Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment

Pouessel, D. ; Neuzillet, Y. ; Mertens, L. S. ; van der Heijden, M. S. ; de Jong, J. ; Sanders, J. ; Peters, D. ; Leroy, K.

; Manceau, A. ; Maille, P. ; Soyeux, P. ; Moktefi, A. ; Semprez, F. ; Vordos, D. ; de la Taille, A. ; Hurst, C. D. ; Tomlinson, D. C.

; Harnden, P. ; Bostrom, P. J. ; Mirtti, T. ; Horenblas, S. ; Loriot, Y. ; Houédé, N. ; Chevreau, C. ; Beuzeboc, P. ; Shariat, S. F. ; Sagalowsky, A. I. ; Ashfaq, R. ; Burger, M. ; Jewett, M. A. S. ; Zlotta, A. R. ; Broeks, A. ; Bapat, B. ; Knowles, M. A. ; Lotan, Y. ; van der Kwast, T. H. ; Culine, S. ; Allory, Y. ; van Rhijn, B. W. G.

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Fibroblast growth factor receptor 3 (FGFR3) is a major potential actionable target in urothelial bladder cancer (BC). We found that FGFR3 mutations appeared conserved in primary BC and corresponding lymph-node metastases. We also showed that the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. This suggests that personalized anti-FGFR3 therapy may improve BC treatment in the perioperative setting.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. 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). We found ZFGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) a parts per thousand yenT2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight >FGFR3 mutant a parts per thousand yenT2-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. >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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