1. Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment
- Author
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Raheela Ashfaq, Patricia Harnden, A. De La Taille, Margaret A. Knowles, Yves Allory, A. Zlotta, Peter J. Boström, Annegien Broeks, Christine Chevreau, Dennis Peters, Yair Lotan, Pascale Maillé, Carolyn D. Hurst, S.F. Shariat, Pascale Soyeux, Dimitrios Vordos, S. Horenblas, Fannie Semprez, Yohann Loriot, P. Beuzeboc, B.W.G. Van Rhijn, T.H. Van Der Kwast, A. Manceau, Y. Neuzillet, Stéphane Culine, Tuomas Mirtti, Joyce Sanders, D. Pouessel, Darren C. Tomlinson, M.S. van der Heijden, Arthur I. Sagalowsky, Anissa Moktefi, Michael A.S. Jewett, J. De Jong, N. Houede, Maximilian Burger, Laura S. Mertens, Bharati Bapat, Karen Leroy, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'urologie [Mondor], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département d'oncologie médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut Claudius Regaud, Institut Curie [Paris], Département de pathologie [Mondor], and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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Oncology ,Male ,medicine.medical_treatment ,030232 urology & nephrology ,Receptor tyrosine kinase ,Targeted therapy ,0302 clinical medicine ,Medicine ,bladder ,Neoadjuvant therapy ,biology ,Hematology ,Middle Aged ,targeted therapy ,3. Good health ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Female ,musculoskeletal diseases ,Adult ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Clinical Decision-Making ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Cystectomy ,03 medical and health sciences ,Genetic Heterogeneity ,Internal medicine ,Biomarkers, Tumor ,cancer ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Perioperative Period ,Aged ,ta3126 ,Bladder cancer ,business.industry ,Genetic heterogeneity ,Cancer ,Original Articles ,Fibroblast growth factor receptor 3 ,ta3122 ,medicine.disease ,mutations ,stomatognathic diseases ,Urinary Bladder Neoplasms ,FGFR3 ,Mutation ,biology.protein ,Lymph Nodes ,heterogeneity ,business - Abstract
International audience; BACKGROUND:Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response.PATIENTS AND METHODS:We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).RESULTS:We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.CONCLUSIONS:FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.
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- 2016