








































Clinical Utility of Bladder Cancer Biomarkers
Laura-Maria Krabbe,1 Georgios Gakis,2 Yair Lotan3

1 The University of Muenster Medical Center, Germany, 2 University Hospital of Würzburg, Germany,  
3 The University of Texas Southwestern Medical Center, United States

Abstract

Each year, there are an estimated 550 000 diagnoses of bladder cancer worldwide, and almost 200 000 deaths from 
bladder cancer. The need for frequent follow-up, including invasive procedures like cystoscopy, repetitive procedures 
like transurethral resection of bladder tumors and intravesical instillation therapy in non-muscle invasive stages, as 
well as systemic treatment with or without radical local treatment in advanced stages, makes bladder cancer one of 
the most expensive cancers to treat. Prognostic and predictive biomarkers have the potential to fundamentally change 
bladder cancer treatment algorithms, which may result in improved patient comfort and oncological outcomes and 
may also decrease the socioeconomic burden of the disease. Intense research has resulted in the recent approval by 
the U. S. Food and Drug Administration of the first agent for this disease that targets a specific mutation (fibroblast-
growth factor receptor). Yet, many areas of bladder cancer diagnosis and treatment have remained unchanged for 
decades, and this is only in part due to their therapeutic success. In order to integrate biomarkers into clinical practice 
patterns, specific considerations for the different disease stages and settings should be kept in mind. Especially in 
the setting of screening, work-up of hematuria, as well as surveillance of patients with non-muscle invasive bladder 
cancer, (urine-)biomarkers may prove useful. They must, however, demonstrate a high enough sensitivity to pick up 
a cancer diagnosis or recurrence, allow easy handling (preferably a point-of-care setting) and adequate cost–benefit 
relationships, while also providing additional information to a full work-up. A biomarker to identify patients with 
muscle invasive bladder cancer who are in need of—and likely to respond to—neoadjuvant therapy would be very 
useful. In later disease, early detection of recurrence or progression, as well as biomarkers guiding treatment decisions 
between the available systemic agents, will be paramount for improved patient care.

Introduction

There are about 550 000 new diagnoses of bladder cancer each year, and it was responsible for almost 200 000 deaths 
worldwide in 2018 [1]. The need for frequent follow-up, including invasive procedures like cystoscopy, repetitive 
procedures like transurethral resection of bladder tumors and intravesical instillation therapy in non-muscle invasive 
stages, as well as systemic treatment with or without radical local treatment in advanced stages, makes bladder 
cancer one of the most expensive cancers to treat [2]. Prognostic and predictive biomarkers have the potential to 
fundamentally change bladder cancer treatment algorithms, which may improve patient comfort and oncological 
outcomes, as well as decreasing the socioeconomic burden of the disease. The U. S. Food and Drug Administration 
has recently approved the first agent for this disease that targets a specific mutation [3]. Yet, many aspects of bladder 
cancer diagnosis and treatment have remained unchanged for decades, and this is due only in part to their therapeutic 
success. In order to integrate biomarkers into clinical practice patterns, specific considerations for the different disease 
stages and settings should be kept in mind. 

Key Words Competing Interests Article Information

Biomarkers, bladder cancer, muscle invasive 
bladder cancer, non-muscle invasive bladder 
cancer, neoadjuvant therapy, hematuria, 
cystoscopy, risk stratification, clinical 
decision-making

None declared. Received on July 14,  2020 
Accepted on August 3,  2020

Soc Int Urol J 2020; 1(1): 62–67  

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Abbreviations 

BCG bacillus Calmette-Guérin 
MIBC muscle invasive bladder cancer
NMIBC  non-muscle invasive bladder cancer
NAC neoadjuvant chemotherapy
NLST National Lung Screening Trial
NPV negative predictive value
PD-L1  programmed death receptor ligand 1
PLCO  Prostate, Lung, Colorectal and Ovarian Cancer 

Screening Trial  
PPV positive predictive value
RC radical cystectomy

Considerations for Biomarkers for Bladder 
Cancer Screening
Because of the low incidence of bladder cancer in the 
general population (and even in high-risk populations), 
there is currently no recommendation for bladder cancer 
screening [4]. In general, for screening purposes in daily 
routine, a point-of-care test on a dichotomous basis 
could be performed easily in the ambulatory setting and 
should provide an initial risk assessment which could be 
used to tailor the need for further clinical investigation. 
Urine is obviously the most promising resource for 
such a test. On the one hand, a urine-based biomarker 
test requires a high sensitivity and negative predictive 
value (NPV) to ensure people at risk are not missed. On 
the other hand, given the low incidence, the test also 
needs a high specificity and positive predictive value 
(PPV) to prevent unnecessary (invasive) evaluation 
that would occur because of false positive results. In 
addition, given its application of a urine marker as a 
screening tool, the costs for test analysis should be low 
and not greatly exceed the usual costs for standard 
diagnostic work-up of bladder cancer. Finally, an earlier 
detection after test analysis should ideally demonstrate a 
significant improvement in oncological outcomes. As it 
seems to be difficult to demonstrate an overall survival 
benefit in the general—or even high-risk—population, 
a reduction of rates of invasive disease may serve as a 
surrogate parameter since there are known significant 
differences in survival between non-muscle invasive 
bladder cancer (NMIBC) and muscle invasive bladder 
cancer (MIBC). Most current urine markers have a 
PPV that is too low to justify their use in screening 
since the number of unnecessary evaluations will far 
exceed the finding of cancer. Targeted screening of very  
high-risk populations may result in a high enough cancer 
incidence, but prospective studies will be necessary to 
demonstrate a survival benefit or at least a reduction 
of muscle invasive disease. It is known that male sex, 
older age, and duration and intensity of smoking are 

associated with higher risk of bladder cancer. A study 
evaluating these factors and incidence of bladder 
cancer in the Prostate, Lung, Colorectal and Ovarian 
(PLCO) Cancer Screening Trial  and the National 
Lung Screening Trial (NLST) found that in men older 
than 70 years with smoking exposure of ≥ 30 pack-years, 
incidence rates were as high as 11.92 (PLCO) and 5.23 
(NLST) per 1000 person-years [5]. There is not a strong 
association between family history and bladder cancer. 
However, in the presence of distinct single-nucleotide 
polymorphisms that are associated with a significant 
risk for bladder cancer, screening for bladder cancer may 
be justified. Upper tract urothelial carcinoma develops 
in up to 28% of patients with known Lynch syndrome. 
These patients may be candidates for screening and 
routine urine analysis, as well as possible further 
evaluation using the American Urological Association 
guideline of ≥ 3 red blood cells per high power field [6]. 
Patients with  Lynch  syndrome who develop upper 
tract disease usually present at a younger age, with a 
higher female preponderance and a predisposition to 
bilaterality.

Diagnosis in Patients With Hematuria
Patients with hematuria have a markedly increased risk 
of having bladder cancer (gross 10% to 40%, depending 
on other risk factors, or microscopic  2% to  5%) and 
therefore need further clinical work-up [7,8]. This  
work-up consists of cystoscopy with cytology, as well as 
contrast-enhanced imaging of the upper urinary tract [4]. 
These procedures are costly, invasive, or uncomfortable. 
Therefore it would be desirable to replace them with a 
biomarker test to spare patients who do not need a full 
evaluation. Again, urine seems to be the most promising 
medium for a biomarker test in such a scenario. Large 
efforts have been undertaken to stratify risk in patients 
with hematuria based on demographic and clinical 
factors as well as various genetic and protein markers [4]. 
Dichotomous or semiquantitative tests indicating 
the individual risk for bladder cancer seem suitable to 
guide clinicians towards or against further testing. As 
with screening, a high sensitivity and NPV is needed to 
ensure a tumor is not missed. A high specificity and PPV 
are also desirable to prevent unnecessary evaluations  
for false positive test results, but are less important than 
in screening, given the lower number of these “quasi”-
pre-screened patients and related costs.

Since the rate of cancer in patients with hematuria 
greatly exceeds the rate in screening cohorts, identifying 
high-risk patients who always need evaluation is 
important. Several studies have found that the cancer 
yield increases with gross hematuria, male sex, and 
increasing age [9,10]. Unfortunately, many patients with 
high-risk disease are not adequately evaluated [11-13]. 
While the incidence of urothelial carinoma in patients 

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with gross hematuria already justifies evaluation, 
risk stratification to select patients for work-up might 
benefit patients with microscopic hematuria. The goal 
for markers could be to improve risk stratification of 
patients so that higher risk patients get evaluation, but 
there is also identification of which lower risk patients 
need to be evaluated and which patients may be safely 
monitored without invasive testing [14,15]. A prospective 
randomized trial is currently open that randomizes 
patients based on clinical risk and marker status 
(NCT03988309). Patients in the control arm will have 
standard evaluation while those in the marker arm 
will have a clinical risk stratification, so patients with 
low clinical risk and a negative marker will not have 
cystoscopy but follow-up only, but those with a positive 
marker or higher risk based on clinical factors will 
undergo a standard evaluation with cystoscopy. Further 
studies of this type will be necessary to change guideline 
recommendations. 

Surveillance of Patients With Non-Muscle 
Invasive Bladder Cancer
When patients are diagnosed with low- to intermediate-
risk NMIBC, the follow-up course is usually associated 
with frequent cystoscopies to rule out recurrent or 
progressive disease, especially in those undergoing 
intravesical instillation therapy. These examinations 
are cumbersome to many patients and are associated 
with significant costs. Therefore, investigators have 
focused on biomarkers to accurately detect t he 
presence or absence of a recurrence as an alterative to 
invasive diagnostic procedures. Given the low risk of 
progression in low- to intermediate-risk NMIBC, (<15% 
at 5 years), but high risk of recurrence, the goals for a 
biomarker need to be considered. A biomarker with a 
high specificity will reduce the number of cystoscopies 
performed because of false positive findings, but if 
sensitivity is not high, it may miss recurrences [16]. 
This may be acceptable in order to reduce the number 
of cystoscopies since low-grade recurrences are unlikely 
to progress. As an alternative, some investigators have 
proposed alternating cystoscopy with a marker. This is 
more practical, as most markers have a better sensitivity 
for high-grade disease and would therefore be more 
likely to catch the rare case of a low-grade tumor that 
progresses. Furthermore, periodic cystoscopy would 
assure patients and urologists that even if a marker 
missed a low-grade recurrence then the cancer would be 
detected at subsequent evaluation. The UroFollow study, 
for example, was developed as a prospective randomized 
trial to compare routine cystoscopy with a urine marker-
guided, noninvasive follow-up of patients with pTa 
G1–2/low-grade NMIBC [17].

On the other hand, patients with a history of high-
risk bladder cancer have the highest risk of recurrence 

(50% at 5 years) [16]. Therefore, a useful biomarker test 
must have a high sensitivity and NPV in order not to 
miss any high-grade recurrence which may result in 
progression to muscle-invasive stages. This could even 
come at the cost of lower test specificity. Ideally a marker 
would be able to detect cancers missed by white light 
cystoscopy, which is known to miss some high-grade 
cancers, especially carcinoma in situ [18]. Unfortunately, 
urine marker studies have not been designed to assess 
whether a patient with a normal cystoscopy and positive 
marker have a true positive or false positive finding. It is 
therefore not clear what steps should be taken if a marker 
assay is positive in this scenario.

Molecular markers could also aid in clinical decision-
making for patients with NMIBC in predicting response 
to intravesical therapy. Adding a biomarker test to a 
standard work-up may identify patients who are unlikely 
to benefit from BCG bacillus Calmette-Guérin and 
require early radical treatment. Nonetheless, this issue 
is difficult to address in clinical trials, as bladder cancer 
is a heterogeneous disease, and the intravesical therapies 
used are non-specific to a distinct molecular target for 
which testing would be possible. Therefore, predicting 
response to intravesical therapy will remain challenging 
in the future. This is also complicated by the fact that 
immunotherapy with BCG and also chemoinstillation 
induce inf lammatory changes, which can sometimes 
impair the diagnosis of a tumor recurrence or influence 
test results. However, adding a biomarker test to a 
standard work-up may identify patients unlikely to 
benefit from BCG, who might require more radical 
treatment, early [19]. Furthermore, markers may be able 
to select populations at higher risk for enrollment in 
clinical trials [20].

Biomarkers With Muscle Invasive Bladder 
Cancer
In MIBC, there are several distinct needs that could 
be addressed by biomarkers. Patients with AJCC 
stages 2 and 3 disease have variable rates of recurrence 
and progression. Furthermore, approximately  40% of 
patients are understaged [21]. There is level 1 evidence 
for use of neoadjuvant chemotherapy (NAC), but 
it is underused because of concerns about toxicity 
and a relatively small survival benefit [22]. There is a 
greater benefit to NAC in patients who have non-organ 
confined disease, so identifying patients likely to have 
micrometastatic disease would be valuable. Since there 
is also variable response to NAC, a marker to identify 
likely responders would be important to prevent toxic 
treatments being given to patients unlikely to benefit 
from them. 

Several possible biomarkers have been described, 
including mutations in DNA repair genes  ATM, RB1, 

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and FANCC, [23] mutations in excision repair cross-
complementation group  2 (ERCC2) gene, [24,25] 
protein biomarkers, [26] and RNA subtyping of bladder 
cancer [27,28].

Furthermore, while cystectomy is the main treatment 
for MIBC, trimodality therapy is a reasonable alternative 
in some patients, and predicting responsiveness to this 
type of treatment would be valuable.

In patients who do not get NAC, there is a role  
for adjuvant therapy in patients with non-organ 
confined disease [29].

In addition, proponents of an adjuvant approach 
argue that there is a considerable risk of overtreatment 
w it h NAC , since histopat hologica l risk factors 
determined in radical cystectomy (RC) specimens have 
a much stronger correlation to survival than histological 
parameters obtained by transurethral resection of 
bladder tumors [30,31]. Pathological complete or 
partial response (downstaging to non-muscle invasive 
tumor stages) after NAC is reported in 40% to 50% of 
the patients and associated with excellent survival [32]. 
On the contrary, the majority of patients will exhibit 
persistent muscle-invasive disease (≥ ypT2) after RC, 
which is associated with poor outcomes [32].

A predictive biomarker in this setting should be 
capable of identifying patients in need of systemic 
treatment and those whose tumors are sensitive to 
systemic treatment (maybe in future even indicate 
which treatment). Given the high degree of intratumoral 
heterogeneity of MIBC [33], biomarker expression 
levels should be homogenous within the tumor lesion 
to reliably predict response. Ideally, a biomarker 
assessed in the transurethral resection specimen should 
have a higher sensitivity than specificity to prevent 
undertreatment of MIBC patients. By contrast, a high 
specificity but low sensitivity may result in the underuse 
of neoadjuvant treatment, but this may be alleviated if 
an effective adjuvant treatment is available that is safe 
even in patients with comorbidities (eg, impaired renal 
function). The currently available histopathological 
parameters (ie, tumor and nodal stage) can be considered 
accurate enough to determine the necessity of adjuvant 
treatment in case of lack of a downstaging effect after 
neoadjuvant therapy; however, a biomarker might help 
in determining the most appropriate treatments in the 
future [34].

Prediction of response in the adjuvant setting after 
failure of a neoadjuvant approach ideally requires a 
biomarker with an even higher specificity than the 
(primary) neoadjuvant setting, because the group 
of ≥ ypT2  patients after RC exhibit a very dismal 
prognosis [32].

For patients with a locally advanced tumor after RC 
who have not received previous neoadjuvant therapy, 
there might be benefit in a prognostic biomarker 
indicating which patients will experience recurrence 
and which will not, as well as a predictive biomarker 
of which treatment might be associated with the best 
response.

Metastatic Bladder Cancer
In the metastatic cancer/disease, predictive biomarkers 
are urgently needed to determine which tumor will 
likely respond to which treatment, as this will help 
ensure patients in this very aggressive disease state are 
not receiving ineffective therapies. These biomarkers 
will likely be blood- or tissue-based. Ideally, biomarkers 
should be assessable sequentially via blood draw so 
the patient does not have to undergo multiple biopsies  
and the biomarker provides an accurate representation 
of tumor characteristics, given that tumors, but 
especially metastases, evolve over time. Groundwork  
on t he s e f ront s ha s b e en done by genom ic 
characterization of bladder tumors; there are, however, 
very few validated biomarkers.

Biomarkers to predict response to therapy are 
critical. There is already an approved targeted therapy 
for metastatic bladder cancer targeting fibroblast-
growth factor receptor mutations [35]. The role for 
biomarkers such as programmed death receptor ligand 1 
(PD-L1) to predict response to checkpoint inhibitors is 
controversial but necessary in certain cases. In first-
line cisplatin-ineligible patients who are eligible for 
carboplatin, the use of PD-L1  inhibitors is currently 
approved only after PD-L1  testing, whereas in the 
second-line, data from a randomized trial support the 
use of for example pembrolizumab in an unscreened 
population of platinum-pretreated patients [36,37]. 
Given the low response rates in both settings (25% 
complete and partial remissions), it will be important to 
combine PD-L1 inhibitors with other targeting agents to 
improve response. Nonetheless, in the future, it can be 
expected that the decision to use single- or multiagent 
targeted therapy in any line of systemic therapy will be 
based on marker expression. Given the high mutational 
burden and heterogeneity of response to treatment in 
metastasized tumors, the critical question is whether 
the tissue obtained at primary diagnosis can accurately 
reflect the tumor biology after multiple lines of systemic 
treatment. Therefore, the implementation of robust 
biomarkers in the different metastatic settings will 
require first a better understanding of the biological 
processes during progression of metastatic disease. 
This will require well-designed biopsy studies to 
systematically assess alterations in tumor biology during 
the process of metastasis formation.

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Conclusion
There are many areas in bladder cancer where 
biomarkers can have an important role in improving 
clinical decision-making. The current information from 
stage and grade of disease is insufficient to adequately 

stage or predict outcomes for most patients. Biomarkers 
have the potential to shed light onto clinical behavior of 
tumors to allow a personalized approach to care. There 
is also a potential for improved understanding of the 
biology of the disease to determine which patients need 
more intensive therapy and which therapies to use. 

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