Journal
ANNALS OF ONCOLOGY
Volume 27, Issue 7, Pages 1311-1316Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdw170
Keywords
FGFR3; mutations; heterogeneity; bladder; cancer; targeted therapy
Categories
Funding
- University of Toronto
- Dutch Cancer Society - KWF Kankerbestrijding
- European Urological Scholarship Programme
- Cancer Research UK
- French Urological Association
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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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