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

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbermdw170
Pages (from-to)1311-1316
Number of pages6
JournalAnnals of Oncology
Volume27
Issue number7
DOIs
StatePublished - Jul 1 2016

Fingerprint

Receptor, Fibroblast Growth Factor, Type 3
Urinary Bladder Neoplasms
Mutation
Neoplasms
Therapeutics
Cystectomy
Receptor Protein-Tyrosine Kinases

Keywords

  • Bladder
  • Cancer
  • FGFR3
  • Heterogeneity
  • Mutations
  • Targeted therapy

ASJC Scopus subject areas

  • Medicine(all)
  • Hematology
  • Oncology

Cite this

Pouessel, D., Neuzillet, Y., Mertens, L. S., van der Heijden, M. S., de Jong, J., Sanders, J., ... Van Rhijn, B. W. G. (2016). Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: Implications for perioperative anti-FGFR3 treatment. Annals of Oncology, 27(7), 1311-1316. [mdw170]. https://doi.org/10.1093/annonc/mdw170

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, Arthur I; Ashfaq, R.; Burger, M.; Jewett, M. A S; Zlotta, A. R.; Broeks, A.; Bapat, B.; Knowles, M. A.; Lotan, Yair; van der Kwast, T. H.; Culine, S.; Allory, Y.; Van Rhijn, B. W G.

In: Annals of Oncology, Vol. 27, No. 7, mdw170, 01.07.2016, p. 1311-1316.

Research output: Contribution to journalArticle

Pouessel, D, Neuzillet, Y, Mertens, LS, van der Heijden, MS, 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, CD, Tomlinson, DC, Harnden, P, Bostrom, PJ, Mirtti, T, Horenblas, S, Loriot, Y, Houédé, N, Chevreau, C, Beuzeboc, P, Shariat, SF, Sagalowsky, AI, Ashfaq, R, Burger, M, Jewett, MAS, Zlotta, AR, Broeks, A, Bapat, B, Knowles, MA, Lotan, Y, van der Kwast, TH, Culine, S, Allory, Y & Van Rhijn, BWG 2016, 'Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: Implications for perioperative anti-FGFR3 treatment', Annals of Oncology, vol. 27, no. 7, mdw170, pp. 1311-1316. https://doi.org/10.1093/annonc/mdw170
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, Arthur I ; Ashfaq, R. ; Burger, M. ; Jewett, M. A S ; Zlotta, A. R. ; Broeks, A. ; Bapat, B. ; Knowles, M. A. ; Lotan, Yair ; van der Kwast, T. H. ; Culine, S. ; Allory, Y. ; Van Rhijn, B. W G. / Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer : Implications for perioperative anti-FGFR3 treatment. In: Annals of Oncology. 2016 ; Vol. 27, No. 7. pp. 1311-1316.
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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.",
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TY - JOUR

T1 - Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer

T2 - Implications for perioperative anti-FGFR3 treatment

AU - Pouessel, D.

AU - Neuzillet, Y.

AU - Mertens, L. S.

AU - van der Heijden, M. S.

AU - de Jong, J.

AU - Sanders, J.

AU - Peters, D.

AU - Leroy, K.

AU - Manceau, A.

AU - Maille, P.

AU - Soyeux, P.

AU - Moktefi, A.

AU - Semprez, F.

AU - Vordos, D.

AU - de la Taille, A.

AU - Hurst, C. D.

AU - Tomlinson, D. C.

AU - Harnden, P.

AU - Bostrom, P. J.

AU - Mirtti, T.

AU - Horenblas, S.

AU - Loriot, Y.

AU - Houédé, N.

AU - Chevreau, C.

AU - Beuzeboc, P.

AU - Shariat, S. F.

AU - Sagalowsky, Arthur I

AU - Ashfaq, R.

AU - Burger, M.

AU - Jewett, M. A S

AU - Zlotta, A. R.

AU - Broeks, A.

AU - Bapat, B.

AU - Knowles, M. A.

AU - Lotan, Yair

AU - van der Kwast, T. H.

AU - Culine, S.

AU - Allory, Y.

AU - Van Rhijn, B. W G

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - Bladder

KW - Cancer

KW - FGFR3

KW - Heterogeneity

KW - Mutations

KW - Targeted therapy

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