D Pouessel1, Y Neuzillet2, L S Mertens2, M S van der Heijden3, J de Jong4, J Sanders5, D Peters6, K Leroy7, A Manceau7, P Maille8, P Soyeux9, A Moktefi8, F Semprez9, D Vordos10, A de la Taille11, C D Hurst12, D C Tomlinson12, P Harnden12, P J Bostrom13, T Mirtti14, S Horenblas2, Y Loriot15, N Houédé16, C Chevreau17, P Beuzeboc18, S F Shariat19, A I Sagalowsky20, R Ashfaq21, M Burger22, M A S Jewett23, A R Zlotta24, A Broeks6, B Bapat25, M A Knowles12, Y Lotan20, T H van der Kwast26, S Culine27, Y Allory28, B W G van Rhijn29. 1. Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil Department of Medical Oncology, Hôpital Saint-Louis, AP-HP, Paris, France. 2. Departments of Surgical Oncology (Urology). 3. Medical Oncology. 4. Pathology. 5. Pathology Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 6. Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. 7. Tissue Biobank Unit. 8. Departments of Pathology. 9. Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil. 10. Urology, Hôpital Henri Mondor, APHP, Créteil, France. 11. Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil Urology, Hôpital Henri Mondor, APHP, Créteil, France. 12. Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, UK. 13. Departments of Urology Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto. 14. Pathology, University of Turku, Turku, Finland. 15. Department of Cancer Medicine and INSERM U981, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif. 16. Department of Oncological Medicine, Institut Bergonié, Bordeaux. 17. Department of Oncological Medicine, Institut Claudius Régaud, Toulouse. 18. Department of Oncological Medicine, Institut Curie, Paris, France. 19. Departments of Urology Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria. 20. Departments of Urology. 21. Pathology, University of Texas, Southwestern Medical Center, Dallas, USA. 22. Department of Urology, Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany. 23. Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto. 24. Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto Departments of Surgery (Urology). 25. Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto. 26. Department of Pathology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada. 27. Department of Medical Oncology, Hôpital Saint-Louis, AP-HP, Paris, France Department of Medical Oncology, Paris 7 University, Paris. 28. Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil Departments of Pathology Department of Pathology, Université Paris Est, UPEC, Créteil, France. 29. Departments of Surgical Oncology (Urology) Department of Urology, Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto Departments of Surgery (Urology) Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto b.v.rhijn@nki.nl.
Abstract
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.
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.
Authors: Ekaterina Olkhov-Mitsel; Andrea J Savio; Ken J Kron; Vaijayanti V Pethe; Thomas Hermanns; Neil E Fleshner; Bas W van Rhijn; Theodorus H van der Kwast; Alexandre R Zlotta; Bharati Bapat Journal: Transl Oncol Date: 2017-02-03 Impact factor: 4.243
Authors: Joshua J Meeks; Hikmat Al-Ahmadie; Bishoy M Faltas; John A Taylor; Thomas W Flaig; David J DeGraff; Emil Christensen; Benjamin L Woolbright; David J McConkey; Lars Dyrskjøt Journal: Nat Rev Urol Date: 2020-03-31 Impact factor: 14.432