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PERSONALIZED MEDICINE IN THE MANAGEMENT OF INVASIVE BLADDER CANCER: Edited by Maximilian Burger and Andrea B. Apolo

Sex difference in presentation and outcomes of bladder cancer

biological reality or statistical fluke?

Wolff, Ingmara; Brookman-May, Sabineb; May, Matthiasc

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doi: 10.1097/MOU.0000000000000198
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Abstract

INTRODUCTION

For personalized medicine, there is an urgent need to elucidate differences and similarities between sexes in various entities by basic and clinical research. Sex-specific patient outcomes could not only possibly be caused by biologic variables such as genetic predisposition or anatomical and endocrine differences but also by divergent behavioural aspects, for example different lifestyle factors, participation in screening programmes and diagnostic work-up and treatment algorithms. The inconsistent use of the terms ‘sex’ (defined biologically) and ‘gender’ (defined by sociocultural aspects) shows the wide field of research activities to focus on.

The impact of sex on prognosis of tumour diseases has been studied in a number of malignancies. In a large European epidemiologic study based on data of almost 1.2 million patients with tumours of different origins diagnosed between 1985 and 1989, an age-adjusted reduction of cancer-specific mortality (CSM) of 30% could be observed in female patients [1]. A multivariate model based on these findings and adjusted for tumour entity, age, country, length of follow-up and sex showed a 5% reduction in mortality in women (P < 0.01). Authors of this study offered the following interpretations: higher awareness of health in women, resulting in faster diagnosis and subsequently more effective (and more often curative) treatment options; less exposure to risk factors in women resulting in a more favourable distribution of tumour-specific prognosis criteria; lower age-adjusted mortality in women, which might result in an interaction with tumour-specific survival; and biological superiority of women concerning tumour response and tolerance of treatment [1]. UCB, however, represents the only tumour entity with a significantly worse survival in female patients even on multivariable analysis (Risk Ratio 1.50; P < 0.001) [1]. On the basis of these findings, one question is consequently raised: What is different in UCB as opposed to other tumour entities?

UCB occurs about 2.5–4 times more often in men than women [2]. Although men consequently develop UCB more frequently, international data show relatively lower CSM in male patients [2,3,4▪,5,6▪▪,7–15] with subsequently higher CSM/incidence ratio for female patients with UCB [2,3,4▪,5,6▪▪,7–16]. A consistent explanation for the impact of sex on CSM is still lacking; variations of effects of environmental carcinogens on oncologic outcome, different recognition of symptoms and time differences in evaluating first symptoms as well as genetic, anatomical and hormonal disparities have been supposed [2,3,4▪,5,6▪▪,7–15]. Due to this presumably multifactorial prognostic impact of sex, a tailored sex-specific care for patients with muscle invasive UCB (MIBC) has been required by some authors, although an obvious scientifically evident key factor is lacking [16]. On the contrary, there are also studies that did not demonstrate any sex-specific prognostic impact [17▪▪].

In this review, we summarize results of recent studies evaluating the impact of sex on prognosis of patients with MIBC. Furthermore, we discuss which potential reasons for this prognostic impact prove to be reliable and which issues have to be addressed by future studies.

Box 1
Box 1:
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EVIDENCE ACQUISITATION

A PubMed/Medline literature search was performed to identify original articles regarding the Boolean operators [gender or sex] and [clinical presentation, diagnosis, therapy or prognosis/survival] in patients with MIBC. Searches were limited to the English language. MeSH-terms included invasive bladder cancer, urothelial carcinoma, transitional cell carcinoma, gender, sex, steroid sensitivity, hormone-receptors, therapy, radical cystectomy, urinary derivation, survival, outcome and prognosis. This review had no timely limit, but focused on the most significant findings from the past 3 years.

Three main issues have been addressed by identified relevant recent articles and are therefore focused on in this review article: Do diagnostic work-up procedures of clinical symptoms vary between sexes and does this induce a time delay from first symptoms to diagnosis or initiation of therapy?; Which studies concerning consistent and thus comparable therapeutic approaches (cystectomy, radiochemotherapy) evaluate the impact of sex on the prognosis of MIBC and how are possible explanations for sex-related differences discussed?; and Are there sex-specific differences in terms of prognostic impact of hormone-receptors (androgen receptor, oestrogen receptor)?

Scientific quality of selected articles is indicated by updated evidence levels according to the Oxford Centre for Evidence-based Medicine [18].

RECENT FINDINGS

In the USA, median patient age at time of UCB diagnosis is 73 years, and more than 70% of patients are older than 65 years [19]. As more than 75% of patients initially present in a nonmuscle-invasive stage, 5-year survival concerning all tumour stages is relatively high (78%) [19]. On the contrary, MIBC constitutes a very aggressive carcinoma in which radical cystectomy is recommended as the only therapeutic option with a grade A recommendation based on current EAU-guidelines when distant metastases are excluded by imaging [20]. However, according to a recent analysis of the US National Cancer Database, only 42% of patients with MIBC actually undergo radical cystectomy, while about one-half of these patients are additionally treated with chemotherapy or radiotherapy [19]. Although first studies describing a sex-specific impact on the prognosis of patients with MIBC date back more than 20 years and although remarkable research activity is observed in this field, no consistent and scientifically evident explanation has been found for the fact that women with MIBC experience a higher CSM than men [21]. In the USA, a total of 74 000 patients with UCB are estimated in 2015, among which 56 320 are male patients (m/f-rate 3.18 : 1). In this period, 16 000 UCB-caused deaths are expected (m/f-ratio 2.56 : 1), which clearly demonstrates the higher and more unfavourable CSM/incidence-ratio in female patients [22▪▪]. Hypotheses concerning the presumable prognostic impact include anatomical, hormonal, genetic, environmental, diagnostic and therapeutic differences between sexes [3].

The following chapters present recent studies (period 2012–2015) concerning the impact of sex on prognosis of MIBC separated by predefined criteria.

Sex-specific differences in the diagnostic work-up of first specific symptoms causing different time delays from first symptoms to diagnosis of urothelial carcinoma of the bladder

Johnson et al.[23] initially showed in 2008 that the probability of referral to a urologist is 65% higher in male patients than women with newly observed and partially recurrent haematuria (median follow-up of 26.5 months: 47 vs. 28%; P < 0.001). In a survey involving 168 consecutive patients (including 38 female patients) with newly diagnosed UCB, Henning et al.[24] found that distribution of initial symptoms were comparable between sexes (P > 0.05). However, 78% of male but only 55% of female patients consulted a urologist directly (P < 0.05). Without prior specific diagnostic work-up, a symptomatic treatment was adopted in 19% of male and 47.2% of female patients (P = 0.04). This did not result in any significant difference of distribution of tumour stages at time of initial transurethral resection [level of evidence (LoE): 3] [24]. These findings were confirmed by Aziz et al.[25] who applied an identical questionnaire on a smaller study group (n = 68). In this study, 61.1% of female, but only 20% of male patients were treated with antibiotics 12 months prior to diagnosis of UCB (P = 0.005; LoE: 3) [25]. Garg et al.[6▪▪] analysed 35 646 patients of the SEER (Surveillance, Epidemiology, and End Results) database 2000–2007 with newly diagnosed UCB after being evaluated for haematuria (LoE: 3). The mean time from first occurrence of haematuria to consultation of an urologist was 27 (0–377) days, although this period was significantly longer for female patients [adjusted hazard ratio 0.90; 95% confidence interval (CI) 0.87–0.92; P < 0.001]. According to a multivariate model adjusted for the most important clinical and demographic criteria, women were significantly more often attributed to a time delay of more than 30 days during the evaluation process of haematuria [adjusted odds ratio (OR) 1.12; 95% CI 1.05–1.20; P < 0.001] [6▪▪]. A methodologically similar study was published by Cohn et al. (LoE: 3) [26▪]. The authors extracted data from the Thomson-Reuters Market-Scan Commercial Claims and Encounters Database, which includes robust data from about 100 health insurance plans of approximately 40 large US employers. In this study, from 2004 to 2010, 7649 patients (2.233 of them female; 29%) initially presented with haematuria and were subsequently diagnosed with UCB within 12 months. It was found that mean time period from proven haematuria to bladder cancer diagnosis was significantly longer in women (85.4 vs. 73.6 days; P < 0.001). In addition, a time delay between presentation with haematuria and diagnosis of bladder cancer exceeding 6 months occurred more frequently in women (17.3 vs. 14.1%; P < 0.001). Furthermore, antibiotics were prescribed significantly more often in female patients prior to diagnosis (40.1 vs. 35.4%; P < 0.001) [26▪].

Studies concerning standardized therapies evaluating the prognostic impact of sex on the outcome of patients with urothelial carcinoma of the bladder

Some older population-based registry studies showed higher tumour stages and diminished survival in female UCB patients [27,28]. A recent study based on the Japanese Kanagawa cancer registry including 13.184 patients with primary UCB from 1954 through 2010 showed an increased CSM of about 40% after adjustment for patient age, time period of therapy and histological subtype (hazard ratio 1.39; 95% CI 1.28–1.52; LoE: 3) [29]. Interpretation of such studies based on cancer registries are frequently hampered by insufficient or lacking adjustment for tumour stages and therapeutic approaches. Table 1 displays all studies with consistent standardized therapy of MIBC published during 2012–2015 focusing on a sex-specific prognostic impact. Among eight studies representing radical cystectomy series, five found a higher CSM in female patients [4▪,13,14,29,30]. Interestingly, two of these studies detected a sex-specific prognostic impact in earlier time periods only [13,30]. Furthermore, in both studies, a worse survival was attributed to female patients especially in younger patients (≤55 and ≤60 years) and in those with lymphovascular invasion (LVI) [13,30]. In two studies focusing on early invasive UCB (T1-high grade) and organ-preserving therapy (TURB with topical instillation therapy), no prognostic impact of sex was detected [15,31]. The only study in patients undergoing radiochemotherapy conducted by Keck et al.[32] precisely analysed the sex-specific prognostic impact and detected a higher CSM in female patients on multivariate analysis (hazard ratio 2.40; P < 0.001).

Table 1
Table 1:
Selected recent studies with standardized therapeutic approaches evaluating the sex-specific impact on the prognosis of invasive urothelial carcinoma of the bladder
Table 1
Table 1:
(Continued) Selected recent studies with standardized therapeutic approaches evaluating the sex-specific impact on the prognosis of invasive urothelial carcinoma of the bladder
Table 1
Table 1:
(Continued) Selected recent studies with standardized therapeutic approaches evaluating the sex-specific impact on the prognosis of invasive urothelial carcinoma of the bladder

Studies concerning sex-specific disparities in the impact of hormone-receptors (androgen receptor, oestrogen receptor) on prognosis of muscle-invasive bladder cancer

Variations of incidence and potential prognostic differences between sexes may be explained on a molecular basis by the fact that UCB represents a malignancy associated with sex-specific steroid hormones (androgens, oestrogens) and their accordant cell-surface receptors [33,34]. Especially androgens and their downstream signal pathways have become of special scientific interest, as they may not only be linked to tumour progression in MIBC, but are also expected to possibly serve as therapeutic targets [33–39]. The androgen receptor (AR) in particular is considered to be a potential mediator for sex-specific variations and represents a ligand-dependent transcription factor found to be expressed in regular bladder epithelium [34]. In UCB, both high (AR+) and low (AR-) expression levels can be observed. Boorjian et al.[37] detected AR-expression in about half of their UCB patients by immunohistochemical staining (26/49; 53.1%) and demonstrated an inverse correlation between protein expression of AR in UCB and more invasive tumour stages (AR-expression in 75% of tumours without muscle invasion vs. 21% in stage pT2-3; P = 0.002). Female patients showed a significantly lower AR-expression in their tumours (30.1 vs. 61.1%, P < 0.05) [37]. This inverse correlation between AR-expression of tumour cells and tumour stages was confirmed in a study with 139 patients by Tuygun et al.[39]. In addition, both studies supported the association between low AR-expression and high-grade tumours [37,39]. No significant difference in terms of tumoural AR-expression was detected between sexes by Tuygun et al. (m/f: 52.5 vs. 43.8%; P = 0.41) [39]. These results were confirmed by Mir et al.[38] who also did not find any significant difference in AR-expression between sexes (m/f: 14 vs. 8.1%; P = 0.14). One recent study by Mashhadi et al.[36] also did not detect any significant sex-specific difference in AR-expression, but a positive correlation between higher AR-expression on the one hand and invasive tumour stage and worse survival on the other hand was found in contrast to all other available data.

Two types of nuclear oestrogen receptors (ERα, ERβ) have been differentiated that both account for transduction of hormonal signals into transcription [34]. In UCB, ERβ is predominantly found and a correlation between high expression levels on the one hand and more invasive tumour stages and high-grade tumours on the other has been described [39,40]. The impact of ERβ might be explained by interactions with various growth factors [e.g. transforming growth factor-beta 1 (TGF-β1)] and its key role in several signalling pathways responsible for tumourigenesis and progression [34]. Tuygun et al.[39] demonstrated significantly worse survival in patients with UCB and higher expression of ERβ. However, downstream pathways after activation of ERβ are not yet understood sufficiently. In a recent study by Izumi et al.[35], a significant negative correlation between ERβ and UDP-glucoronosyltransferase 1A (UGT1A)-expression was detected. The extent of this negative correlation between ERβ and UGT1A was more pronounced in female patients [−0.7 (women) < correlation <−0.4 (men)] [35]. The authors also showed that CSM of patients with MIBC was lower when associated with a high UGT1A-expression (hazard ratio 0.293; P = 0.010) [35]. All studies concerning clinical implications of expression of AR and ERβ mentioned above have been assessed LoE 3 [35–40].

DISCUSSION AND FURTHER PERSPECTIVES

Women with UCB present with a lower incidence and a higher CSM in Western countries as opposed to men [8,19,22▪▪]. That is undoubted, but the objective of this review article is not sufficiently fulfilled by this fact. The impact of sex on the prognosis of UCB may be approved if sex-associated factors (anatomy, hormone-receptors, genetics, tumour biology) that vary between sexes prove to influence prognosis within studies of acceptable methodological quality. However, to date, the evidence for all these factors is not sufficient to claim an independent impact of sex on prognosis. In addition, sex-associated variations in terms of delay between initial presentation and UCB diagnosis, differences in diagnostic work-up, therapeutic approaches and quality and exposition to carcinogenic noxa may also result in a different outcome between sexes. These criteria are not linked to biological sex, as they would potentially influence prognosis of UCB patients as well even in case of inverse manifestation. However, there is indirect evidence that especially these criteria are applied in a different way between sexes. Time delay between initial presentation of symptomatic female patients with UCB and deferred referral to an urologist has been presented in previous chapters [23–25,26▪]. Recently, Schmid et al.[41▪▪] prospectively analysed a European radical cystectomy series and revealed a four times higher rate of incontinent urinary diversion in female patients as opposed to male patients (after being adjusted for all relevant clinical criteria on multivariate analysis). Actually, urinary diversion is not a variable interfering with prognosis of patients in the first place, but on the other hand, it may serve as a surrogate parameter for quality of treatment and may as such represent further factors directly influencing prognosis [5].

Research activities in the future should therefore include time delay from first symptoms to diagnosis of UCB in female patients, variations in sex-specific tumour biology by evaluation of molecular markers and analysis of subsequent signal pathways of hormone receptors. Assertion of a comparably high therapy standard in female patients is another important objective, as the lower rate of continent urinary diversion in women undergoing radical cystectomy indeed may serve as a surrogate for lower quality of therapy.

CONCLUSION

Quality of research data concerning the impact of sex on the prognosis of patients with MIBC are still insufficient. Recent studies from population-based cancer registries indicate a relatively higher CSM in female patients, but the reason for this difference is not clear.

Research activities in the future should therefore include time delay from first symptoms to diagnosis in female patients, variations in sex-specific tumour biology by evaluation of molecular markers and analysis of subsequent signal pathways of hormone receptors. Assertion of comparably high therapy standards in female patients is another objective, as the lower rate of continent urinary diversion in women undergoing radical cystectomy may serve as a surrogate for lower quality of therapy. Interaction between sex and oncologic outcome of patients with MIBC seems to be multifactorial, although an independent prognostic impact of sex cannot be proven validly on the basis of available research data.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

Sabine Brookman-May is an employee (Director, Regional Therapeutic Area Expert Oncology EMEA) of Janssen Research and Development, Beerse, Belgium, which, however, has neither influenced composition of this review article nor evidence and conclusions. Ingmar Wolff and Matthias May declare no conflict of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

bladder cancer; diagnostic work-up; prognosis; radical cystectomy; radiochemotherapy; sex; survival; therapy; urinary diversion; urothelial cancer

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