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Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation,

“HIGHLIGHTS IN ADVANCED RENAL CELL CARCINOMA MANAGEMENT” Rome, February 24 th , 2012. Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy. Czech Republic. Estonia. USA. France. Canada. Australia. Denmark. United Kingdom. Japan.

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Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation,

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  1. “HIGHLIGHTS IN ADVANCED RENAL CELL CARCINOMA MANAGEMENT” Rome, February 24th, 2012 Dr.CamilloPorta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy

  2. Czech Republic Estonia USA France Canada Australia Denmark United Kingdom Japan Brazil Ethiopia China Egypt Indonesia India 0 5 10 15 20 25 Rate per 100,000 population The epidemiology of RCC • RCC accounts for: • 80–85% of renal cancers1 • 2–3% of all adult malignancies2 • 63,000 new cases/year in Europe • 26,000 mortalities annually • RCC is: • More common in men than women3,4 • Most frequently occurs in 60–70 year olds4 • More common in people from Northern European and North American countries3,4 Incidence Mortality 1. Motzer RJ et al. N Engl J Med 1996;335:865–75; 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559; 3. GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/; 4. Cancer Research UK, UK kidney cancer statistics. 2008 http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441.

  3. RCC: an unrelenting, progressive disease Presentation at diagnosis1: 45% with localized disease 25% with locally advanced disease 20–30% metastatic disease 33% of patients treated for localized disease will develop metastatic disease2 Common sites of metastasis include lung (75%), liver (18%), bone (20%), brain (8%)3 Median survival for patients with metastatic RCC (before the era of targeted agents) was 6–12 months4–7 1. National Cancer Institute. SEER cancer statistics fact sheet: cancer of the kidney and renal pelvis. Accessed 2009; 2. Flanigan RC et al. Curr Treat Options Oncol 2003;4:385–90. 3. Sachdeva K et al. Renal cell carcinoma., in eMedicine. 2008; 4. Gay PC et al. J Neurooncol 1987;5:51–6; 5. Decker DA et al. J Clin Oncol 1984;2:169–73; 6. Culine S et al. Cancer 1998;83:2548–53; 7. Doh LS et al. Oncology 2006;20:603–13.

  4. RCC: form the bench to the bedside RCC is a mainly sporadic (non-inherited) disease that occurs in 5 histologic subtypes, each caused by a different gene Clear cell (75-85%) Papillary (Type I + II) (12-14%) Chromophobic (4-6%) Oncocytic (2-4%) Collecting duct (1%) VHL C-met FH Birt-Hogg-Dubé

  5. VHL in RCC: a link to angiogenesis … In the presence of a mutated/deleted VHL gene, HIF-1 is not destroyed via the proteasome/ ubiquitin pathway, and thus accumulates, leading to the transcription of hypoxia inducible genes This results in the production of a series of growth factors, including VEGF and PDGF-, ultimately leading to increased angiogenesis

  6. VHL mutation/deletion Multiproteincomplex Increased glucose efflux VHL complex disrupted VHL protein Glut-1 -domain Mutant-domain HIF1-, HIF2- accumulation HIF HIF HIF VEGF CXCR4 PDGF TGF- Organ-specific metastasis Endothelial stabilisation Autocrine growth stimulation Angiogenesis … and much more Modified from: Bernards R. Nature 2003;425:247–8 & Lineham WM, et al. J Urol 2003;170:2163–72

  7. The ‘embarassment of the riches’ … *AVOREN study

  8. ThankYou for Your kindattention!!! T c.porta@smatteo.pv.it

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