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EUROPEAN UROLOGY 67 (2015) 202–203
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Platinum Priority – Editorial
Referring to the article published on pp. 198–201 of this issue
The Molecular Background of Urothelial Cancer: Ready for Action?
Michiel S. van der Heijden a,b, Bas W.G. van Rhijn c,*
a
Department of Medical Oncology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; b Division of Molecular
Carcinogenesis, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; c Department of Surgical Oncology (Urology),
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
Bladder cancer is a common cancer worldwide, with a
prevalence of 2.7 million patients. Although bladder cancer
is often noninvasive at diagnosis, 30–40% of patients
present with more advanced disease or progress to more
aggressive disease. Urothelial carcinomas can be staged
clinically or classified into various histologic subtypes.
Although these classification systems convey some
information on prognosis, individual clinical behavior
cannot easily be predicted [1]. Urothelial cancers that
appear similar under the microscope can vary greatly in
their clinical behavior. For example, patients with
extensive lymph node metastases can have remarkable
and lasting remissions on cisplatin-containing chemotherapy, whereas patients with small urothelial cancers
can have an aggressive and short clinical course from
presentation to death.
In recent years, knowledge about the molecular background of bladder cancer has greatly increased with the
completion of several comprehensive sequencing studies.
The most influential of these studies is the effort by The
Cancer Genome Atlas consortium, providing an in-depth
overview of the genetic background of bladder cancer [2].
These efforts have produced several important new
insights.
First, the average number of somatic mutations per
cancer genome is among the highest mutation rates of any
cancer. This high number of mutations in bladder cancer is
presumably caused by toxic compounds (eg, related to
cigarette smoking). Second, several mutations in kinases
such as the receptor tyrosine kinases and members of the
PI3K pathway are present, providing potential targets for
treatment. Finally, it has become clear that epigenetic
reprogramming could play an important role in bladder
cancer, as evidenced by a very high frequency of mutations
in histone-modifying enzymes and chromatin-remodeling
genes. Because it was expected that these molecular
characteristics could possibly predict clinical behavior, a
plethora of studies have aimed to establish prognostic
biomarkers. Mutations in the fibroblast growth factor
receptor 3 (FGFR3) and phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) genes
are known to be associated with lack of progression from
superficial disease to muscle-invasive bladder cancer [3].
Whether these mutations are associated with prognosis
when they occur in muscle-invasive disease is still unclear.
Several studies reported recently on frequent mutations
in the stromal antigen 2 (STAG2) gene. However, association
with prognosis appears conflicting [4,5]. Many of these
studies are difficult to interpret because of small sample
size and the mixed composition of tumor sets (eg, muscle
invasive and superficial). The use of assays that do not
assess the full spectrum of genetic cancer-related aberrations that can occur in a gene has perhaps also resulted in
false-positive or negative results. One such an example
would be the assessment of hotspot mutations in the FGFR3
gene without testing for gene fusions.
In a retrospective single-center study by Kim et al. [6] in
this month’s issue of European Urology, 300 genes commonly associated with cancer were sequenced using a
capture-based assay in 109 patients with high-grade
bladder cancer, and mutations/pathways were compared
with clinical outcome in 89 radical cystectomy cases.
Mutations in the tumor protein p53 (TP53) gene were most
common (57%) and associated with poor histopathologic
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.06.050.
* Corresponding author. Department of Surgical Oncology (Urology), Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121,
1066 CX Amsterdam, The Netherlands. Tel. +31 20 5122553; Fax: +31 20 5122459.
E-mail address: [email protected] (Bas W.G. van Rhijn).
http://dx.doi.org/10.1016/j.eururo.2014.07.017
0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 67 (2015) 202–203
characteristics (pT/pN) but not independently with clinical
outcome. PIK3CA mutations were associated with favorable
clinical outcome but not with histopathologic characteristics. Cyclin-dependent kinase inhibitor 2A (CDKN2A)
alterations were associated with worse clinical outcome
but not with histopathologic characteristics.
The authors should be applauded for achieving such a
comprehensive analysis of a relatively large collection of
clinically annotated samples. However, this study has some
limitations that make it difficult to predict how the results
can be used in clinical practice. Multivariable testing of 22
genes or pathways, in a cohort of 89 cases with 33 events,
impairs the reliability of the analysis. Statistical type I and
type II errors are likely to occur if multiple variables are
tested in a relatively small patient population. Also, groups
were heterogeneous in the tissue used (transurethral
resection or cystectomy), and patients who both did and
did not receive perioperative chemotherapy were included.
The genes found to carry prognostic value should therefore
be confirmed in an external data set to establish the validity
of these biomarkers. Even if confirmed in an independent
data set, it is unclear how this will change our approach in
clinical practice because prognostic biomarkers are not
necessarily predictive of treatment effects [1].
More than ever before, detailed knowledge of most of the
genes and pathways that are altered in bladder cancer is
available. Using this information to direct treatments by
matching the right drug to the right patient should be the
highest priority. As an example, actionable alterations
include activating point mutations and translocations in the
FGFR3 gene. Highly selective inhibitors can now target these
alterations. Early data suggest that these new inhibitors
may be effective [7]. Other drug targets include v-erb b2
avian erythroblastic leukemia viral oncogene homolog 2
(ERBB2) (point mutations and amplification) and members
of the PI3K/AKT pathway. In a recent elegant study,
inactivation of tuberous sclerosis 1 (TSC1) was found to
be associated with a remarkable response to the mammalian target of rapamycin inhibitor everolimus [8].
Because single drugs for single targets are unlikely to be
sufficiently active in most patients, exploring combinatorial
approaches based on preclinical evidence should accompany
early-phase trials of targeted agents. Using a conceptually
different approach, early trials with immunotherapy are
aimed at the expression of PD-L1 [9] and MAGE-A3 [10]. The
epigenetic events that contribute to the development of
bladder cancer are still largely unknown, but judging by the
high mutation rate in histone- and chromatin-modifying
genes, epigenetic reprogramming is likely to play an important
203
driving role. As compounds that target epigenetic pathways
are increasingly developed, opportunities to test hypotheses are mounting. Again, dedicated preclinical efforts
exploring the best combinations to be tested in patients
are of paramount importance.
In conclusion, the molecular landscape of bladder cancer
has greatly expanded in recent years, providing various
targets for treatment. Our therapeutic toolbox has never
been richer, with drugs targeting the immune system,
epigenetic programs, and kinases involved in key growthpromoting pathways. Laboratory researchers and dedicated
clinicians should therefore join forces to put these tools into
action and finally improve the prognosis for our patients
with this deadly disease.
Conflicts of interest: The authors have nothing to disclose.
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