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



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.
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.
D
D
Pouessel
Departments of Surgical Oncology (Urology).
Y
Y
Neuzillet
Departments of Surgical Oncology (Urology).
L S
LS
Mertens
Medical Oncology.
M S
MS
van der Heijden
Pathology.
J
J
de Jong
Pathology Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
J
J
Sanders
Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
D
D
Peters
Tissue Biobank Unit.
K
K
Leroy
Tissue Biobank Unit.
A
A
Manceau
Departments of Pathology.
P
P
Maille
Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil.
P
P
Soyeux
Departments of Pathology.
A
A
Moktefi
Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil.
F
F
Semprez
Urology, Hôpital Henri Mondor, APHP, Créteil, France.
D
D
Vordos
Inserm U955, Hôpital Henri Mondor, APHP, Team 7 Translational Research of Genito-Urinary Oncogenesis, Créteil Urology, Hôpital Henri Mondor, APHP, Créteil, France.
A
A
de la Taille
Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, UK.
C D
CD
Hurst
Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, UK.
D C
DC
Tomlinson
Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, UK.
P
P
Harnden
Departments of Urology Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto.
P J
PJ
Bostrom
Pathology, University of Turku, Turku, Finland.
T
T
Mirtti
Departments of Surgical Oncology (Urology).
S
S
Horenblas
Department of Cancer Medicine and INSERM U981, Gustave Roussy, Cancer Campus, Grand Paris, Villejuif.
Y
Y
Loriot
Department of Oncological Medicine, Institut Bergonié, Bordeaux.
N
N
Houédé
Department of Oncological Medicine, Institut Claudius Régaud, Toulouse.
C
C
Chevreau
Department of Oncological Medicine, Institut Curie, Paris, France.
P
P
Beuzeboc
Departments of Urology Department of Urology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.
S F
SF
Shariat
Departments of Urology.
A I
AI
Sagalowsky
Pathology, University of Texas, Southwestern Medical Center, Dallas, USA.
R
R
Ashfaq
Department of Urology, Caritas St Josef Medical Centre, University of Regensburg, Regensburg, Germany.
M
M
Burger
Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto.
M A S
MA
Jewett
Department of Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto Departments of Surgery (Urology).
A R
AR
Zlotta
Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
A
A
Broeks
Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto.
B
B
Bapat
Leeds Institute of Cancer and Pathology, St James's University Hospital, Leeds, UK.
M A
MA
Knowles
Departments of Urology.
Y
Y
Lotan
Department of Pathology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.
T H
TH
van der Kwast
Department of Medical Oncology, Hôpital Saint-Louis, AP-HP, Paris, France Department of Medical Oncology, Paris 7 University, Paris.
S
S
Culine
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.
Y
Y
Allory
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.
B W G
BW
van Rhijn
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D000066491:Clinical Decision-Making; D015653:Cystectomy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059035:Perioperative Period; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000601:surgery
D014408:Biomarkers, Tumor; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
FGFR3; bladder; cancer; heterogeneity; mutations; targeted therapy