Complexity of FGFR signalling in metastatic urothelial cancer.
BACKGROUND
Urothelial cancers (UC) are the fourth most common tumours worldwide after prostate (or breast), lung and colorectal cancer. Despite recent improvements in their management, UC remain an aggressive disease associated with a poor outcome. Following disease progression on first-line platinum-based chemotherapy, very few effective treatment options are available and none of them have shown significant improvement in overall survival. Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC. Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors.


METHODS
We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547.


RESULTS
To date, the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria. Exploratory biomarker analysis showed FGFR3, FGFR1, FGF-ligand and fibroblast growth factor receptor substrate 2 (FRS2) expression in the patient's tumour, together with the presence of a germ-line mutation in the FGFR3 extracellular binding domain. This is not a known hotspot mutation, and the functional significance remains unclear.


CONCLUSIONS
The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1, FGFR3, FGF-ligand and FRS2 expression. This lends support to the further exploration of FGFR inhibitors in urothelial cancer. Further studies are required to determinate the most effective way to select those patients most likely to respond.
Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK. arodriguezvida@parcdesalutmar.cat.|Hospital del Mar, Barcelona, 08003, Spain. arodriguezvida@parcdesalutmar.cat.
Alejo
A
Rodriguez-Vida
Sarah Cannon Research Institute UK, London, W1G 6AD, UK. matildesaggese@gmail.com.|University College London Hospital, London, NW1 2BU, UK. matildesaggese@gmail.com.
Matilde
M
Saggese
Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK. Simon.Hughes@gstt.nhs.uk.
Simon
S
Hughes
Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK. Sarah.Rudman@gstt.nhs.uk.
Sarah
S
Rudman
Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK. Simon.Chowdhury@gstt.nhs.uk.|Sarah Cannon Research Institute UK, London, W1G 6AD, UK. Simon.Chowdhury@gstt.nhs.uk.
Simon
S
Chowdhury
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Neil.n.r.Smith@astrazeneca.com.
Neil R
NR
Smith
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Peter.Lawrence@astrazeneca.com.
Peter
P
Lawrence
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Claire.Rooney@astrazeneca.com.
Claire
C
Rooney
Oncology iMED, AstraZeneca, Gatehouse Park, Boston, USA. Brian.Dougherty@astrazeneca.com.
Brian
B
Dougherty
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Donal.Landers@astrazeneca.com.
Donal
D
Landers
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. Elaine.Kilgour@astrazeneca.com.
Elaine
E
Kilgour
Sarah Cannon Research Institute UK, London, W1G 6AD, UK. Tobias.Arkenau@sarahcannonresearch.co.uk.|University College London Hospital, London, NW1 2BU, UK. Tobias.Arkenau@sarahcannonresearch.co.uk.
Hendrik-Tobias
HT
Arkenau
D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007682:Kidney Pelvis / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010879:Piperazines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014516:Ureteral Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; D066246:ErbB Receptors; C496348:FGFR1 protein, human; C496365:FGFR3 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3