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

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.

• Authors: D Pouessel, Y Neuzillet, L S Mertens, M S van der Heijden, J de Jong, J Sanders, D Peters, K Leroy, A Manceau, P Maille, P Soyeux, A Moktefi, F Semprez, D Vordos, A de la Taille, C D Hurst, D C Tomlinson, P Harnden, P J Bostrom, T Mirtti, S Horenblas, Y Loriot, N Houédé, C Chevreau, P Beuzeboc, S F Shariat, A I Sagalowsky, R Ashfaq, M Burger, M A S Jewett, A R Zlotta, A Broeks, B Bapat, M A Knowles, Y Lotan, T H van der Kwast, S Culine, Y Allory, B W G van Rhijn
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 27 Issue 7 Pg. 1311-6 (07 2016) ISSN: 1569-8041 [Electronic] England
• PMID: 27091807 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Biomarkers, Tumor
• FGFR3 protein, human
• Receptor, Fibroblast Growth Factor, Type 3

Topics

• Adult
• Aged
• Biomarkers, Tumor (genetics)
• Clinical Decision-Making
• Cystectomy
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Heterogeneity
• Humans
• Lymph Nodes (pathology)
• Male
• Middle Aged
• Mutation
• Perioperative Period
• Receptor, Fibroblast Growth Factor, Type 3 (antagonists & inhibitors, genetics)
• Urinary Bladder Neoplasms (drug therapy, genetics, pathology, surgery)