 I'm Perry Canoski and welcome to this month's edition of Kidney Cancer News. Research published in the International Journal of Cancer has shown that daily consumption of whole fruits and vegetables, especially bananas, is highly protective to kidney health. The results show that over 13 years women eating more than 2.5 servings of fruits and vegetables per day cut the risk of kidney cancer by 40%. Among the fruits, bananas were especially protective. Women eating bananas four to six times a week have their risk of developing the disease compared to those who did not eat this fruit. So as some of the other speakers have already alluded to, kidney cancer is really not one disease. It's a collection of many different types of cancers. I do believe that as we learn more about the molecular makeup of these tumors, we'll find even more breakdowns of different kidney cancers. And this is a slide that a lot of us show. This is from Marston Linehan who studies a lot of these inherited cancer genes. And as Dr. Chari already pointed out, these cell types look very different under the microscope. But there are roughly, there are several different inherited cancers that have given us a lot of insight into how to go about treating these cancers. And this is a list from the World Health Organization. This is their classification of some of the malignant kidney tumors that exist. And as you can see, clear cell is the most common type. But as you can see, there are many other types of cancer that don't really fit that classification. And that's what we're going to, what I'm going to talk about today. So what is rare? Well, papillary kidney cancer is 15% of all kidney cancers. So I don't really think it's rare if you multiply, if you take 15% of 40,000 cases, it's still thousands of patients that are affected. And chromophobe is 3% and the others make up an even smaller proportion of those. But I think you can consider these rare because they are rare to industry. And it's hard to get people to focus their attention on these kinds of cancers because the squeaky wheel, it isn't, you know, there aren't as many voices shouting about these particular types of cancers. And as Tony already alluded to, sarcomatoid features are these little spindly cells and they can arise from any of these other types of kidney cancer. So the cells can actually change into these spindly types of cells and that can sometimes make the behavior different. And the cancers come from different parts of the kidney. So clear cell and papillary cancer come from the nephrons, which are the area that's really kind of making the urine and breaking down the toxins in the body. But the distal nephron, which is the part that carries it more into the collecting system of the kidney, has other cancers that arise from it. And the chromophobe cancer arrives a little bit more distally as does collecting duct cancer. And somebody earlier in the audience this morning asked one of the speakers this morning about tumors of the lining and they're really collecting duct cancer is very uncommon, but it's kind of a cancer that's in between the upper tract tumors and kidney cancer. So we don't treat it as much like we do the more common types of kidney cancer and we do tend to treat it more like we treat bladder cancer, but it's still considered a kidney cancer. So there's a little bit of a gray area in there as well. This is a, Dr. Chowari has already lined this up for me, but the things that I'm going to be talking about are drugs that are attacking different targets. And VHL, as he alluded to before, is something that's a predominant target in clear cell kidney cancer. But there are other targets that are, these targets are also important in papillary cancer and chromophobe and as you can see it gets very complicated and I'll be mentioning these also when I'm talking about these rare histologies. So several hereditary syndromes have helped to advance the field and these are these syndromic things that don't occur in very large numbers of patients, but when we study these patients we learn an awful lot about how to treat the more sporadic kidney cancer. Bonhippalindo is an inherited clear cell cancer of the kidney. These patients are prone not just to cancers and cysts in the kidney, but these can also occur in the brain and in the spine and the eye and the adrenal glands and many different parts of the body. And about 40% of patients can actually have multiple tumors on their kidneys on both sides. And inactivation of the VHL gene is what's in their germ line, in their, not just in their tumors cancer cells but also in their body and that's driving this. So this is a picture of a patient of mine who has Bonhippalindo disease and this is an MRI and you can see these are his kidneys and you can see just there are just hundreds and thousands of cysts in both of the kidneys and most of us don't have that but by studying these unusual patients and looking at their tissue we can learn a lot about how to treat sporadic kidney cancer. Papillary cancer on the other hand is driven by other genes and papillary kidney cancer falls into two main subtypes right now and I'll say right now because we may end up in a few years dividing this into even more different subtypes but at least under the microscope type 1 kidney cancer has a kind of more regular distribution of the cells. It's the more common type of papillary kidney cancer but it's also a little bit more indolent in that the behavior can show up as hundreds and hundreds of little tumors in both kidneys but they might not spread so fast so at least early on what happens is that surgeons will watch this and when a kidney cancer gets to a particular size they'll take it out but they know that they can't get rid of all of the hundreds of tumors so a lot of it has to do with monitoring. But as the kidney cancer gets more aggressive and spreads one of the things that's been at least in the hereditary population important is this gene which makes a protein called MET and MET is a target that a number of different drugs are in development now for some of these drugs are specific to MET some of them are drugs that treat both VEGF and also MET and so they're important both in clear cell kidney cancer but they're also important in some of these non-clear cell types and some other things that have been discovered to be important in the type 1 papillary are the pathway related to MET which drives a protein called hepatocyte growth factor and hepatocyte growth factor is a common target of a number of different drugs for example Nexivar targets hepatic growth factor and that's why Nexivar is being looked at in liver cancer as well so a lot of these drugs are quite ubiquitous in the types of cancer we use them in but we think that a number of mechanisms including the blood vessel formation such as angiogenesis cell proliferation and also motility of cells may be important targets whereas hereditary papillary type 2 cancer is a very different cancer it's much more aggressive in its growth it can come up very quickly it can spread very quickly the cells look very different under the microscope there's more of a reddish or an eosinophilic component to the cells and in the hereditary form of papillary kidney cancer the type 2 patients can sometimes get tumors involving the uterus and also tumors involving muscles within the skin so they can get bumps on their skin and in this particular cancer the fumarate hydratease gene defect has been found to be an important mutation next slide this is back to if any of you ever took organic chemistry this is the energy cycle that's present in the mitochondria and what we're finding is that different enzymes in this energy production pathway are important in different kinds of cancer so here's fumarate hydratease it's important in this part of the energy metabolism but down here for example sesanil coa or sesanate dehydrogenase is important in a tumor called pereganglioma which is a small tumor that sometimes shows up right next to the kidney and then in the glutamyl pathway which is down here that's been found to be very important in brain tumors so there's a lot of this is a very important pathway for some of these aggressive cancers this is a slide that shows some of the experiences that have been captured for non-clear cell kidney cancer and I think that the biggest thing to point out in this slide is that these are going back to some of the big studies that were done in kidney cancer in general so some of your big expanded access trials and the big first phase 3 trial for Satora cell and so there were hundreds of patients enrolled on these trials and we weren't back at that time there wasn't as the bigger phase 3 trials were directed toward clear cell but as the drugs became more available for you know before they went to commercial availability there were these expanded access trials and in these some of the patients who enrolled registered to have access to the drug had non-clear cell cancers but a lot of these patients had what we call mixed histology so they had both some clear cell parts of their kidney cancer and also some non-clear cells so looking back retrospectively at these we can see that there were some responses to sutent and also to nexivar or seraphonib and there was also activity in temsarylimus at least or torus cell but most of these studies are kind of looking back in time and then this is Dr. Chowari's report where he went back and looked at 41 patients and saw a much smaller response to these patients and these patients I think were more pure papillary cancer and this was a prospective study that was done here at MD Anderson of 23 patients and I didn't put the number here but it was a very low response rate of about 2% or so and what I would say about these studies is don't get discouraged because even in this grouping where these studies were looking at papillary maybe pure papillary we're not looking at whether you know what kind of mutations these patients had and so there may be big differences in patients even in the papillary subtypes where some of these drugs would still work and they might not work in other patients and I think the take home message here is that we really need to look at these in a more integral marker kind of sense in where patients have biopsies and analysis of their tumor specimens and then we look at these tumor specimens after they've you know get perhaps more tissue after they've been treated to see are we hitting targets and this is a list this is an excellent review that just came out and this is a review of some of the different strategies this is for papillary type 1 so this is there have been antibodies now that have been directed against hepatocyte growth factor some against met and then there are other drugs that directly inhibit the gene and don't inhibit kind of the molecules that work against the gene or the protein product and these are some of the therapies some of which have been completed and some of them are ongoing and Dr. Bukowski is going to talk about clinical trials later on this afternoon so I won't spend a lot of time focusing on these but it just shows you that there's a whole range of new molecules that are being looked at in papillary kidney cancer and I think a particularly interesting one is this Excel 880 which is for ratinib and this was a trial that was open to patients who either had a mutation of met or were hereditary or where we didn't know anything about the patients and the company collected information on all of these patients and I was under the impression that they're going to go do a phase 3 trial of this but I'm not sure that that's up and running and where that is in its current form and then for the sporadic papillary again we don't know quite as much about it but the approaches that are being taken are similar to what we're seeing in the hereditary and then for hereditary papillary type 2 there's definitely this inactivation of the fumarate hydratease gene and there's some rationale based on the HIF production that results from this that VEGF pathways are important there was also an EGF trial of erlotinib that was done in papillary renal cell and there was an improvement in survival and based on that there are a number of different trials going on some of them looking at a kind of a dual anti-angiogenic approach with bevacizumab and erlotinib and there have been responses in that as well what I'd say about sporadic papillary is we really don't know a lot about it yet but MIC activation may be playing a role and so MIC is a very active tumor oncogene and perhaps some of the approaches that we use in some other solid tumors such as lung cancer may be important in approaching this cancer as well so the conclusions for papillary are again we need prospective trials with integral markers to really determine which patients with papillary kidney cancer benefit from VEGF tyrosine kinase inhibitors, mTOR inhibitors and other agents but the standard of care for right now are really to include any and all of the commercially available agents for renal cell except perhaps hydro-center lukin-2 and I'd really like to make a plug for participation in clinical trials I think that's really the only way to move the disease forward I'm going to go a little bit more rapidly over these this is Burt-Hogg-Dubey which is another inherited disorder and what I'd like to say about that is that a proportion of chromophobe tumors arise from oncocytomas and there's a mutation in the Burt-Hogg-Dubey gene which leads to this kind of aberrant production of this folliculine protein and this is perhaps important in again in energy metabolism and there's some data to suggest that mTOR inhibitors such as temserolimus or a virulimus may be potentially important therapies for this subtype this is an overlap just to show you how complicated this is this is Burt-Hogg-Dubey, this is something called multiple endocrinoplasia these are people that get many different kinds of cancer and this is tuberous sclerosis which is another gene that affects that part of the pathway called mTOR and leads sometimes to mental retardation, to brain tumors and to a lot of other unusual kinds of malignancy but there are some overlaps in some of the syndromic things that we see here and this is a patient of mine who took a picture of his skin he has the Burt-Hogg-Dubey gene and these are fibrophiliculomas so these are kind of they have a kind of a whitehead appearance this is a very close-up picture he took of his cheek and emailed to me and it's unknown again in sporadic chromophobe if Burt-Hogg-Dubey plays an important role certainly we see kit overexpression and so that lends some interest to whether and to satinib all which have kit as one of their targets may be an important important things to explore but these drugs historically have been looked at in mutated kit not overexpressed kits so again it's very complicated but these are things that are falling out of what we're learning by studying these cancers up front and there has been some reports of improvement 25 percent response rate in non-clear cell in a population of patients who had sous-tent and then there are some other you know an mTOR certainly has a role here but my conclusions for chromophobe again are that chromophobe can behave quite indolently initially and so local therapies may help to control ablative therapies may be important in this but commercially available drugs or a prospective clinical trial that enrolls non-clear cell with integral markers would be a good thing to consider here and then sarcomatoid kidney cancer as we said before can be present in any of these but it's characterized by a kind of a switch to a much more aggressive form of cancer and it's thought to be represent a biologic transformation to a more aggressive behavior so patients who have these in their kidneys at the time the kidney is removed may have a much more aggressive active cancer and this is an area where I think we can say that chemotherapy does have some activity and not just the targeted therapies so this is a busy slide that shows a number of the clinical trials that have been done in sarcomatoid renal cell and this was a trial that was initially done in New York by Janice Dutcher and David Nannis looking at some very aggressive renal tumors of which a large proportion were had sarcomatoid features and they saw these responses in these patients but I think what's the most interesting is that some of these patients had quite durable responses and I realize I made a mistake in the slide this should be here and this should be here so they did a follow-up report and four of the patients that were on this original trial had a remission that was longer than two years and two patients were six and eight years since completion of their treatment we followed up in the Eastern Cooperative Oncology Group and did another clinical trial using the same regimen which is a gem cytobine given at a higher dose, 1,500 milligrams every two weeks and doxorubicin which is also known as Adria mycin and that's given intravenously every two weeks and you have to get the last to keep your blood counts up it's a pretty intense regimen but we looked at patients and 38 of these patients had one complete response, seven partial responses and 10 stable disease and this was a trial that was open all over the country whereas this was a two instance tuition study and so sometimes we do bigger trials all over the country to see if in real life if there's a bunch of different doctors treating with this regimen does it work as well as if you have just a couple of doctors working with the regimen and I think that we also confirmed that we had some patients who did better for a two year period of time or longer and that's how long we followed them but there's been movement in the direction of looking at targeted therapies and so up in Boston, drawer Michelson and his group looked at a small trial where phase one where they treated patients with gem cytobine and a lower dose of suthent so 37.5 milligrams of suthent and in this small, in the initial small group of patients and I think he's treated a larger number but I don't have the updated information about a third of these patients had responses and so that lends some credibility to combining chemotherapy with targeted therapy in this approach and others have taken this farther this was a review that the Cleveland Clinic did of their patients who had sarcomatoid renal cancer features they went back and looked at who got VEGF targeted therapy so who got retrospectively bevacizumab or suthent or seraphonib and they found in 43 patients that there were four partial responses and 20 stable disease and so they did see responses in patients it did seem that the patients who had less sarcomatoid features did better if they had more clear cell it was more useful and others have taken this and combined different chemotherapies gem cytobine with an oral 5FU based drug and then bevacizumab this one was, can't report everything, but this was done up in Chicago and they again saw some well tolerated and some partial responses and oh and I missed Taurus cell down there in the analysis of the ARCS trial they also had sarcomatoid features and had some responses so I'm going to, in the interest of time, skip over this this is the ECOG trial, but what I wanted to point out here is we broke it down into as much as we could and this was kind of a disappointment because we weren't able to get tissue from all of the patients even though it was an eligibility requirement we had a lot of patients where we couldn't actually get the tissue to follow up and be sure of this but in looking at what we know the patients we did see responses in patients who had a lot of their tumor replaced by sarcomatoid features and we did see responses in both clear cell and non-clear cell cancers with this regimen so what I would say is that, I'll skip over this but I think the doxorubicin and gemside bean therapy can lead to durable remissions tyrosine kinase and mTOR inhibitors have some activity and combinations of angiogenic therapies are an area of intense focus and then I wanted to just briefly talk on some kind of cool tumors that have popped out recently and Dr. Chowari is getting a lot of attention at this talk he's done a lot of this work this is his slide from a paper and this is a fish analysis which is staining showing that these chromosomes have moved around, parts of the chromosome have jumped to another chromosome and they've created a protein together and caused these fusion proteins and it's now recognized that a proportion of mainly clear cell cancers can be these translocation tumors and I think it just points out that we're getting to realize that more and more of these cancers are very different when we look up close but the bottom line with this is there may be a particular kind of a tubular papillary pattern that we see with these under the microscope but there have been two reports now looking and it does look as if some of these cancers at least respond quite well to the standard therapies that we use in clear cell kidney cancer and then finally this is a very unusual kidney cancer this is medullary kidney cancer this is present only in young patients generally African American who have sickle cell trait and probably due to inflammation of the medullary portion of the kidney it's a very very aggressive disease uniformly fatal in almost everybody and we typically use approaches such as chemotherapy and bladder cancer there were some reports I guess MD Anderson did an analysis of their patients and found that patients who got anti-angiogenic therapy bevacizumab based therapy seemed to do better in combination with chemo and then recently there was a report of a mutation in the ALC gene and there are now ALC inhibitors that are under development so another area to branch out and then finally collecting duct cancer is as I was mentioning before it's of the lining of the kidney but it's not quite a protract tumor it's kind of a transitional area between kidney cancer and yourothelial and we tend to treat those also with chemotherapy agents so these are trials that are directions that I would point people to for consideration of therapies and I listed here the adjuvant trials because these are adjuvant trials that are open this is open in the United Kingdom this is imminently open in the US and the Usur trial is now closed but these all are enrolling non-clear cell patients and I'd like to make a plea that if anybody participates in this please please let us study your tissue so we can learn more about who would benefit so final conclusions what is it for you the more we look at kidney cancers I think the more differences and the more complicated it gets but the molecular characteristics that we're identifying are opening new avenues indeed and your participation in clinical trials and willingness to allow characterization of your individual cancers is crucial for advancing the field and I'll stop there, thank you very much join us again next month for another edition of kidney cancer news I'm Keri Konoski wishing you good health Hi, I'm Denise Richards in 2007 I lost my mom to kidney cancer like most people who are diagnosed with this disease my family didn't know much about it and unfortunately by the time she was diagnosed there wasn't much that could be done so I'm asking you to help the kidney cancer association stop the pain and suffering caused by this disease check out kidneycancer.org for information on how the association is helping patients and their families through research, education and advocacy and please consider making a donation by clicking on donate now and help us achieve our vision of a world without kidney cancer