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Eleventh International Kidney Cancer Symposium Presentation Notes An Overview of the Proceedings Joyce Graff FounderWellness Director VHL Family Alliance Michael B. Lawing Patient Advocate Liaison Kidney Cancer Association During the Symposium James Larkin, Ph.D., MRCP Royal Marsden Hospital, London, England displayed a slide showing alternative routes around a blocked passage in the London Subway System In his presentation Biologic Mechanisms of Resistance

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 2 The Eleventh International Kidney Cancer Symposium 2012 Reporting by Joyce W. Graff, VHL Family Alliance Executive Summary I was honored to be invited again this year to report on this important conference. This report is prepared with patients and families in mind. The meeting was designed as a Continuing Medical Education event for doctors, providing them with enrichment in this important area. Kidney cancer is the

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 3 significantly shrink the tumor, so surgery is probably the first course of action, but there should be a plan in place for what to do after the surgery. Some of the treatment options require analysis of the tumor tissue itself, or even tissue for formulation of personalized treatments. Without this prior planning, some options might be lost. There was a section on treatment options for a patient with metastatic disease

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 4 CommentaryLayout Michael B. Lawing, KCA Patient Advocacy Volunteer Dear Fellow Travelers As I complete my fifteenth year of survivorship of clearcell RCC, and a dozen years of dealing with active metastatic disease the information presented at the 11th International Kidney Cancer Symposium in Chicago can only begin to speak of how far we have come in dealing with this cancer. Presently we have more options for treatme

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 5 A World Without Kidney Cancer The Vision of the Kidney Cancer Association The Kidney Cancer Association KCA is a charitable organization made up of patients, family members, physicians, researchers, and other health professionals globally. It is the worlds first international charity dedicated specifically to the eradication of death and suffering from renal cancers. It is also by far the largest organization of its k

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 6 smartphone educational applications for the iPad, iPhone, and Android platforms. We sponsored the Sixth European Kidney Cancer Symposium in Warsaw, Poland. More than 700 medical professionals registered. Later in the year, more than 300 medical professionals attended the annual International Kidney Cancer Symposium in Chicago. Patient advocates who attended this meeting prepared summaries of the medical presentations t

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 7 Our capacity to attain these objectives, as well as being able to identify new ones, relies primarily on the level of public support for our mission. Monetary contributions are essential to this accomplishment. Even in the most difficult times, we strive to identify new sources of revenue, as well as identify new volunteers willing to assist us, so that our goals continue to be met. Our fulltime staff is very small, so

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 8 Contents The Eleventh International Kidney Cancer Symposium 2012 ....................................................................... 2 Executive Summary................................................................................................................................. 2 Management of Small Renal Masses .....................................................................................................

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 9 Management of Small Renal Masses This section, moderated by Dr. Jason Abel of the University of Wisconsin, was framed as a case study of a 30yearold man with a 3 cm tumor found when he had appendicitis. He underwent an appendectomy, followed by a closer evaluation of this kidney tumor. The six following presentations constituted a debate of the optimal surgical approaches for this patient. Dr. Jeffrey Cadeddu UTSW, Dal

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 10 the natural movements of the surgeons hands, so the training time is lower. Nonetheless the technology is still relatively new not all centers own these expensive machines, and not all surgeons have had significant experience in operating in this manner. Open surgery may be preferred for anyone who is a good surgical candidate with at least a 10year life expectancy. The goal is to remove the tumor completely, minimize

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 11 Dr. Inderbir Andy Gill, University of Southern California, was tasked with taking the Con position. He began by telling us that in his practice, robotic partial nephrectomy is a well established technique. His team has now done more than 2000 robotic or laparoscopic partial nephrectomies. The most important goal is to save nephrons. 33 of partial nephrectomies are now being done robotically or laparoscopically. The gr

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 12 Dr. Houston Thompson Mayo Clinic, Minnesota presented methods for saving nephrons during partial nephrectomy for small renal masses, in order to preserve kidney function and quality of life. In previous years it was thought that it was safe to clamp off the kidney for 3090 minutes. A series of studies have helped us to understand better what happens when the kidney is deprived of blood flow, and just how long it is sa

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 13 Dr. David Miller U Michigan spoke about partial nephrectomy. As a clinical oncologist, he works with outcome analysis how can we reduce death and suffering for patients with small renal masses Who needs treatment at all What is the role of surveillance How can we reduce morbidity and mortality from local therapy We need better treatments for patients who progress despite local therapy. We need to improve palliati

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 14 Management of Localized and Locally Advanced RCC Dr. Christopher Weight U Minnesota Case presentation 56 year old man with RCC and tumor thrombus into the artery. What to do Dr. Alan J. Pantick UCLA, Update on CAIX Imaging CAIX say CAnine is also called G25, MN75. It is a membraneassociated enzyme induced by tissue hypoxia. It is a member of the carbonic anhydrasse family, and is expressed in many cancer tissues, most

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 15 A Biopsy can tell you about the tissue type, but not about the grade and stage. The ECOG performance status scale rates the vigor of an individual from normal and healthy 1 to dead 5. Eastern Cooperative Oncology Group There is no standard measure for comorbidities. The more points accumulated, the greater the risk. This index is not a predictor of overall survival but it does indicate the complexity of management.

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 16 Consider pretreatment with anticoagulation medication to keep from encountering more problems during surgery. Dr. Leibovich recommends not installing a filter before surgery, as they get clogged and are difficult to remove. The larger the thrombus, the greater the risk that it has invaded the wall of the vein. He does frozen sections of the wall during surgery, to ensure that all the cancer has been removed. If necess

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 17 Dr. E. Jason Abel U Wisconsin, Role of Lymph Node Dissection Dr. Abel began by stating that all studies of this question are retrospective and involve a small number of patients, selection bias, and the lack of a standardized template for the procedure. Do RCC patients benefit from lymph node dissection NO in patients with small organconfined tumors YES if the patient has enlarged lymph nodes or is at high risk for

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 18 Dr. Chris Wood MD Anderson Cancer Center, Summary of Options for Locally Advanced Disease Dr. Wood summarized by presenting a patient case for the panel to consider A 58yo WM presents with gross hematuria and shortness of breath pulmonary embolism workup revealed ECOG performance status of 1, multiple medical comorbidities including a drug eluting stent to help prevent arterial fibrosis and blood clots and was placed

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 19 A Dedication to Andrew C. Novick, M.D. Excerpts from the Dedication page of Guideline for Management of the Clinical Stage 1 Renal Mass F or Andrew C. Novick, MD 19482008 Chairman of the Cleveland Clinic Glickman Urological and Kidney Institute many, Andy Novicks career was both the quintessence of leadership and the embodiment of the best in academic u rology. Andys clinical and intellectual contributions in the

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 20 Sept, 2010 Michael L. Blute, MD, invested as the Mary C. DeFeudis Chair of Cancer and Research at the University of Massachusetts Pictured from left UMass President Jack M. Wilson, Mary C. DeFeudis, Dr. Blute and Chancellor Michael F. Collins Photo Credits John Gillooly, Professional Event Images Dr. Michael Blute U Mass The Future of Multidisciplinary Care for Metastatic RCC RCC facts 60,000 people diagnosed each y

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 21 One major predictor of poor survival no surgical history. Metastatic RCC treated with targeted therapy without cytoreductive nephrectomy shows a 10 survival at the end of 5 years. Resecting the primary tumor and the mets yields 50 5y survival Version 2.2012, 021612 National Comprehensive Cancer Network, Inc. 2012, All rights reserved. A study from MSKCC shows that complete resection of mets was more important than t

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 22 Where are we going presurgical targeted therapy followed by debulking surgery risk of major surgical complications is not much greater than without targeted therapy 3040 of these patients will progress up to 25 will progress during a surgical break In addition to CARMENA, there are 22 phase II trials of neopresurgical TKI in progress We agonize over patients with metastatic kidney cancer and whether or not surge

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 23 Invited Abstracts from Young Investigators Dr. Benjamin P. Casavant U Wisconsin Isolation of RCC Cells Dr. Casavant is an inventor with a patent application pending. He presented his invention, VerIFAST, for our consideration an integrated system for flexible isolation and analysis of circulating tumor cells. Cancers shed cells into the bloodstream which can then be trapped by this device and used to diagnose cancer.

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 24 Kritti Mittal, M.D., Cleveland Clinic, Detection of Circulating Tumor Cells Dr. Mittal uses immunomagnetic enrichment to tag the CTCs, and microfilters capture these larger cells, or Bens method above. She does immunohistochemical staining. Cellsearch or Veridex assay finds cells that express EpCAM epithelial cell adhesion molecule. Only 21 of patients demonstrated EpCAM expression, so it is clear that the Veridex met

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 25 Sumanta Pal, M.D. City of Hope Comprehensive Cancer Center, Sumanta CA Duarte, Impact of Age on Treatment Trends and Clinical Outcomes As the population ages, we are seeing more mRCC in older adults. Approximately 60 of cancer incidence, and 70 of cancerrelated mortality, occurs in individuals over 65. The mean age at diagnosis of RCC is age 64. The efficacy of immunotherapy and targeted therapies in older adults wi

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 26 Tumor Suppressor Screens of 3p Chromatic Modulators Link BAPI Mutations to Poor Clinical Outcomes in ccRCC Abraham Hakimi, M.D., MSKCC We have known for a long time that genetic alteration of the VHL gene in kidney cancer Abraham Hakimi marker. tumors is an important prognostic MSKCCIt is lost in more than 90 of kidney cancer tumors. PBRM1 is the second most frequent genetic event in We have known for a long time that

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 27 Recent Insights into RCC Biology Does Hereditary and Sporadic Type 2 Papillary RCC Converge at Sustained NRF2 Activation Phenotype Aikseng Ooi, Ph. D., Van Andel Research Institute, Singapore The FH mutation is the hallmark of HLRCC, and causes papillary type 2 kidney cancer. Both FH and VHL mutations cause upregulation of HIF. NRF2 transcriptionactivation is a convergence point of these two tumor subtypes. What is N

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 28 Charles Swanton, M.D., Univ College London The Challenges of Genetics Heterogeneity to RCC Translational Research Is there evidence that heterogeneity is important to the success of targeted therapy Most tumors are heterogeneous. 5275 of somatic mutations are heterogeneous. A biopsy may not capture and profile all the mutations in a single tumor. They exhibit a branched evolution one change happens first, then others

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 29 Pankaj Seth, Ph.D. Beth Israel, Boston, Inhibiting RCC Metabolism In addition to the VEGF pathway, VHL also performs a function in control of metabolism, specifically the Warburg effect, which shifts energy production from oxidative phosphorylation to fermentative glycolysis. The more lactate is present, the less pyruvate is available to metabolism. Loss of VHL increases HIF1 activity, which further facilitates produc

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 30 Dr. Elisabeth Henske, Beth Israel Deaconess Dana Farber Harvard New Targets for the NonCC RCC BirtHoggDube Rare genetic syndromes can advance our understanding of sporadic cancers. Just as VHL has helped us to understand clear cell RCC 90 of all kidney cancer, so too BirtHoggDub syndrome BHD is helping us understand chromophobe kidney cancer about 5 of all kidney cancer. The VHL syndrome familial increases the risk of

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 31 W. Kimryn Rathmell, M.D., Ph. D., U North Carolina, Future Directions in RCC Translational Research What have we learned this year about RCC A L OT RCC is diverse, metabolism features prominently ccRCC features 3p loss, associated mutations, few other classic mutations ccRCC itself is genetically heterogeneous. RCC is interlinked with metabolism Linehan 2012 All the RCCs are linked in one way or another We are now

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 32 Patient Management Issues Elisabeth Heath, M.D., Karmanos Cancer Institute, Wayne State Univ, Michigan Importance of Dose in RCC Therapy, The Renal EFFECT trial RP2D is designed to evaluate dosing methods for Sunitinib 50 mg orally daily 4 weeks on2weeks off vs 37.5 mg orally daily continuously Median time to tumor progression is 9.9 months vs 7.1 months Axitinib is a second generation oral TKI 5 mg twice daily

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 33 There is a model of tumor growth dynamics using serial measurements of the sum of the longest tumor diameter from patients on the RECORD1 trial. Evaluating Everolimus, oral inhibitor of mTOR at 10 mg daily vs 5 mg daily. 10 mg daily dose shrinks target lesions more compared to 5 mg daily, although there is still antitumor activity. Now 3rd generation drugs TIVO1 trial evaluating tivozanib T vs sorafenib S in mRCC. Bet

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 34 Disparities in RCC Therapy, Dr. Ulka Vaishampayan Karmanos, Wayne State, Michigan Patients over 65 do respond, but not to temrisolimus. Overall, age as an isolated factor is unlikely to lead to therapeutic disparity. Comorbidities affecting performance status and delivery of therapy continue to have an impact. age 2059 African American White 4.46 2.87 60 4.35 3.6 With every 10,000 increase in income, the prevalence o

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 35 Dr. Naomi Haas U Penn Does Adjuvant Therapy Produce Toxicity Concerns There have been concerns about cardiac related adverse events. In one clinical trial the one patient who had a serious cardiac event was in fact on placebo. Patients who developed hypertension did better throughout, whether or not they had HBP therapy. Hypothyroidism as a predictive marker yes Handfoot syndrome as a marker of action These patients

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 36 Special Session Results of the BeST Trial Bevacizumab, Sorafenib, Temsirolimus Keith Flaherty, M.D., Massachusetts General. Boston The hypothesis is that targeting multiple growth and survival pathways in vascular endothelial cells will result in suppression of escape mechanisms to angiogenesis resistance. There is a randomized phase II trial, of the most active 2drug therapy singleagent bevacizumab chosen as

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 37 Rational Combination Therapy for RCC, Bernard Escudier, M.D, Institut GustaveRoussy France The combination of mTOR inhibitors and TKIs is toxic sunitinib temsirolimus impossible sutent everlimus impossible sorafenib temsirolimus impossible sutent bevacizumab impossble at full dose mTOR bevacizumab combination recommended for further testing dream strong enough to proceed, BUT mirage confirmed. temsiro

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 38 Surgery The Setting of Metastatic Disease Moderator Dr. Andrew Wagner, Beth Israel Deaconess, Boston Stephen Culp, M.D., PhD, U Virginia, Cytoreductive Nephrectomy and its Role in Metastatic RCC People who use cytoreductive surgery tend to be younger, have better insurance, and may be those who do more research in selfadvocacy. Newer therapies may result in primary tumor regression. Using neadjuvant therapy, most pa

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 39 Role of Neoadjuvant Medical Treatment Dr. Eric Jonasch MDACC Today the standard of care is cytoreductive surgery targeted therapy In 2012 the role of neoadjuvant therapy an alternate therapeutic paradigm that requires validation a discovery platform to detect new targets Presurgical therapy is safe bevacizumab delayed healing some, but the others do not Presurgical therapy can act as a litmus test restaging after 68

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 40 Having the posttreatment renal mass gives us information about how things change, so we can evaluate the results did the drug actually achieve its target and make a difference Cell Signaling Technology, Inc. 19992012 A higher total AMPK level is associated with better PFS AMPactivated protein kinase AMPK plays a key role as a master regulator of cellular energy homeostasis.

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 41 Role of Metastastectomy, Stephen Boorjian, M.D. Mayo clinic What is the role of surgical resection of mets does it help How to integrate it into the total treatment plan RCC does not respond to radiation, traditional chemotherapy, minimally responsive to cytokines While targeted responses are achieved, only 3 or less achieve complete response. Removing mets offers potentially curative treatment for mRCC. It avoids the

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 42 Scott Eggener, M.D., U Chicago, Summary of surgical options for metastatic disease Cytoreductive Nephrectomy CN randomized trials in the cytokine era showed median survival benefit of 6 months. Most trials for current systemic agents show benefit. Laparoscopic CN speeds time to targeted therapy when patient is a good candidate for it. Mets can metastasize to the sentinel lymph nodes in the area around the met, though

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 43 QA On Surgery and The Setting of Metastatic Disease Blute We are redesigning our approach to cancer patients. Jonasch Anyone who goes off these agents will have some rebound. Will it be a problem In the Sutent neoadjuvant study, where we stopped the agent and did surgery, we saw that some patients had brain mets that were not there 3 months before. Health care access is a major problem. We have patients who are qualif

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 44 Case for Moving Axitinib into the Front Line, Dr. Brian Rini, Cleveland Clinic Rini feels axitinib is now the standard of care. RCC is fundamentally VEGF driven. Potent inhibition of VEGF will produce the most robust clinical effects, and should be applied as soon as possible. Axitinib is doing well. The trial design starts patients off with 4 weeks at 5 mg, evaluated to see if their reactions were okay, if not, conti

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 45 Dr. Camillo Porta Pavia, Italy, San Matteo Univ How Does Recent Pazopanib Data Impact Our Prescription Paradigm The PISCES trial consists of 10 weeks of Pazopanib or Sutent 2 wks off then switch to the other drug another 10 weeks. At that point 22 weeks, they asked the patients which drug they preferred. Patients preferred Pazopanib due to better quality of life and less fatigue, less foot and mouth soreness. It de

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 46 Tivozanib as Firstline Therapy for mRCC, Dr. Robert J. Motzer, MSKCC Dr. Motzer said that Tivozanib is showing efficacy, safety, and tolerability. Tivozanob targets VEGFR. Most of the currently approved firstline therapies have a PFS of 11 months of less. Safety is a big issue for our patients they are looking for tolerability and good quality of life QoL Tivozanib inhibits VHGFR types 1, 2, and 3. Its a once daily d

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 47 Dr. Tim Eisen, Univ of Cambridge, England Does Emerging Data Justify a Change in the Standard of Care for Treatment of Nave Patients Are the data credible can we choose which drug is best for which patient Tivozanib and axitinib and 2x more potent than sutent, sorafenib. Disease assessments are not optimal in the studies. High Blood Pressure, hypothyroidism, and dysphonia disturance of vocal function are ontarget effe

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 48 Therapy for the VEGF Resistant Patient Biologic Mechsnisms of Resistance, Dr. James Larkin Royal Marsden Hospital, London AntiVEGF drug resistance is inevitable patients die because of resistance can be dynamic and reversible The issue is that while the drug blocks the primary path from A to B, there are many other compensatory routes similar to London Underground. The tumor figures out a way to grow in spite of the a

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Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 50 Existing Clinical Data in VEGF Resistant Disease Jennifer Knox, M.D., Princess Margaret Hospital, Toronto Does the sequence of treatements matter TKI followed by an mTOR inhibitor TKI followed by a 2nd line TKI Among the people who did not gain significant benefit from 1st line therapy, there were very poor outcomes. What should we do following tumor progression on a VEGFinhibitor TKI Follow with.. . Everolimus vs pla

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 51 VEGF vs mTOR How does the Wyeth 404 result impact Decision making Dr. Thomas Hutson Texas Oncology, Dallas The results of this trial were presented at ESMO the previous Monday October 1, 2012 so the audience had not yet seen it. Temsirolimus was approved with only a narrow indication in Europe, so Wyeth launched another trial to broaden the indication. Does sequence matter The INTORSECT trial enrolled 512 people in 2

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 52 Audience dialogue Kaelin why not combination therapy to manage resistance Just because they have not worked to date doesnt mean that there might not be a combination in future. In the 1990s Kaelin worked with the drug companies to try VEGF inhibitors they said that medical therapy had never worked in kidney cancer and therefore never would. Combination therapy has been the answer is many other diseases, why not in kid

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 53 Emerging new agents Once we determine that VEGF is no longer a valid target, what else is there PI3K, Dr. Dan Cho Beth Israel, Boston Allosteric inhibitors of TORC1 torisel, RAD001 have shown activity in mRCC. TORC1 is sensitive to the rapalogues, cells can get around it pretty easily. Inhibiting TORC1 can drive TORC2 and Mak Kinase, another negative effect. Dependence on the HIFs by TORC 1 or 2 activitiy. HIF2 is the

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 54 cMET as a target in RCC cabozaninib, Dr. Toni Choueiri Dana Farber, Boston MET and VEGFR cooperate to promote tumor survival through angiogenesis, invasionmotility, proliferation, survival. Cabozantinib XL184 characteristics dual VEGF and MET inhibitor ALLIANCECALGB trial, Cabo vs Sunit N150 untreated ccRCC with poor risk and bone mets, randomize to Cabo vs Papillary RCC oncogenic events in PRC are largely unknown,

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 55 How Should You Choose Secondline Therapy for mRCC, Dr. Jorge Garcia Cleveland Clinic What is the biologic or molecular data What are the goals of care How should we interpret the existing clinical data to choose Secondline therapy is a moving target sutinitinib vs pazopanib vs interferonbevacizumab vs highdose IL2 vs tivozanib. We do not know enough at this point about the underlying biological mechanisms to choose am

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 56 Schoenfeld Lecture ScienceDriven Kidney Cancer Clinical Trials In 1989 Eugene Schonfeld was diagnosed with kidney cancer. What he accomplished within the span of a few short years afterwards is quite remarkable. When Gene was diagnosed he found there was nothing useful at the patient level available about his diagnosis of kidney cancer. His physician challenged him his exact words were Gene if it bothers you so God da

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 57 Award Presentation and Speaker Introduction by Dr. David McDermott Bill Kaelin is the Chief Resident in Kidney Cancer he has provided leadership, and better outcomes for people not only with cancer but also stroke and myocardial infarction. When your slides begin with VHL HIF angiogenesis ... thats the work of his lab. Also as a good chief he sets high standards. No one can find the weaknesses in a plan than Bill, b

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 58 The genes most commonly mutated in ccRCC are VHL, PBRM1, SETD2, BAP1, mTOR. Four of these are on 3p. When you lose 3p, you lose multiple tumor suppressor genes relevant to kidney cancer. Other genes found to be mutated PTEN, PI3KCA, TP43, ATM, MLL3, NRF2, ARID1A. Several of these are on the mTOR pathway. Kaelin is seeing too many of what he calls Emperors new clothes trials outcomes that show very small differences,

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 59 What we have used so far are different selectivity profiles of kinase inhibitors. Sunitinib is a multitargeted kinase inhibitor. By contrast, PTK787 was more specific, Sorafenib has 34 targets. HIG is inhibited by rapamycinlike drugs VEGF is inhibited by Avastin KDR is inhibited by sorafenib or sunitinib All three are inhibiting the same pathway, and if resistance arises, they are all out of business Rapamycinlike

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 60 QA Preclinical models will be important VHL does more than HIF. What about the other branches If you turn off HIF2alpha you would be well on your way to inhibiting tumor growth. Many of the other pathways are not so easily druggable. Emerging Therapeutic approaches Experimental Immunotherapy, Vaccine Strategies Dr. Robert A. Figlin Cedars Sinai, Los Angeles immune system plays an imporant role in controlling tumor gr

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 61 PD1PDL1 Blockade David F. McDermott, M.D. Beth Israel Deaconess, Boston Immunotherapy is important and we need to work on improving immune responsiveness and to improve responsiveness through possible potential combination therapies. we need to implement even earlier therapy focusing on the immune response. We are looking at the PD1 antibodies in combination with dendritic cell vaccines which makes sense. Perhaps most

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 62 Role of Tumor Microenvironment in RCC James H. Finke, M.D. Cleveland Clinic PDL1 B7H1 expession by RCC and its suppression of T cell function. They modified the tumor microenvironment through the use of Sunitinib. In mouse models, using the melanoma vaccine, the combination is much more robust. The combination improved the T cell response. Clinical trials with sunitinib plus immunotherapy are going on now under the a

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 63 Immune Checkpoint Inhibitors, Biomarker Development, Rational Combinations, Charles Drake, M.D., Ph. D., Johns Hopkins Why immunotherapy mRCC presents an array of diverse and moving targets phylogenetic relationships of tumor regimens. Can the immune system hit the targets yes In the most current trials, there have been 2 complete responses, colorectal cancer, 3 doses, watched 2 years, brain lesion, and there is sti

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 64 The PISCES and COMPARZ trials showed that Pazopanib was preferred by patients over Sunitinib. However the therapeutic results of the two agents were very similar, and half the patients on each agent required dose reductions due to side effects. 20 Sunitinib and 24 Pazopanib of the participants had to discontinue therapy due to serious adverse effects. By contrast, in the Tivozanib trial, only 12 of patients needed dos

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 65 Atkins proposed a new RCC Therapy Algorithm for 2012 RCC Therapy Algorithm 2012 Tumor Markers Treatment choice PDL1 expression AntiPD1 based therapy PDL1 VHL null, Selective VEGF BAP1 WT inhibitor PDL1 VHL null, VEGF inhibitor 1stline therapy BAP1 mutant agent X mTOR activation, TOR inhibitor high LDF Other mutation specific inhibitor 2ndline therapy Not necessary Refs Future leaders of RCC investigation Setting I

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 66 Editorial Addenda A Closing Note for Consideration by Michael B. Lawing Gap Between Urologist and Survivor Perceptions Tips for Survivors and Caregivers Interesting statistics were released in the American Association for Cancer Research Cancer Progress Report earlier this year. The report states that in 2012 there will be approximately 13.7 million cancer survivors in the United States that is a drastic increase

Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 67 On this question 73 of the doctors that responded strongly agreed they gave their patients clear information whereas 38 of the patients strongly agreed and 22 somewhat agreed that they wished for more clear information about their kidney cancer after surgery. 36 the patients strongly agreed that they should have had more detailed information from the pathology etc. and 22 somewhat agreed 68 of the doctors stated they

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Eighth International Kidney Cancer Symposium Chicago 2012 Graff Lawing 69 It should go without saying that the surveys listed above are from a very small group of individuals with no control as to how many are patients of any particular care facility or how large a practice the urologists have. Nevertheless the disconnect between what the patients and the doctors perceive appears to be significant. When considering the comments made by Dr. Porta of the Pisces trial and takehome messages the

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