The role of molecular subtypes in LA/mUC management
A detailed molecular understanding of UC has resulted in the identification of distinct subtypes that could help guide treatment approaches.[1] This means knowing the molecular subtype of a given UC could help predict the clinical outcomes and treatment benefits for patients.[1][2]
The current approach to LA/mUC management
A bladder cancer patient’s chance of survival is highly stage-dependent, and progression from MIBC to metastasis is common[3][4][5]
- Despite guideline-recommended radical cystectomy, up to 50% of patients with MIBC may experience distant recurrence.[6]
- In fact, systemic recurrence is more common in locally advanced disease (ranging from 32-62%) as well as in patients with lymph node involvement (ranging from 52-70%).[6]
The treatment approach in LA/mUC remains controversial, with evidence in some areas of bladder cancer management limited and/or conflicting[6]
- In UC, molecular biomarkers are not commonly used in routine clinical practice.[7][8]
- For over 30 years, the standard 1L treatment option has been broad-acting cisplatin-based chemotherapy, with a survival rate as low as 5% at 5 years after treatment.[5][9]
- Notwithstanding, the efficacy of I-O and ADCs in FGFR+ patients has not been studied.[10][11]
Knowing the molecular profile of your patients' tumours could inform treatment decision-making, helping to improve patient outcomes[12][8][13]
The molecular subtypes of LA/mUC
The molecular biomarkers and pathways involved in UC are key to understanding its biological heterogeneity and identifying specific subtypes, which may be used to predict treatment outcomes[1]
Knowing the molecular subtype of a given UC could help predict the clinical outcomes and treatment benefits for patients.[1][2] What’s more, molecular subtypes of MIBC have been associated with different responses to treatments such as chemotherapy or immunotherapy.[2][14][15]
The molecular understanding of MIBC has led to a consensus classification of tumour classes with distinct oncogenic mechanisms[2]
Recent developments in our understanding of the pathology of bladder cancer have led to the identification of six distinct tumour types with specific molecular disease drivers, histological characteristics, prognosis and even response to therapy.[2]
Adapted from Kamoun A et al. 2020.[2]
In certain types of cancer, an improved understanding of molecular pathology has enabled the arrival of precision medicine, which can help improve treatment outcomes for patient subpopulations with the appropriate biomarkers[12][16]
The identification of targets in tumours such as colorectal, breast, ovarian and non-small cell lung cancer has led to the development of targeted therapies.[16]
Targeting tumours with inhibitors that block aberrant signalling has improved patient outcomes across different cancers, providing efficacy and toxicity benefits.[12][16]
FGFR3 alterations in UC
FGFR3 alterations are more prevalent in UC than in any other human cancer[17]
The type of FGFR alterations most commonly found can differ in different cancer types, with FGFR3 mutations predominating in bladder and other urothelial tumours.[17]
Indeed, FGFR3 alterations can cause aberrant signalling that is implicated in multiple tumourigenic processes.[18]
The incidence of FGFR alterations in UC was investigated with a dataset of 126 cases representing urothelial (transitional cell) cancer of the bladder, renal pelvis and ureter.*,[17]
Adapted from Helsten T et al. 2016.[17]
FGFR3 alterations are most commonly found in UC and have been identified across all grades and/or stages of bladder cancer[17][19]
In particular, FGFR3 alterations show different prevalence based on the tumour stage:[5][20]
- ~80% of patients with Ta stage NMIBC
- ~15% of patients with LA/mUC
Adapted from Knowles MA et al. 2015 and Teo M et al. 2020[5][20]
International guidelines recommend the routine use of molecular testing in advanced or metastatic tumours, owing to its potential benefits for oncology patient care[21][22]
Explore more
How do the prevalence and role of FGFR3 alterations drive disease for different tumour types?
How might optimised molecular testing protocols enable the timely identification of relevant genetic alterations that could be driving your patients’ tumour growth?[12][21][23][24]
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*This dataset did not include cases of bladder sarcoma, small cell carcinoma, squamous cell carcinoma or neuroendocrine carcinoma. The majority of aberrations were activating mutations in FGFR3, including S249C (8 instances), R248C (6 instances), Y373C (2 instances), G370C (2 instances) and K650M (1 instance). Three of these FGFR3 mutations were also about to transform cells in vitro (S249C, S248C, Y737C). Frequencies are expressed as percentages of all 126 cases. There were 44 aberrations in 40 cases (4 cases had more than one aberration), so the total is greater than 100%.[17][25]
1L: first-line; 2L: second-line; ADC: antibody-drug conjugate; APOBEC: apolipoprotein B mRNA editing catalytic polypeptide-like; CD8 T cells: cytotoxic T lymphocytes; CDKN2A: cyclin-dependent kinase inhibitor 2A; E2F3: gene encoding E2F transcription factor 3; EGFR: epidermal growth factor receptor; ELF3: gene encoding E74-like ETS transcription factor 3; ERBB2: gene encoding receptor tyrosine-protein kinase erbB-2; ERCC2: gene encoding XPD protein; FGFR: fibroblast growth factor receptor; I-O: immuno-oncology; KDM6A: gene encoding lysine-specific demethylase 6A; LA: locally advanced; MIBC: muscle-invasive bladder cancer; mUC: metastatic UC; NK cells: natural killer cells; NMIBC: non-muscle invasive bladder cancer; PD-1: programmed cell death protein 1; PD-(L)1: programmed cell death ligand 1; PPARG: peroxisome proliferator-activated receptor gamma; RB1: gene encoding tumour suppressor retinoblastoma protein 1; Ta: non-invasive papillary carcinoma; T2: tumour growth into muscle; T3: tumour growth into fat layer; T4: tumour growth outside of the bladder; TMB: tumour mutational burden; TP53: gene encodes p53; UC: urothelial carcinoma.
