Paris Cancer Institute: CARPEM has a strong activity in uro-oncology and involves 3 departments of APHP.Centre (Hematology and Oncology department, Imaging, Nuclear Medicine and Pathology department and Biology, Physiology and Genomic Medicine department). It is the most important surgical center dedicated to uro-oncology tumor in the Great Paris with national and international expertise in prostate, bladder and kidney tumors. Specifically, 28 beds in urology are dedicated to uro-oncology. This program took in charge 2995 new cases of prostate, kidney, bladder cancers during the last 3 years (see table 2), 1339 new cases of urological tumors have been surgically removed during the last 3 years and 2415 cycles of chemotherapy/immunotherapy have been performed (for detail see annex 1). It involves 2 sites of the APHP.Centre (Pompidou and Cochin hospitals) with very similar organization with both medical and surgery strengths. Furthermore, a dedicated genetic counselling is proposed for patients in case of suspicion of Von Hippel Lindau disease, Birt-Hogg-Dubé syndrome, etc…. One hundred patients and their relatives are addressed to this consultation each year for suspicion of hereditary renal cancers. All these clinical activities are structured around 2 weekly cancer multidisciplinary team meetings. These meetings follow the INCA national guidelines, and ESMO guidelines.

This program developed intensive clinical and translational research in broad fields from surgery to personalized medicine. A strong expertise in the clinical care of metastatic kidney disease from surgery to immunotherapy has been acquired during last years. A first trial based on genomic characterization of kidney cancers has been launched (BIONIKK trial). The program developed also an expertise in robotic prostatic surgery and on focal treatment modalities as well as in personalized medicine and immunotherapy in bladder cancer.

Clinical research

Clinical research is developed according to 2 axes (clinical interventional trial and surgery) with strong commitment of both medical physicians and surgeons. In the following section we will highlight the major successes in medical and surgical innovation in treatment of urologic cancers of 2018. In a nutshell 37 clinical trials are open to inclusion (22 phase III, 15 phase Ib/II) see annex 2. Twelve are dedicated to prostate cancer, 14 are dedicated to bladder cancer and 11 are dedicated to renal cancer.

Prostate Cancers

Recent studies on chemotherapy and new hormonal therapies in prostate cancers were conducted and have shown the lack of treatment efficacy of hormonal therapy combo or alone or with docetaxel in patients with rising PSA and hormone sensitive (Oudard S et al, JAMA Oncol 2019). We also led a large European retrospective study based on CATS registry showing that clinical progression in metastatic castration-resistant prostate cancer patients is associated with poor outcomes as compared to prostate-specific antigen or radiological only progression (Delanoy N et al, Eur J Cancer 2019). We participated to the phase 3 SPARTAN trial to evaluate the effect of apalutamide on metastasis-free survival in nonmetastatic castration-resistant prostate cancer and a PSA doubling time of 10 months or less showing metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo (Smith MR et al, New Engl J Med  2018).

Concerning surgery, we focused our research on focal treatment modalities. Prof. N. Barry Delongchamps set up the FOSTINE trial (NCT03023345) which is a “first-in-man” pilot study evaluating microwave focal ablation, delivered through a trans-rectal approach, with organ-based tracking image fusion. The main endpoint was reached in 8 among the 10 patients already treated (80%) with no reported adverse event after one-year follow-up. A multicentric European trial coordinated by Prof. N. Barry Delongchamps, will start in December 2019. Primary endpoint will be the absence of tumor within the treated area at 1 year.

Renal, Urothelial and Bladder cancers

Pr. A Mejean led an international phase III trial in metastatic renal carcinoma demonstrating the non-inferiority of the sunitinib arm as compared to the nephrectomy-sunitinib arm with regard to overall survival. No significant differences in response rate or progression-free survival was observed (Méjean A et al, New Engl J Med 2018).

NEMIO design

Set-up by our group, we are conducting 2 phase II trials : BIONIKK trial (NCT02960906) first gene expression based randomized phase II trial in renal cell carcinoma (see research translational section), and NEMIO phase II trial (NCT03549715) testing the combination of chemotherapy with immune checkpoint blocker (ICB) in muscle invasive bladder cancer in neoadjuvant setting (see figure). The first 12 patients have been enrolled from December 2018 and July 2019 and we expect recruitment to be completed in 2021.

Translational research

Our translational research is based both on the characterization of genetic alterations in tumors cells and on the study of tumor microenvironment (immune and endothelial cells). This programinvolves 4 research teams of the SIRIC CARPEM. These research teams are led by E. Tartour, AP. Roqueplo, I. Cremer, and J. Zucman-Rossi. A collaboration was set-up with V.Coffin team at the INEM.

Microenvironment and genomics in clear-cell Renal Cell Carcinoma RCC

BIONIKK design

One of the major achievements in the last 5 years is the molecular characterization of the tumor cells and their microenvironment in kidney cancer. A significant contribution has been done to the molecular transcriptomic analysis of RCC within the “Programme Carte d’Identité des Tumeurs” leading by the French League Against Cancer. Based on these characterizations, 4 different RCC groups were identified. These results lead us to set-up the first gene expression based randomized phase II trial in RCC, BIONIKK-1 trial (NCT02960906) testing either tyrosine kinase inhibitors or ICB according to the determination of molecular metastatic RCC subgroups. Two hundred patients were randomized, the last being in July 2019.

We participated to TRACERx Renal program, using combination of whole-genome sequencing analysis and multi-region sampling approach to provide insights into the nature and key oncogenic events in RCC (Mitchell TJ et al, Cell 2018).

Pr. Helley and Dr. Mauge (E. Tartour team at PARCC) conduct a translational program that focuses on the study of the circulating vascular compartment including mature or progenitor circulating endothelial cells, and plasma factors related to angiogenesis. They assessed the role of plasma biomarkers to predict the response to antiangiogenic treatments in 2 clinical trials including patients with renal and prostate cancer. They showed in PREINSUT phase II trial (NCT00930345) that biomarkers associated with primary renal tumor size change under sunitinib treatment were stromal cell-derived factor-1 (SDF1) and platelet-derived growth factor (PDGF) (Mauge L et al, Clin Cancer Res 2018).

Dr Burnichon, Dr Favier, Dr Verkarre and Pr Timsit (J Favier & AP Roqueplo Team) are developing a program dedicated to rare RCC. Based on their former studies on integrative genomic characterization of pheochromocytoma and paraganglioma that led to the identification of new therapeutic targets and biomarkers (Job S, Clin Cancer Res, 2019), they built a program dedicated to the molecular profiling of rare subtypes of kidney tumors. Their main objective is the identification of carcinogenesis pathways involved in the different rare RCC subtypes and their relevance for targeted therapy. Chromophobe RCCs are currently extensively studied.

Based on 2 different studies PREINSUT and BIONIKK, Pr. L. Fournier (B. Tavitian team) developed a radiomics approach in RCC. A radiomic signature that differentiated two groups of patients with very different outcomes in terms of PFS (1.4 vs. 16.1 months, p = 0.0075) and OS (5.6 vs 29.2 months; p = 1.78.10^-5) was identified. Confirmation of these results is being analyzed on an independent validation population from the BIONIKK study.

Stem cell studies in prostate cancers

The team of V. Goffin uses various preclinical models and clinical samples to understand the molecular and cellular bases of prostate cancer resistance to castration. The team recently identified stem/progenitor cells that resist castration and promote cancer recurrence. Current researches aim to identify clinically relevant biomarkers of these castration-resistant primitive cells and actionable pathways to eradicate them.

All these research areas are developed in programs 1 and 2 of the SIRIC CARPEM.

The Urologic cancer Program integrates 20 residents and 18 fellows each year. Weekly dedicated internal seminars are organized on both sites.

Medical and surgical teams are widely involved in the university teaching of urologic pathologies in University of Paris and in several national teaching degrees/master’s degrees in the field of oncology :

• Inter University Diploma in urology oncology coordinated by Albiges L & Fizazi K from Paris Diderot University & Mejean A & Oudard S from University of Paris
• University Diploma on therapeutic immunology from Paris Descartes : W.H. Fridman, F Pages, E Tartour
• Master 2 in clinical oncology: Prs F Goldwasser, J Alexandre & S Oudard
• Surgery diploma of urology at the University of Paris
• ILLUMENS on animals (Prs Mejean & Timsit)
• Urology diploma (ECU, Pr Mejean)
• Master in oncology on Targeted therapies and Checkpoint inhibitors (Prs JY Pierga, J Alexandre & S Oudard).

Based on our skillness we would like to

• Increase the rate of inclusion in trials to 15% of all patients with urological cancer of less than 75 years old
• Implement prostate cancer screening and developing in parallel focal treatment
• Reinforce translational research activities, by focusing on microenvironment and biomarkers of response to immunotherapies in bladder and kidney cancers.
• Develop our expertise in translational research on rare tumors: adrenal tumors, neuroendocrine prostate and bladder cancers, Bellini and medullary kidney cancer and joint this effort with the national France Genomics 2025 program dedicated to whole genome sequencing of rare cancers
• Develop a translational research on prostate cancer by applying to an emergent research grant to the SIRIC CARPEM

The selected following publications highlight the strength of clinical and translational research developed in the urologic program:

1. Carton E, Noe G, Huillard O, Golmard L, Giroux J, Cessot A, Saidu NE, Peyromaure M, Zerbib M, Narjoz C, Guibourdenche J, Thomas A, Vidal M, Goldwasser F, Blanchet B, Alexandre J. Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients. Eur J Cancer. 2017;72:54–61.
2. Clément-Zhao A, Auvray M, Aboudagga H, Blanc-Durand F, Angelergues A, Vano YA, Mercier F, El Awadly N, Verret B, Thibault C, Oudard S. Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer. BJU Int. 2018;121:203-208.
3. Oudard S, Latorzeff I, Caty A, Miglianico L, Sevin E, Hardy-Bessard AC, Delva R, Rolland F, Mouret L, Priou F, Beuzeboc P, Gravis G, Linassier C, Gomez P, Voog E, Muracciole X, Abraham C, Banu E, Ferrero JM, Ravaud A, Krakowski I, Lagrange JL, Deplanque G, Zylberait D, Bozec L, Houede N, Culine S, Elaidi R. Effect of Adding Docetaxel to Androgen-Deprivation Therapy in Patients With High-Risk Prostate Cancer With Rising Prostate-Specific Antigen Levels After Primary Local Therapy: A Randomized Clinical Trial. JAMA Oncol. 2019;5:623-32.
4. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, Lopez-Gitlitz A, Trudel GC, Espina BM, Shu Y, Park YC, Rackoff WR, Yu MK, Small EJ; SPARTAN Investigators. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378:1408-1418.
5. Delanoy N, Hardy-Bessard AC, Efstathiou E, Le Moulec S, Basso U, Birtle A, Thomson A, Krainer M, Guillot A, De Giorgi U, Hasbini A, Daugaard G, Bahl A, Chowdhury S, Caffo O, Beuzeboc P, Spaeth D, Eymard JC, Fléchon A, Alexandre J, Helissey C, Butt M, Priou F, Lechevallier É, Deville JL, Goupil MG, Morales R, Thiery-Vuillemin A, Gavrikova T, Barthelemy P, Sella A, Fizazi K, Baciarello G, Fererro JM, Laguerre B, Verret B, Hans S, Oudard S. Sequencing of Taxanes and New Androgen-targeted Therapies in Metastatic Castration-resistant Prostate Cancer: Results of the International Multicentre Retrospective CATS Database. Eur Urol Oncol. 2018;1:467-475.
6. Mauge L, Mejean A, Fournier L, Pereira H, Etienne-Grimaldi MC, Levionnois E, Caty A, Abadie-Lacourtoisie S, Culine S, Le Moulec S, Linassier C, Théodore C, Ravaud A, Albiges L, Grine A, Tartour E, Milano G, Gille AS, Verkarre V, Helley D, Oudard S; PREINSUT study group. Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial. Clin Cancer Res. 2018;24:5534-5542
7. Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, Geoffrois L, Thiery-Vuillemin A, Cormier L, Lang H, Guy L, Gravis G, Rolland F, Linassier C, Lechevallier E, Beisland C, Aitchison M, Oudard S, Patard JJ, Theodore C, Chevreau C, Laguerre B, Hubert J, Gross-Goupil M, Bernhard JC, Albiges L, Timsit MO, Lebret T, Escudier B. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2018;379:417-427
8. Mitchell TJ, Turajlic S, Rowan A, Nicol D, Farmery JHR, O’Brien T, Martincorena I, Tarpey P, Angelopoulos N, Yates LR, Butler AP, Raine K, Stewart GD, Challacombe B, Fernando A, Lopez JI, Hazell S, Chandra A, Chowdhury S, Rudman S, Soultati A, Stamp G, Fotiadis N, Pickering L, Au L, Spain L, Lynch J, Stares M, Teague J, Maura F, Wedge DC, Horswell S, Chambers T, Litchfield K, Xu H, Stewart A, Elaidi R, Oudard S, McGranahan N, Csabai I, Gore M, Futreal PA, Larkin J, Lynch AG, Szallasi Z, Swanton C, Campbell PJ; TRACERx Renal Consortium.Cell. Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal. Cell 2018 Apr 19;173:611-623.e17.
9. Job S, Draskovic I, Burnichon N, Buffet A, Cros J, Lépine C, Venisse A, Robidel E, Verkarre V, Meatchi T, Sibony M, Amar L, Bertherat J, de Reyniès A, Londoño-Vallejo A, Favier J, Castro-Vega LJ, Gimenez-Roqueplo AP. Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma. Clin Cancer Res. 2019 Jan 15;25:760-770.
10. Bernichtein S, Pigat N, Barry Delongchamps N, Boutillon F, Verkarre V, Camparo P, Reyes-Gomez E, Mejean A, Oudard SM, Lepicard EM, Viltard M, Souberbielle JC, Friedlander G, Capiod T, Goffin V. Vitamin D3 prevents calcium-induced progression of early-stage prostate tumors by counteracting TRPC6 and calcium sensing receptor upregulation. Cancer Res. 2017; 77:355-36.
11. Granier C, Dariane C, Combe P, Verkarre V, Urien S, Badoual C, Roussel H, Mandavit M, Ravel P, Sibony M, Biard L, Radulescu C, Vinatier E, Benhamouda N, Peyromaure M, Oudard S, Mejean A, Timsit MO, Gey A, Tartour E. Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma. Cancer Res 2017; 77: 1075-1082.
12. Blanchet B, Carton E, Alyamani M, Golmard L, Huillard O, Thomas-Scheomann A, Vidal M, Goldwasser F, Sharifi N, Alexandre J. A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients. Pharmacol Res. 2018;136:56-61.
13. Motzer RJ, Rini BI, McDermott DF, Arén Frontera O, Hammers HJ, Carducci MA, Salman P, Escudier B, Beuselinck B, Amin A, Porta C, George S, Neiman V, Bracarda S, Tykodi SS, Barthélémy P, Leibowitz-Amit R, Plimack ER, Oosting SF, Redman B, Melichar B, Powles T, Nathan P, Oudard S, Pook D, Choueiri TK, Donskov F, Grimm MO, Gurney H, Heng DYC, Kollmannsberger CK, Harrison MR, Tomita Y, Duran I, Grünwald V, McHenry MB, Mekan S, Tannir NM; CheckMate 214 investigators. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomized, controlled, phase 3 trial. Lancet Oncol.2019 Aug 16.

Annex 1:  Main indicators of clinical activities

_{KC: Kidney cancer; TKi: Tyrosine kinase inhibitor}

 _{CT chemotherapy}

 _{CT chemotherapy}

Annex 2:  Ongoing Clinical Trials

If you are interested by this program and want to candidate to a PhD, post doctoral position, contact the leader

Pr Stéphane Oudard