The impact of patient sex on characteristic-adjusted bladder cancer prognosis

Abstract

Context:
Bladder cancer is one of the most common malignancies worldwide. Some studies noted sex differences in the prognosis of bladder cancer, but results are inconsistent.

Subjects and methods:
In this study, we assessed whether women with bladder cancer exhibit a worse prognosis, after adjustment for disease stage, age, and body mass index (BMI), using clinical data from The Cancer Genome Atlas. We used a Student's t-test to compare age and BMI in groups with different sexes.

Statistical analysis used:
The Kaplan-Meier method with log-rank test was used to determine clinical prognosis.

Results:
The BMI (30.15 vs. 26.68, P = 0.0035) and age (67.54 years vs. 66.01 years, P = 0.045) of female patients with muscle-invasive bladder cancer (MIBC) were higher than those of male patients. The overall survival (OS) prognosis of female patients was worse than that of male patients. After grouping by disease characteristics, the disease-free survival (DFS) and OS prognoses of female patients under 60 years of age were worse than those of male patients. In the group with BMI >24, the OS prognosis of female patients was worse than that of male patients, but no difference was found in DFS prognosis. In the group with BMI ≤24, the DFS prognosis of female patients was worse than that of male patients, but no difference was found in OS prognosis. Compared to males, female patients with Stage III disease demonstrated a worse DFS prognosis and poorer OS prognosis, women with stage T3 demonstrated a worse DFS prognosis, and women with stage N0 demonstrated a poorer OS prognosis. No difference was found in prognosis between male and female patients in all other groups.

Conclusions:
In patients with MIBC, women tended to exhibit a worse prognosis than men. More specifically, we found a correlation between prognosis and sex after grouping patients by BMI.

Full text

Official Journal of
Association of Radiation Oncologist of India
November 2021 Volume 17 Issue 5
Journal of Cancer Research and Therapeutics • Volume 17 • Issue 5 • November 2021 • Pages ****-****
Spine 12 mm
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1241
© 2021 Journal of Cancer Research and Therapeutics | Published by Wolters Kluwer - Medknow
Chunchun Zhao,
Kai Li,
Mujia Zhu,
Fei Wang,
Ke Zhang,
Caibin Fan,
Jianqing Wang
Department of
Urology, Suzhou
Municipal Hospital,
The Afliated Suzhou
Hospital of Nanjing
Medical University,
Gusu School, Nanjing
Medical University,
Suzhou, Jiangsu, PR
China
For correspondence:
Dr. Jianqing Wang,
Department of
Urology, Suzhou
Municipal Hospital,
The Afliated Suzhou
Hospital of Nanjing
Medical University,
Gusu School, Nanjing
Medical University,
26 Daoqian Rd,
Suzhou, Jiangsu
215000, PR China.
E‑mail: jqwang14@
fudan.edu.cn
Dr. Caibin Fan,
Department of
Urology, Suzhou
Municipal Hospital,
The Afliated Suzhou
Hospital of Nanjing
Medical University,
Gusu School, Nanjing
Medical University,
26 Daoqian Rd,
Suzhou, Jiangsu
215000, PR China.
E‑mail: fancaibin
@sina.com
The impact of patient sex on
characteristic-adjusted bladder cancer
prognosis
ABSTRACT
Context: Bladder cancer is one of the most common malignancies worldwide. Some studies noted sex differences in the prognosis
of bladder cancer, but results are inconsistent.
Subjects and Methods: In this study, we assessed whether women with bladder cancer exhibit a worse prognosis, after adjustment
for disease stage, age, and body mass index (BMI), using clinical data from The Cancer Genome Atlas. We used a Student’s
t
‑test
to compare age and BMI in groups with different sexes.
Statistical Analysis Used: The Kaplan–Meier method with log‑rank test was used to determine clinical prognosis.
Results: The BMI (30.15 vs. 26.68,
P
= 0.0035) and age (67.54 years vs. 66.01 years,
P
= 0.045) of female patients with
muscle‑invasive bladder cancer (MIBC) were higher than those of male patients. The overall survival (OS) prognosis of female patients
was worse than that of male patients. After grouping by disease characteristics, the disease‑free survival (DFS) and OS prognoses
of female patients under 60 years of age were worse than those of male patients. In the group with BMI >24, the OS prognosis of
female patients was worse than that of male patients, but no difference was found in DFS prognosis. In the group with BMI ≤24, the
DFS prognosis of female patients was worse than that of male patients, but no difference was found in OS prognosis. Compared to
males, female patients with Stage III disease demonstrated a worse DFS prognosis and poorer OS prognosis, women with stage T3
demonstrated a worse DFS prognosis, and women with stage N0 demonstrated a poorer OS prognosis. No difference was found
in prognosis between male and female patients in all other groups.
Conclusions: In patients with MIBC, women tended to exhibit a worse prognosis than men. More specifically, we found a correlation
between prognosis and sex after grouping patients by BMI.
KEY WORDS: Bladder cancer, body mass index, disease stage, prognosis, sex, the Cancer Genome Atlas
Original Article
INTRODUCTION
Bladder cancer is one of the most common
malignancies worldwide, causing almost 150,000
deaths each year.[1] Bladder cancer is prone to
recurrence and is strongly invasive. It develops
into muscle‑invasive bladder cancer (MIBC) or
metastatic disease, which has a worse prognosis,
either as an initial diagnosis or during treatment
in approximately 25% of patients. Many factors are
associated with the development and prognosis
of bladder cancer,[2,3] among which a history of
smoking is the most common risk factor.[4] In
addition, patient sex has always been considered
to be an important factor affecting the prognosis
of bladder cancer;[5] however, the influence of
body mass index (BMI) combined with sex remains
unclear. The discovery of new prognostic factors
can allow for a better understanding of bladder
cancer while providing a basis for disease guidance
and prognosis evaluation.
To date, many studies explored the relationship
between sex and bladder cancer prognosis, but
they produced inconsistent conclusions. Previous
studies showed that the prevalence of male patients
with MIBC is about three times that of female
patients. However, compared with male patients,
female patients with bladder cancer exhibit a
higher risk of cancer‑specific mortality (CSM)[6,7] and
Access this article online
Website: www.cancerjournal.net
DOI: 10.4103/jcrt.jcrt_875_21
Quick Response Code:
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For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
Cite this article as: Zhao C, Li K, Zhu M, Wang F, Zhang K, Fan C, et al. The impact of patient sex on characteristic-adjusted
bladder cancer prognosis. J Can Res Ther 2021;17:1241-7.
Submitted: 31‑May‑2021
Accepted in revised
form: 23‑Sep‑2021
Published: 27‑Nov‑2021

Zhao, et al.: Sex differences in bladder cancer prognosis
1242 Journal of Cancer Research and Therapeutics - Volume 17 - Issue 5 - November 2021
the 5‑year survival rate of women in every disease stage is
poorer.[8] Moreover, being a female is an independent predictor
and risk factor of CSM for bladder cancer as well as requiring
a radical cystectomy (RC).[9,10]
Nevertheless, the relationship between sex and prognosis
post‑RC remains unclear. After matching female and male
patients with respect to demographic characteristics, tumor
characteristics, and therapy, one study noted no difference
in the disease‑free survival (DFS) prognosis and overall
survival (OS) prognosis of males and females.[11] In another
study, no association was found between sex and postoperative
survival after stratifying patients according to a number of
variables, including tumor stage.[12,13] Several other large‑scale
studies found that, among patients with stage T4 bladder
cancer, women exhibited a notably worse prognosis, and
they were at a higher risk of CSM and disease recurrence.[14,15]
However, an additional study of 128 patients with T4 bladder
cancer tumors did not find any association between sex and
survival.[5,16]
Controversy Inconsistencies have also been found in the
relationship between sex and non‑MIBC (NMIBC) prognosis.
Some studies found that, among patients with T1G3 bladder
cancer who received Bacillus Calmette–Guerin (BCG) treatment,
recurrence, progression, and death from bladder cancer were
more likely in females;[17,18] however, since the patients in
this study were not treated with secondary electrotomy, the
application of these results is limited. Other studies found
that females with NMIBC exhibit a higher CSM than male
patients,[19,20] and among patients with carcinoma in situ,
women exhibited a high risk of CSM.[21,22] Nonetheless, other
research studies suggested that no association exists between
sex and disease progression or mortality risk.[18,23] For instance,
in patients with NMIBC treated with BCG, no correlation is
found between patient sex and recurrence or progression.[24]
A meta‑analysis of 15,215 patients with high‑grade T1 bladder
cancer found that being a woman was associated with a risk
of disease progression but demonstrated no relevance to the
risk of tumor recurrence or cancer‑specific survival.[25,26]
Since the relationship between sex and bladder cancer
prognosis remains unclear, in this study, we aimed to
analyze the relationship between patient sex and prognosis
in patients with bladder cancer using recent clinical data
for patients with MIBC and NMIBC in The Cancer Genome
Atlas (TCGA) database. In addition, we aimed to evaluate the
relationship between sex and bladder cancer prognosis from
new perspectives, such as including BMI, while verifying the
results of previous studies, thus providing a basis for disease
prevention and treatment.
SUBJECTS AND METHODS
The authors state that they have been approved by the Ethics
Committee of Nanjing Medical University and have followed
the principles outlined in the Declaration of Helsinki for all
human or animal experimental investigations.
Clinical information for patients with MIBC was downloaded
directly from TCGA (https://portal.gdc.cancer.gov/) and
cBioPortal for Cancer Genomics (http://www.cbioportal.org/
index.do) websites.[27] Clinical data for 413 eligible patients were
downloaded. Inclusion criteria included being chemotherapy
naive and presenting with invasive, high‑grade MIBC. In
addition, only patients with complete clinical data, including
sex, age, BMI, tumor stage, tumor‑node‑metastasis (TNM) stage,
tumor grade, OS prognosis, and DFS prognosis, were selected
for follow‑up analysis. All informed signed consent had been
obtained from all subjects during the original research.
After screening, a total of 233 patients were selected for
inclusion in the analysis, including 177 males (76%) and
56 females (24%). The clinical information for all patients is
summarized in Table 1. In addition, to evaluate the effects of
sex in patients with NMIBC, we also downloaded the clinical
information of 105 eligible patients with NMIBC from the same
websites; this information is summarized in Table 2.
Table 1: Clinical characteristics of patients with
muscle‑invasive bladder cancer
Characteristic Sex P
Male Female
Age (years) 66.01 67.54
Range 47‑90 37‑89
Tumor stage
T0 1 0 0.8447
T1 2 0
T2 22 7
T2a 20 3
T2b 23 8
T3 20 8
T3a 32 8
T3b 37 15
T4 2 0
T4a 16 7
T4b 2 0
Metastasis stage
M0 75 25 0.2512
M1 4 0
MX 98 31
Lymphnode stage
N0 114 34 0.5755
N1 24 6
N2 23 12
N3 2 1
NX 14 3
Disease stage
Stage I 2 0 0.7669
Stage II 56 16
Stage III 68 21
Stage IV 51 19
Histologic grade
High grade 159 55 0.0457
Low grade 18 1
Tumor histologic subtype
Nonpapillary 114 38 0.6365
Papillary 63 18
P<0.05 was considered statistically signicant, using Chi‑square test

Zhao, et al.: Sex differences in bladder cancer prognosis
1243
Journal of Cancer Research and Therapeutics - Volume 17 - Issue 5 - November 2021
Patientdemographiccharacteristics, including age(≤60
and>60yearsold),BMI(≤24and>24),andclinicopathological
characteristics, including grade and TNM stage, were collected.
TNM stages of bladder cancer were determined according
to the American Joint Committee on Cancer (AJCC) staging
system using available clinical and pathological data on
tumor invasion, lymphnode status, and distant metastasis,
respectively.
In terms of survival outcome, OS was defined as the
time between the date of surgery and the date of death
or last follow‑up. DFS was defined as the time from the
date of surgery to the date of bladder cancer recurrence.
Cause of death was obtained from death certificates. All
patients with MIBC exhibited a median follow‑up period
of 19.02 months (range: 0.43–165.9 months) for OS and
15.9 months (range: 0.43–142.7 months) for DFS.
All statistical analyses were performed using GraphPad Prism®
8.0.2 (GraphPad Software, La Jolla, CA, USA). The Kaplan–
Meier method was used to calculate outcome functions,
and differences were assessed using the log‑rank statistic.
A two‑tailed Chi‑square test was used to examine differences
between categorical variables. All reported P values are two
sided, and a P < 0.05 was considered statistically significant.
RESULTS
A total of 233 eligible patients with MIBC were included
in this study. They consisted of 177 male patients (76%)
and 56 female patients (24%). The median follow‑up
period was 19.02 months (range: 0.43–165.9) for OS and
15.9 months (range: 0.43–142.7) for DFS. Among patients with
NMIBC, there were 80 male patients (76.2%) and 25 female
patients (23.8%) in all. The association between sex and
the demographic and clinicopathological characteristics of
patients with MIBC is presented in Table 1, whereas those
for patients with NMIBC are presented in Table 2. The clinical
data for patients with NMIBC did not contain prognostic
information, so for this group, we could only compare the
relationship between disease characteristics and sex. Female
patients with both MIBC and NMIBC demonstrated a lower
risk of exhibiting a high histologic grade tumor than male
patients (P = 0.0457 and P = 0.05, respectively). Moreover,
in patients with MIBC, BMI (30.15 vs. 26.68, P = 0.0035) and
age (67.54 years vs. 66.01 years, P = 0.045) were higher in
female patients than in male patients [Figure 1a and b].
A total of 63 (27.04%) patients with MIBC died during this study.
In the Kaplan–Meier analyses, female patients demonstrated a
significantly lower OS than male patients (P = 0.0429), but no
difference was found between sexes in terms of DFS [Figure 1c
and d].
To further analyze the relationship between patient sex and
prognosis, we divided all patients into groups, and then, we
compared the prognostic differences to the sex differences
within each group, in an attempt to uncover a new relationship
between sex and prognosis. First, we divided all patients into
one of two groups based on age (over 60 and under 60 years
old)and then analyzedOS and DFS.In the ≤60‑year‑old
patient group, female patients exhibited a shorter DFS and
poorer OS [P = 0.0011 and P = 0.0272, respectively; Figure 2a
and c]. In the >60‑year‑old patient group, no association
was found between sex and prognosis [Figure 2b and d]. In
summary,amongyoungerpatients(≤60yearsold),females
exhibited a worse prognosis than males, but among older
Table 2: Clinical characteristics of patients with
nonmuscle‑invasive bladder cancer
Clinical characteristic Sex P
Male Female
Age (years) 67.43 65.2
Range 36‑87 25‑87
Concomitant carcinoma in situ
Yes 33 6 0.1192
No 47 19
Number of tumors
Multiple 2+ 31 11 0.6478
Single 1 49 14
Recurrence
Yes 33 11 0.5178
No 42 14
NA 4 0
Grade
LGTa 13 10 0.05
HGTa 24 8
HGT1 33 5
Tis 10 2
Tumor size (cm)
>3 34 90.564
<3 46 16
P<0.05 was considered statistically signicant using Chi‑square test.
LGT=Low Grade Tumor, HGT=High Grade Tumor
Figure 1: Characteristics of patients with MIBC according to patient sex.
(a) correlation between age and sex in MIBC, (b) correlation between
BMI and sex in MIBC, (c) Kaplan–Meier disease recurrence curves for
patients with MIBC, stratied by sex, (d) Kaplan–Meier survival curves
for patients with bladder cancer, stratied by sex. MIBC = Muscle‑
invasive bladder cancer, BMI = Body mass index
d
c
b
a

Zhao, et al.: Sex differences in bladder cancer prognosis
1244 Journal of Cancer Research and Therapeutics - Volume 17 - Issue 5 - November 2021
patients (>60 years old), no notable difference was found in
prognosis across sex.
Then, we divided the patients into an overweight group and
a healthy‑weight group, using a BMI of 24 as the cutoff. In the
group of patients with BMI >24, no differences were found in
DFS across sex [Figure 3a], but OS was lower in women than
men [P=0.0431,Figure3c].InpatientswithBMI≤24,DFS
was shorter in women than men [P = 0.0205, Figure 3b], but
no difference was found in OS across the two sexes [Figure 3d].
In summary, overweight women (BMI >24) demonstrated a
worse survival rate than men, but healthy normal weight
women(BMI ≤24) weremorelikelythan men toexhibit
disease recurrence.
Next, we divided the patients into groups according to disease
stage, according to the AJCC. We found that, among patients
with stage III disease, female patients exhibited shorter DFS
and worse OS than male patients [P = 0.0427, P = 0.0078,
Figure 4b and e].
No association was found between sex and prognosis among
Stage II and IV patients [Figure 4]. Thus, women with Stage III
disease exhibited a worse prognosis; however, no difference
was found in the prognosis of male and female patients in
other stages of disease. This result is consistent with those
of previous studies.
Finally, in terms of the effect of the patient’s TNM stage,
we found that among patients in stage T3, the DFS of
female patients was notably shorter than that of male
patients [P = 0.0212, Figure 5b]. Among patients with stage
N0 disease, female patients also exhibited worse OS than male
patients [P = 0.0289, Figure 6c]. For patients in the other T
and N stages, sex resulted in no effect on prognosis [Figures 5
and 6]. The 5‑year survival rates for all groups are summarized
in Table 3.
DISCUSSION
Bladder cancer remains one of the most common malignancies
worldwide.[1,28] The characteristics of bladder tumors ensure
that it is more prone to recurrence, invasion, and metastasis.
Therefore, further analyses of the factors related to the
progression, recurrence, and prognosis of bladder cancer
improve our understanding of the disease, and they can
provide a basis for disease guidance and prognosis evaluated
the effect of sex on the prognosis of bladder cancer (mainly
MIBC). Moreover, we divided patients into groups according
to different patient and tumor characteristics, then analyzed
Table 3: Overall survival estimates according to
clinicopathological characteristics and patient sex
Characteristics Five‑year survival probability
Male Female
Age (years)
≤60 58.19 58.49
>60 54.81 60.28
BMI
≤24 51.06 42.19
>24 69.27 53.07
Disease stage
Stage II 75.03 88.21
Stage III 76.75 45.77
Stage IV 32.92 32.57
Tumor stage
T2 71.85 84.85
T3 54.2 49.14
T4 36.62 0
Lymph node stage
N0 78.89 70.14
N1-N3 32.9 32.57
BMI=Body mass index
Figure 2: Kaplan–Meier analyses for DFS and OS within each age
group of patients with MIBC, stratied by sex. (a and b) Kaplan–Meier
analyses of DFS within each age group. (c and d) Kaplan–Meier
analyses of OS within each age group. DFS = Disease‑free survival,
OS = Overall survival, MIBC = Muscle‑invasive bladder cancer
d
c
b
a
Figure 3: Kaplan–Meier analyses of DFS and OS within each BMI
group of patients with MIBC, stratied by sex. (a and b) Kaplan–Meier
analyses of DFS within each BMI group, (c and d) Kaplan–Meier
analyses of OS within each BMI group. DFS = Disease‑free survival,
OS = Overall survival, MIBC = Muscle‑invasive bladder cancer, BMI
= Body mass index
d
c
b
a

Zhao, et al.: Sex differences in bladder cancer prognosis
1245
Journal of Cancer Research and Therapeutics - Volume 17 - Issue 5 - November 2021
the effect sex on different prognosis characteristics. On the
one hand, we obtained partial results that were consistent
with those from previous studies. On the other hand, we
also found a new association between sex and prognosis in
different BMI groups.
With regard to the relationship between sex and bladder cancer
prognosis, previous studies found that, upon stratification by
patient stage, women with bladder cancer exhibited a worse
prognosis than men. Our research revealed that, compared to
men, women with Stage III exhibited shorter DFS and worse
OS, women with Stage T3 exhibited shorter DFS, and women
with Stage N0 exhibited worse OS; this reconfirmed the results
from previous studies. Conversely, no difference was found
in prognosis across the sexes in Stages II and IV, as well as in
other T and N stages. These results indicate that the prognosis
of female patients with bladder cancer was worse than that of
male patients and that patients with specific stages should be
paid particular attention since early intervention and active
treatment may improve their prognosis.
As for the causes of poor prognosis in women, some research
attributed this effect to hormones, whereas other research
suggested an association with metabolism.[22] In this study,
we compared the tumor characteristics of patients with
NMIBC and MIBC, noting that the number of patients with
higher‑grade tumors was lower in women with NMIBC, but
among those with MIBC, the proportion of female patients with
high‑level tumors was significantly higher. As for the reason for
poorer prognosis in some women, the average diagnostic age
and BMI were higher in female patients than in male patients.
In this study, we introduced BMI stratification for the first
time; previous studies have not examined the relationship
between sex and BMI in terms of bladder cancer prognosis.
Our study found that, among patients with bladder cancer,
Figure 4: Kaplan–Meier analyses of DFS and OS within each stage group of patients with MIBC, stratied by sex. (a‑c) Kaplan–Meier analyses
of DFS within each stage group, (d‑f) Kaplan–Meier analyses of OS within each stage group. DFS = Disease‑free survival, OS = Overall survival,
MIBC = Muscle-invasive bladder cancer
d
c
b
f
a
e
Figure 5: Kaplan–Meier analyses of DFS and OS within each T‑stage group in patients with MIBC, stratied by sex. (a‑c) Kaplan–Meier analyses
of DFS within each T‑stage group. (d‑f) Kaplan–Meier analyses of OS within each T‑stage group. DFS = Disease‑free survival, OS = Overall
survival, MIBC = Muscle-invasive bladder cancer
d
c
b
f
a
e

Zhao, et al.: Sex differences in bladder cancer prognosis
1246 Journal of Cancer Research and Therapeutics - Volume 17 - Issue 5 - November 2021
female patients exhibited a higher BMI than male patients, and
after stratification by BMI, these patients exhibited different
DFS and OS; In the group of patients with BMI >24, female
patients exhibited worse OS than male patients, whereas in
thegroupwithBMI≤24,femalepatients exhibitedshorter
DFS than male patients. These results suggest that overweight
women (BMI >24) exhibited a worse survival rate than men,
buthealthy‑weight women (BMI≤24) were more likely to
relapse than men. These results suggest a role of metabolism
and obesity in the disease process. Female patients with
different BMIs should be offered different clinical treatment
and follow‑up strategies to increase their clinical benefits.
Conversely, some of our results differed from those of previous
studies. For example, in the Stage II patient group, although no
difference was found in prognosis across sex, the prognosis and
5‑year survival rate of female patients tended to better than that
of male patients, unlike in previous studies. Upon the addition of
new clinical data, future studies may find statistically significant
differences across sex; this is worthy of further study.
This study demonstrated some limitations. Although the
latest TCGA clinical data was used, the clinical sample that
met the study requirements was small, the clinical data
were limited, and the data for patients with NMIBC did not
contain prognostic information. In future studies, we aim to
further study the relationship between sex and bladder cancer
prognosis using a larger clinical sample and more complete
clinical data, in addition to seeking its molecular mechanism
through basic research.
CONCLUSION
This study found that, compared to male patients, female
patients with bladder cancer exhibited a worse prognosis
when in specific stages, obese women with a high BMI
exhibited a worse survival rate, and women with a healthy
weight (BMI <24) were more likely to relapse. Uncovering
new factors related to bladder cancer prognosis can provide
a basis for disease guidance and patient prognosis evaluation.
Acknowledgment
The authors disclosed receipt of the following financial support
for the research and publication of this article; this study
was supported by the National Natural Science Foundation
of China (grant no. 81802565); Natural Science Foundation of
Jiangsu Province (grant no. BK20180216).
Financial support and sponsorship
This study was supported by the National Natural Science
Foundation of China (grant no. 81802565); Natural Science
Foundation of Jiangsu Province (grant no. BK20180216).
Conflicts of interest
There are no conflicts of interest.
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Figure 6: Kaplan–Meier analyses of DFS and OS within each N‑stage
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analyses of DFS within each N‑stage group, (c,d) Kaplan–Meier
analyses of OS within each N‑stage group. DFS = Disease‑free survival,
OS = Overall survival, MIBC = Muscle‑invasive bladder cancer
d
c
b
a

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Journal of Cancer Research and Therapeutics - Volume 17 - Issue 5 - November 2021
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