 I'm Keri Konoski and welcome to this month's edition of kidney cancer news. I have no conflicts of interest to disclose. The outline of my presentation is as follows. I will start with a short introduction on synitinib for the treatment of advanced renal cell cancer. Thereafter, my presentation will be focused on the potential role of genetic polymorphisms in personalized medicine. In particular, I will discuss the role of genetic polymorphisms for the prediction of efficacy and toxicity of synitinib treatment in patients with metastatic renal cell cancer. In 2006, synitinib has been approved for the treatment of advanced renal cell cancer and currently synitinib is the most widely prescribed drug for this disease. However, about one third of patients experience progressive disease and do not benefit from synitinib treatments. In addition, synitinib treatment is associated with a wide range of toxicities. Therefore, pretreatment markers are needed to identify MRCC patients who will benefit from synitinib treatment and who will not. Pharmacogenetics may be useful for this purpose. As pharmacogenetics investigates, the relationship between genetic polymorphisms and the response to treatment as well as drug-related toxicities. In particular, single nucleotide polymorphisms may be useful for personalized treatment planning in patients with MRCC. As Dr. Heng already pointed out, a single nucleotide polymorphism is a variation within a DNA sequence. The DNA code is specified before nucleotide letters, A, T, C, and G. A SNP variation occurs when a single nucleotide is replaced by one of the other three nucleotide letters. In this example, the DNA molecule below differs from the DNA molecule above at the single base pair location. This represents a CT polymorphism. Although single nucleotide polymorphisms do not result in physical changes nor affect the production of proteins, it is believed that other single nucleotide polymorphisms may predispose to disease or may even influence response to drugs. In case of synitinib, the efficacy and toxicity of synitinib is determined by pharmacokinetic factors. After oral administration, synitinib is absorbed in a gastrointestinal tract for which the efflux transporters, ABCB1 and ABCG2, may be important. In addition, SIP3A4 is an important enzyme for the biotransformation of synitinib. SIP3A4 is expressed in a liver, and its expression is regulated by the nuclear receptors NR1I2 and NR1I3. In addition, other SIP enzymes, SIP3A5, SIP1A1, and SIP1A2, may be involved in the metabolism of synitinib. Besides pharmacokinetic factors, pharmacodynamic factors regulate the efficacy and toxicity of synitinib. Important factors of synitinib include the vascular and nautilio growth factor receptors, the platid-derived growth factor receptors, and FLID3. In case of RCC, inhibition of VGFR by synitinib is an important mechanism as it results in the inhibition of mitosis. Considering these pharmacokinetic and pharmacodynamic factors, we decided to investigate single nucleotide polymorphisms in these factors. The selected single nucleotide polymorphisms are depicted in green. Of note, we could not investigate genetic polymorphisms in SIP3A4, as no functional polymorphisms have been identified yet. The objectives of our studies were to identify genetic polymorphisms that are associated with a prolonged progression-free and or overall survival in synitinib-treated MRCC patients. In addition, we investigated the correlation between genetic polymorphisms and synitinib-induced toxicities, as well as hypertension that develops during synitinib treatments. For these studies, patients treated with synitinib were recruited from six Dutch medical centers. For the efficacy analysis, 136 synitinib-treated patients with clear cell histology were included. For the toxicity analysis, 219 synitinib-treated patients with various malignancies were selected. For the hypertension analysis, the cohort was extended to 291 synitinib-treated patients with various malignancies. Of all patients, germline DNA was isolated from blood samples, and a total of 37 polymorphisms in 50 candidate genes were analyzed. For the efficacy analysis, progression-free and overall survival were determined, and the toxicity was graded according to the CTC guidelines, version 3. Starting with the efficacy analysis, we performed multivariate analysis for progression-free survival in 136 patients with clear cell histology. Among the clinical characteristics, the MSKCC risk factors, the number of metastatic sites in age, were associated with progression-free survival. Among the genetic polymorphisms, polymorphisms in CYB3A5, the NR1I3 haplotype and the ABCB1 haplotype were associated with an improved progression-free survival. We also performed multivariate analysis for overall survival. And among the clinical characteristics, the MSKCC risk factors were the only clinical characteristics that were associated with overall survival. In addition, the presence of an A allele in the feature of R2 gene was associated with an improved overall survival in these patients. Going back to the results for progression-free survival, we were able to define a faithful genetic profile. Patients were carriers of the faithful genetic profile if they had at least an A allele in the CYB3A5 gene or a missing CAT copy in the NR1I3 haplotype or a TCG copy in the ABCB1 haplotype. Nineteen-five out of 136 patients were carriers of the faithful genetic profile. When carriers were compared to non-carriers, carriers appeared to have an improved progression-free and overall survival. This was 13 versus seven months for progression-free survival and 19 versus 12 months for overall survival. In multivariate analysis, the faithful genetic profile was still associated with an improved progression-free survival and showed a trend for overall survival. To the left, the survival curves for progression-free survival are presented, and to the right, the curves for overall survival. The genetic polymorphisms that were investigated for relation with efficacy were also investigated for relation with synethanib-induced toxicity. Previously, Van Urpet all have shown that genetic polymorphisms are associated with synethanib-induced toxicity in 219 patients with various malignancies. In that study, genetic polymorphisms in CYB1A1, FLIT3 and the NR1I3 haplotype were associated with development of leukopenia. In addition, genetic polymorphisms in CYB1A1 were associated with development of mucosal inflammation, and the presence of a TTT copy in the ABCB1 haplotype was associated with an increased risk of hand-food syndrome. Finally, genetic polymorphisms in VGFR2 and the ABCG2 haplotype were associated with development of any toxicity higher than grade 2. Among synethanib-induced toxicities, hypertension is a common reported side effect. However, the mechanism by which synethanib-induced hypertension has not been clarified yet. These studies have shown that VGFR2 is an important factor in the regulation of the vesculotone. Activation of VGFR2 by PI3 kinase in its downstream act stimulates endothelium-derived nitric oxide synthase, leading to the production of the potent vasodilator nitric oxide. Nitric oxide itself is able to inhibit the production and activity of endothelium-1, which is a vasoconstrictor. But when the bioavailability of nitric oxide decreases, the activity and production of endothelium-1 increases, leading to vasoconstriction. It can be hypothesized that inhibition of VGFR2 by synethanib results in imbalance between vasodilation and vasoconstriction, leading to the development of hypertension. Considering these factors in the regulation of the vesculotone, we investigated polymorphisms in VGFR2, enos, and endothelium-1. In that study, 291 patients treated with Sunicnib and with various malignancies were included, and we found that single nucleotide polymorphisms in VGFR3 were associated with the development of grade III hypertension during the first treatment cycle. In conclusion, our studies show that pharmacokinetic, but not pharmacodynamic, polymorphisms are independent predictor factors of progression-free survival in Sunicnib-treated MRCC patients. In addition, polymorphisms in genes encoding from metabolizing enzymes, efflux transporters and drug targets are associated with Sunicnib-related toxicities. And genetic polymorphisms in VGFR3 independently predict development of grade III hypertension during the first treatment cycle of Sunicnib. These results show that genetic polymorphisms are promising for the prediction of the efficacy and toxicity of Sunicnib in patients with MRCC. And these studies indicate that prospective studies are needed to validate the clinical value of genetic polymorphisms for individualized treatment planning in patients with metastatic renal cell cancer. And with this, I would like to end, and I would like to thank all patients and investigators who participated in these studies. Currently 25, I live in New York with my family, and I'm about an hour and 15 minutes north of New York City and Westchester County. I'm a fellow student, I actually graduated in about two weeks. I'm an applied psychology major, and it will be for my undergraduate degree, but I'm looking forward to finishing very much. At the time, I was 23 years old, it was the fall of 2009, early October, I was working with a development and disabled girl respite hours at her home, soliciting the appropriate social behaviors, so to speak, and I would take her out into the community and do things with her. And she was very heavy, and she had a lot of action on one side of her body, so I'd have to pick her up a lot. And in doing so, I got a bulge disc in my spine. I went to an orthopedist, because I just felt shooting pains in my back and in my legs, and it was the same old thing that I always feel with most people when they go to the doctor, they go, okay, well, here's some anti-inflammatories, and here's some painkillers, seen me in two weeks if it still hurts. So that's what I did, and I saw him back in two weeks, his name was Dr. Daniel Southern in Richfield, Connecticut, and he said, okay, well, you know, if the pain is still here, let's get an MRI, and I said, okay, good, that's great, because I don't, you know, this pain is not going away, and it was awful. So then I went to get the MRI, and then it took about a couple of days to get that back, and I came to meet with him in his office with my mother at the time. And he said, yeah, you know, the MRI got confirmed, you have a bulge disc in your lower spine, and I said, okay, great, and then we talked about how we would fix that with either oral pregnant zone or an epidural into the lower spine into the disc. And that went well, and that was taken care of, and we had the whole discussion about how I was going to recuperate from that, and what I needed to do for my back, and maybe a little more proactive about how I'm listing people and things along those lines. And from there on, I was about to actually get up and leave the office that day, and he had said, you know, would you just mind sitting back down, I wanted to share something with you that I had also seen on your MRI, and I said, okay, sure, with my mother there, and he said, okay, he said, when I looked at your MRI, he said, these are your kidneys, and I said, okay, you know, I don't know what an MRI, I can't read an MRI, I have no knowledge of that whatsoever, and he said, this is what normal kidneys look like, and I said, okay, you know, looking at it, and then he showed me what mine looks like, and in my right kidney, he said, you see this part, and he said, it's really dark shadow, rather big, and he's like, I would like to know you to go see a urologist to just follow up, he's like, I'm sure it's just a cyst, or a kidney stone, or something like that, it's nothing to worry about. When I left that office that day, and it sounds silly to say it, but I just think that intuition told me that it's not going to be a good outcome, and then maybe I'm sure you can relate to that. And from there, I went to go see a urologist in Danbury, Connecticut named Dr. Broder, who sent me to get a CT scan and an ultrasound, and that whole process with Dr. Broder took about a month and a half or so for the end of October through most of November, and when he had concluded of doing the CT scans and the ultrasounds, he said, you know, he's like, it just, he's like, it can't really be cancer, you're 23 years old, you're a healthy female, you have no predisposition to it, no one in your family has ever had kidney cancer, he's like, I'm really leaning towards an abscessed cyst. He said that his urologist in his department had gotten together and assessed my case and said that that's what it was, and he sounded very convincing. In that day, specifically, my mother and my father were there with me, and the way he had said it just wasn't enough for me, he kind of looked at me and just said, I'm 98.9% positive it's not cancer, and I, as sippy as it sounds, came back and said, but you can't tell me that it's not, right? And he said, well, no. And I said, okay, well, then I would really like a referral. So from there, I went to go see Dr. John Colberg at Yale Urology in New Haven, Connecticut, and I had met with him several times. And at first, I think that he kind of also dismissed my case saying, you know, it doesn't really look like it, it was grayish and black, there was really no definitive answer. And then one day I was sitting in his office again, it was the fourth or fifth time that I had seen him because I was so adamant about wanting an answer because it had taken so long so far with no responses to what was really going on. And he started listing symptoms and asking me if I could recall having any of them. And the one that struck me the most when he was reading through different various symptoms was that I remembered having terrible night sweats that summer, the summer of 2009, all the way through the fall and thinking I'm like, you know, I always would sweat through my sheets. And my mom and my dad would always say, oh, it's hormones, you're hormonal, you're a female, you're 23 years old, and he would dismiss it. But when I told that to Dr. Colberg, everything changed that day. He wanted to do a biopsy that week. So I went and had a biopsy at Yale. And about five days later, he said, just call the office, we'll have the results, and we're absolutely going to know what's going on at this point. And I said, okay, great. You know, finally, I'd get some answers. However, I would call every day. I still remember his secretary's name, Lucille, because I would call her every day after the five-day period of when those results should have been in. And every day she'd said, oh, Jessica, they're still testing them. They're still testing them. Don't worry, you know, we'll get it, we'll call you. And I said, okay, but I would be persistent and call her every day. I think at one point she was terribly annoyed with me because I would call her multiple times a day because then it was about three weeks later in that grace period of, you know, the five days. And on one day I called her. This was like mid-December, about December 18th or so of 2009. And she said, oh, Jessica, your slides were sent out for confirmation to Sloan Memorial in New York City. And I said, oh, okay, great. And as I knew as this was going to sound, I didn't even know about Sloan Memorial Hospital. So when I looked it up on the Internet, it said Sloan Memorial, you know, Cancer Hospital. I said, oh, well then that's really what it must be, which, you know, I had always felt that that's where it was going to be, but no one, I think, wanted to say that to me. No one wanted to put themselves out there to say that a 23-year-old perfectly healthy female with no previous medical history at all has cancer. And on December 21st, 2009, Dr. Colbert called me. I was actually walking into a mass statistics final at my university. And he told me that it was confirmed that I had papillary renal cell carcinoma type 1. You know, people ask me all the time, like, how the story of it happening, how they even found it, because the odds of it, and Dr. Colbert had told me the odds of them ever having found it wouldn't have been until it was way later hadn't I gotten hurt. And it was also interesting for multiple other reasons that my tumor was inside, embedded, right into my urinary tract or urinary ducts in the kidney itself. It was inside and not on the outside of the kidney. So that my understanding that is why they had suggested that they would have had an abscessed cyst and so forth, or a benign tumor of some sort. I can never pronounce the name of the one they always talked about. Angela Pyle and no mothers. I don't really know how to say it, but I know that they always they kept saying that it was probably that. But it all changed when I had gone over that I had night sweats with him. I had surgery December 30 2009. I was in the hospital for seven days. It was there for a week. We had decided it was my decision. Well, sort of my decision. I knew that I was going to have to have it removed, but it was either a decision between a full nephrectomy or a partial nephrectomy. You know, removing the kidney. And to my knowledge as well, at the time, there was no doctor who was willing to do this laparoscopically because of the where my tumor was in my kidney. And it quite honestly was mortifying and probably one of the most terrifying experiences of my life to date. And I think that most people have been through quite a lot, whether it's medical or anything in your life. And this was the most terrifying experience. I also had an extreme phobia of needles. So even thinking about someone cutting me open and removing a part of my body was just absolutely horrifying. So I went in for surgery December 30. And I was there for five days. I woke up out of surgery. And he had felt like someone had taken a saw blade to the side of my body like they were cutting down a tree. It was an awful excruciating pain. I've never felt anything like that in my life. But I think that it makes me a stronger person now, looking back. But I didn't get up the first day. I wouldn't get out of the bed. And partially also because I found out that I was allergic to morphine. And I couldn't breathe when I woke up right away. I was on oxygen for a few days. And I had hives and I was very swollen. And then I was put on, I'm going to forget the name of pain medication, but I was on that for the entirety of my stay there. And I didn't get out of bed till about day three. I had sat up on the second day, but it was just I can't I just can't even describe the pain. It's unbelievable. And then after my seven days, I also spent a year leave in the hospital. That year, I went home. My parents took me home and I didn't leave my house for about six weeks, according to what my doctor had wanted me to do. He said that I would not feel comfortable in a car. And I had I was such cabin fever because all I wanted to do is leave the house. But you know, you can hardly sit up. You can hardly get out of bed. It took me about three weeks. I stayed in the guest room in my family's house because I couldn't walk up a flight of stairs because it was just too painful. But after about six weeks, I had gone back to let him look at my scar and how it was healing. And it, it looks fine. It looks great. I mean, other than the fact that I will have this, you know, six to eight inch scar on the body from the rest of my life, I think that I'm fine. I'm perfectly healthy now. It's just, sorry. It's such a difficult memory to talk about, but a very positive one too, because it only makes anyone who's dealt with it or is dealing with that much stronger. I think that it has made me an incredibly strong individual. I was never I wasn't a weak person prior. I always found myself to be a strong person, an outgoing person, a leader in some ways. And after this happened, I think for the first year afterwards, I was, I was distraught. I felt like, you know, why me? And it was a very self-pitying attitude. And I was never that person. And my mom would talk to me, she was the biggest and my father, my mother and my father and my brother and sister have been the most supporting people. Without them, I don't know where I would be, especially my mother and father, they would support me like no other. And I think that it was through what they would tell me. And you know, that nothing, if I could beat this, that I could do anything. And, you know, you grow up and you hear people tell you that you could do anything in life. And if you can do this, you'll be a stronger person for this. Having this experience, having gone through this experience, I am such a strong person now. I don't let things get to me like they used to. And if they do, I have to remind myself where I've been and where I am. And I think that it really has impacted my life in a weird way for the better, to be a better person. If I could say this bluntly, I would say to keep your head up and to realize that today sucks, tomorrow might be worse, the following few months might be even worse than the day that you had today. But if you can get through this, and if you can keep your head up and realize that there are people who love you and support you, and that you're not alone, and that there are so many other people out there who are dealing with what you're dealing with, that you can, you can push through it. You can realize that there's more to life than letting something like this trying to ruin it. And that's what I've gotten personally from my own experience. And that's the best advice I could give anyone is that kidney cancer sucks. The experience is not wonderful. But if you can get through it, you are going to be a very strong person. And you're going to love yourself even more. Join us again next month for another edition of kidney cancer news. I'm Kari Kanoski, wishing you good health.