularly the young patient that has renal cell carcinoma, but this is the biggest problem is that you can order very expensive sequencing, but you get mutations that are not actionable, I mean this is kind of what we are going to get in our report from some of these companies, and it is not really going to change a lot because you can’t really figure out what exactly you want to do or if you have some that are associated with some of these mutations that we can identify in the lab by immunohistochemistry, so histology is the primary determinant of first-line therapy, we know that clear cell is what is going to drive the use of all of these drugs, and it’s changed over time.  A few years ago it was if you had variant histology, you used an MTOR inhibitor like everolimus or temsirolimus, something different than a TKI, but it is my understanding from my medical oncology colleagues that now the party line is everyone is going to get a TKI up front, particularly pazopanib because it is just a little bit better tolerated.  

Now the question is do epigenetic classifications provide prognostic information.  No, they are going to tell us about cancer outcome.  Well, what is interesting is you might be aware there are two main prognostic scoring systems out there for renal cell carcinoma, the Mayo sign score, which is just stage, size, grade and what really makes it different than the UCLA score is necrosis or tumor necrosis and it is very predictive, and if you think about it, tumor necrosis is just reflective of what a rapidly growing tumor because it is essentially out growing its blood supply, and it’s been demonstrated pretty clearly that the SIGN score is the most predictive out there on external validation.  UCLA score is good as well, and this is what is interesting about all of the sequencing and all of the companies that are coming out with what we are trying to do, so you have BAP1 loss of expression.  These are the different things we can sequence, but what we found is that the Mayo SSIGN is the cheapest or even if you want to use the UCLA index is the cheapest or even if you want to use the UCLA index is the cheapest and most reliable on outcomes.  There are advantages to using immunohistochemistry and it can activate or excuse me, identify inactivation of certain areas of the tumor and certain proteins, but they are not that cost effective when you compare it to the Mayo Science score and particularly less—what is more expensive is genome sequencing, very expensive, what we are spending, but what we do know is that if we do BAP1 IHC it is associated with a worse prognosis.  We’ll keep going.  

So the question is sequencing tumors can it change what our patients are going to do, how are they going to do, and people asked this yesterday with respect to bladder cancer.  I think it was Mike that asked, are we sequencing people up front, and the answer is no, and the reason is that it doesn’t change much, and IHC and looking for BAP1, looking for SET D2 might actually be a little bit cheaper than spending thousands of dollars on some sort of foundation medicine sequencing or some other industry sequencing.

Here is an example of a 72-year-old female with stage 2 clear cell.  They get their sequencing, this is what they find out.  Here are all of your options, and it is really not going to change what we are going to do for this patient even if it is a partial or radical nephrectomy.  

We do know that we’ve tried sequencing it a variety of different sites, TCGA if everyone is familiar it is called the cancer genome atlas, it is essentially a national federally funded approach to coming up with sequencing that is occurring in patients that have annotated samples.  Centers are submitting, we submitted patients for bladder cancer, kidney cancer, and prostate cancer and can come up with these incredible lists of all of the different mutations that we’re looking for but an example is that the vast majority are going to be what VHL, which we all knew already.  

We’ll keep going here.  We’ll move along here.  So remember the other issue is that kidney cancer, and can come up with these incredible lists of all of the different mutations that we’re looking for, but an example is that the vast majority are going to be what, VHL, which we all knew already.  

We’ll keep going here.  We’ll move along here.  So remember the other issue is that kidney cancer is a heterogeneous disease, and what we’re really looking for that is going to predict treatment is this, clear cell.  We have some type 2 papillaries that have some clinical trials that are out there.  There are some translocation tumors, and there really isn’t a lot that is available for those patients short of even hitting them with standard first-line therapy that we use for clear cell, but here is what you need to know in your practice is that he age of onset is going to change how you refer these patients for genetic counseling, and these are the hereditary tumors basically your younger patients and you kind of see where they are presenting.

So if you get a 35-year-old or a 40-year-old, with a small renal mass and you decide either to excise it or ablate it, I hope you are going to excise it in a young patient like that, you really need to start thinking about inherited mutations as opposed to somatic mutations.  So, it is going to be linked to a hereditary syndrome, and we see this.  We’re not talking about tuberosclerosis or the young kids that have AMLs, we’re talking about clear cell carcinoma in these younger patients.  So looking at again at age, you kind of see where we are falling and here is the age of onset for inherited syndromes, and you are going to see this is kind of the number that you are looking for.  We’re going to move along, the same thing.  

Here is what is going to be a guide for referral for genetic testing, and in our practice if they are 45 or younger, we are going to refer them to a genetics counselor, and that is going to actually be helpful in some small percentage of cases where it might change the way you survey that patient with repeated imaging, especially now in the areas where even the guidelines aren’t clear how long you are supposed to follow renal cell carcinoma patients.  

Real quick, this is some work we are working on which is CAMLS, which are cancer associated cells that are in the blood stream.  Not only do you have CTC specifically, which are circulating tumor cells, but you can have a response from an inflammatory standpoint, and we used a microfiltration assay.  Now, there are a variety of different companies that are out there, and they basically can filter the blood and they pick up theoretically circulating tumor cells.  It hasn’t really changed treatment.  What we were looking for was specifically circulating cells that are associated with renal cell carcinoma, particularly macrophages.  

This is just an example of how we can do IHC on them.  I’ll move quickly.  Let me go back, and what we were able to do is we were able to identify taking blood spiking it in the lab, and then running it with renal cell carcinoma, a cell line, and we could reliably pick up the macrophages that are associated with those cancers in the blood stream or using this technique, and the beauty of it now is we can do it from banked blood.  What a lot of people don’t realize is that all circulating tumor cells, or any flow dynamics in living cancer have to be done with fresh blood.  We’ve come up with a way to bank the blood in such a way that those cells are preserved so that we can now go back and use it as a marker down the road if a patient recurs, and see if there is something we can identify when they had the original tumor.  

CAR-T cell therapy very exciting.  It’s the concept of, it’s kind of like immunotherapy on steroids, and there is kind of a version of it, Provenge was a version of boosting someone’s immune system.  

We talked about checkpoints.  You’ll see this slide numerous times. PDL1 and PD1 are the things we look at most.