Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The sex gap in bladder cancer survival — a missing link in bladder cancer care?

Nature Reviews Urology volume 21, pages 181–192 (2024)Cite this article

Subjects

Abstract

The differences in bladder cancer outcomes between the sexes has again been highlighted. Uncommon among cancers, bladder cancer outcomes are notably worse for women than for men. Furthermore, bladder cancer is three to four times more common among men than among women. Factors that might explain these sex differences include understanding the importance of haematuria as a symptom of bladder cancer by both clinicians and patients, the resultant delays in diagnosis and referral of women with haematuria, and health-care access. Notably, these factors seem to have geographical variation and are not consistent across all health-care systems. Likewise, data relating to sex-specific treatment responses for patients with non-muscle-invasive or muscle-invasive bladder cancer are inconsistent. The influence of differences in the microbiome, bladder wall thickness and urine dwell times remain to be elucidated. The interplay of hormone signalling, gene expression, immunology and the tumour microenvironment remains complex but probably underpins the sexual dimorphism in disease incidence and stage and histology at presentation. The contribution of these biological phenomena to sex-specific outcome differences is probable, albeit potentially treatment-specific, and further understanding is required. Notwithstanding these aspects, we identify opportunities to harness biological differences to improve treatment outcomes, as well as areas of fundamental and translational research to pursue. At the level of policy and health-care delivery, improvements can be made across the domains of patient awareness, clinician education, referral pathways and guideline-based care. Together, we aim to highlight opportunities to close the sex gap in bladder cancer outcomes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: 1-year, 2-year, 3-year and 4-year bladder cancer survival (%) for adults (aged between 15 and 99 years) diagnosed in England from 2015 to 2019, followed until to 2020 (ref. 17).
Fig. 2: Overall survival for patients with T1–T4 bladder cancers treated in England from 2013 to 2019, plotted using the Kaplan–Meier method with respect to sex.
Fig. 3: A summary of immunological sex differences in bladder cancer.
Fig. 4: An overview of different approaches to decreasing the sex gap in bladder cancer outcomes.

Similar content being viewed by others

References

  1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  PubMed  Google Scholar 

  2. Babjuk, M. et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur. Urol. https://doi.org/10.1016/j.eururo.2021.08.010 (2021).

    Article  PubMed  Google Scholar 

  3. Witjes, J. A. et al. European Association of Urology Guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur. Urol. 79, 82–104 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Sylvester, R. J. et al. European Association of Urology (EAU) Prognostic Factor Risk Groups for non-muscle-invasive bladder cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: an update from the EAU NMIBC guidelines panel. Eur. Urol. 79, 480–488 (2021).

    Article  PubMed  Google Scholar 

  5. Herbert, A. et al. Population trends in emergency cancer diagnoses: the role of changing patient case-mix. Cancer Epidemiol. 63, 101574 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Teoh, J. Y. et al. Global trends of bladder cancer incidence and mortality, and their associations with tobacco use and gross domestic product per capita. Eur. Urol. 78, 893–906 (2020).

    Article  PubMed  Google Scholar 

  7. Cumberbatch, M. G. K. et al. Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. Eur. Urol. 74, 784–795 (2018).

    Article  PubMed  Google Scholar 

  8. Bryan, R. T. et al. A comparison of patient and tumour characteristics in two UK bladder cancer cohorts separated by 20 years. BJU Int. 112, 169–175 (2013).

    Article  PubMed  Google Scholar 

  9. Richters, A. et al. Bladder cancer survival: women only fare worse in the first two years after diagnosis. Urol. Oncol. 37, 853–861 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Freedman, N. D., Silverman, D. T., Hollenbeck, A. R., Schatzkin, A. & Abnet, C. C. Association between smoking and risk of bladder cancer among men and women. J. Am. Med. Assoc. 306, 737–745 (2011).

    Article  CAS  Google Scholar 

  11. Uhlig, A. et al. Gender specific differences in disease-free, cancer specific and overall survival after radical cystectomy for bladder cancer: a systematic review and meta-analysis. J. Urol. 200, 48–60 (2018).

    Article  PubMed  Google Scholar 

  12. Wang, S. C. et al. The gender difference and mortality-to-incidence ratio relate to health care disparities in bladder cancer: national estimates from 33 countries. Sci. Rep. 7, 4360 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Mungan, N. A. et al. Gender differences in stage-adjusted bladder cancer survival. Urology 55, 876–880 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Kluth, L. A. et al. Gender-specific differences in clinicopathologic outcomes following radical cystectomy: an international multi-institutional study of more than 8000 patients. Eur. Urol. 66, 913–919 (2014).

    Article  PubMed  Google Scholar 

  15. Liu, S. et al. The impact of female gender on bladder cancer-specific death risk after radical cystectomy: a meta-analysis of 27,912 patients. Int. Urol. Nephrol. 47, 951–958 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Mossanen, M. & Gore, J. L. The burden of bladder cancer care: direct and indirect costs. Curr. Opin. Urol. 24, 487–491 (2014).

    Article  PubMed  Google Scholar 

  17. NHS Digital. Cancer Survival in England, cancers diagnosed 2015 to 2019, followed up to 2020. NHS Digital https://digital.nhs.uk/data-and-information/publications/statistical/cancer-survival-in-england/cancers-diagnosed-2015-to-2019-followed-up-to-2020#resources (2022).

  18. Catto, J. W. F. et al. Diagnosis, treatment and survival from bladder, upper urinary tract, and urethral cancers: real-world findings from NHS England between 2013 and 2019. BJU Int. https://doi.org/10.1111/bju.15970 (2023).

    Article  PubMed  Google Scholar 

  19. Theodorescu, D., Li, Z. & Li, X. Sex differences in bladder cancer: emerging data and call to action. Nat. Rev. Urol. 19, 447–449 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sadighian, M. & Porten, S. Gender differences in oncologic and functional outcomes in patients with bladder cancer undergoing radical cystectomy with urinary diversion. Curr. Opin. Urol. 29, 542–547 (2019).

    Article  PubMed  Google Scholar 

  21. Burge, F. & Kockelbergh, R. Closing the gender gap: can we improve bladder cancer survival in women? - A systematic review of diagnosis, treatment and outcomes. Urol. Int. 97, 373–379 (2016).

    Article  PubMed  Google Scholar 

  22. Koti, M. et al. Sex differences in bladder cancer immunobiology and outcomes: a collaborative review with implications for treatment. Eur. Urol. Oncol. 3, 622–630 (2020).

    Article  PubMed  Google Scholar 

  23. Shu, T. D. et al. Disparities in cause-specific mortality by race and sex among bladder cancer patients from the SEER database. Cancer Causes Control https://doi.org/10.1007/s10552-023-01679-x (2023).

    Article  PubMed  Google Scholar 

  24. Dong, M. et al. Sex differences in cancer incidence and survival: a pan-cancer analysis. Cancer Epidemiol. Biomark. Prev. 29, 1389–1397 (2020).

    Article  Google Scholar 

  25. Marcos-Gragera, R. et al. Urinary tract cancer survival in Europe 1999–2007: results of the population-based study EUROCARE-5. Eur. J. Cancer https://doi.org/10.1016/j.ejca.2015.07.028 (2015).

    Article  PubMed  Google Scholar 

  26. Richters, A., Leliveld, A. M., Goossens-Laan, C. A., Aben, K. K. H. & Ozdemir, B. C. Sex differences in treatment patterns for non-advanced muscle-invasive bladder cancer: a descriptive analysis of 3484 patients of the Netherlands Cancer Registry. World J. Urol. 40, 2275–2281 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Blindheim, A. et al. T1 bladder cancer in Norway: treatment and survival. Scand. J. Urol. 54, 370–375 (2020).

    Article  PubMed  Google Scholar 

  28. Mori, K. et al. Impact of sex on outcomes after surgery for non-muscle-invasive and muscle-invasive bladder urothelial carcinoma: a systematic review and meta-analysis. World J. Urol. https://doi.org/10.1007/s00345-022-04116-x (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Dobruch, J. et al. Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes. Eur. Urol. 69, 300–310 (2016).

    Article  PubMed  Google Scholar 

  30. Foxman, B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am. J. Med. 113, 5S–13S (2002).

    Article  PubMed  Google Scholar 

  31. Zhou, Y. et al. Quality of the diagnostic process in patients presenting with symptoms suggestive of bladder or kidney cancer: a systematic review. BMJ Open 9, e029143 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bolenz, C., Schroppel, B., Eisenhardt, A., Schmitz-Drager, B. J. & Grimm, M. O. The investigation of hematuria. Dtsch. Arztebl Int. 115, 801–807 (2018).

    PubMed  PubMed Central  Google Scholar 

  33. Lyratzopoulos, G., Abel, G. A., McPhail, S., Neal, R. D. & Rubin, G. P. Gender inequalities in the promptness of diagnosis of bladder and renal cancer after symptomatic presentation: evidence from secondary analysis of an English primary care audit survey. BMJ Open 3, 002861 (2013).

    Article  Google Scholar 

  34. Ngo, B., Perera, M., Papa, N., Bolton, D. & Sengupta, S. Factors affecting the timeliness and adequacy of haematuria assessment in bladder cancer: a systematic review. BJU Int. 119, 10–18 (2017).

    Article  PubMed  Google Scholar 

  35. Bryan, R. T. et al. A comparative analysis of the influence of gender, pathway delays, and risk factor exposures on the long-term outcomes of bladder cancer. Eur. Urol. Focus. 1, 82–89 (2015).

    Article  PubMed  Google Scholar 

  36. Zhou, Y. et al. Prolonged diagnostic intervals as marker of missed diagnostic opportunities in bladder and kidney cancer patients with alarm features: a longitudinal linked data study. Cancers https://doi.org/10.3390/cancers13010156 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Danforth, K. N. et al. Care quality and variability in the use of intravesical therapy for initial treatment of nonmuscle invasive bladder cancer within a large, diverse integrated delivery system. Urology 131, 93–103 (2019).

    Article  PubMed  Google Scholar 

  38. Grajales, V. et al. Associations between female sex and treatment patterns and outcomes for muscle-invasive bladder cancer. Urology 151, 169–175 (2021).

    Article  PubMed  Google Scholar 

  39. Marinaro, J. et al. Sex and racial disparities in the treatment and outcomes of muscle-invasive bladder cancer. Urology 151, 154–162 (2021).

    Article  PubMed  Google Scholar 

  40. Heberling, U. et al. Gender and mortality after radical cystectomy: competing risk analysis. Urol. Int. 101, 293–299 (2018).

    Article  PubMed  Google Scholar 

  41. Farber, N. J. et al. Disparities in the use of continent urinary diversions after radical cystectomy for bladder cancer. Bladder Cancer 4, 113–120 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Bachour, K. et al. Trends in urinary diversion after radical cystectomy for urothelial carcinoma. World J. Urol. 36, 409–416 (2018).

    Article  PubMed  Google Scholar 

  43. Chang, S. S. et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J. Urol. 198, 552–559 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Gross, T., Meierhans Ruf, S. D., Meissner, C., Ochsner, K. & Studer, U. E. Orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence. Eur. Urol. 68, 664–671 (2015).

    Article  PubMed  Google Scholar 

  45. Gupta, N. et al. Practice patterns regarding female reproductive organ-sparing and nerve-sparing radical cystectomy among urologic oncologists in the United States. Clin. Genitourin. Cancer https://doi.org/10.1016/j.clgc.2023.01.010 (2023).

    Article  PubMed  Google Scholar 

  46. Bree, K. K. et al. Contemporary rates of gynecologic organ involvement in females with muscle invasive bladder cancer: a retrospective review of women undergoing radical cystectomy following neoadjuvant chemotherapy. J. Urol. 206, 577–585 (2021).

    Article  PubMed  Google Scholar 

  47. Lobo, N. et al. Is it safe to spare gynaecological organs in female patients undergoing radical cystectomy? A multi-institutional study of three tertiary pelvic cancer centres. J. Clin. Urol. 15, 94 (2022).

    Google Scholar 

  48. Rosiello, G. et al. The effect of sex on disease stage and survival after radical cystectomy: a population-based analysis. Urol. Oncol. 39, 236 e231–236 e237 (2021).

    Article  Google Scholar 

  49. Krimphove, M. J. et al. Sex-specific differences in the quality of treatment of muscle-invasive bladder cancer do not explain the overall survival discrepancy. Eur. Urol. Focus. 7, 124–131 (2021).

    Article  PubMed  Google Scholar 

  50. Ballas, L. K. et al. Disparities in male versus female oncologic outcomes following bladder preservation: a population-based cohort study. Cancer Med. 10, 3004–3012 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Williams, S. B. et al. Survival differences among patients with bladder cancer according to sex: critical evaluation of radical cystectomy use and delay to treatment. Urol. Oncol. 35, 602 e601–602 e609 (2017).

    Article  Google Scholar 

  52. Venkat, S. et al. Does neoadjuvant chemotherapy diminish the sex disparity in bladder cancer survival after radical cystectomy? Urol. Oncol. 40, 106 e121–106 e129 (2022).

    Article  Google Scholar 

  53. Hoskin, P. J., Rojas, A. M., Bentzen, S. M. & Saunders, M. I. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J. Clin. Oncol. 28, 4912–4918 (2010).

    Article  PubMed  Google Scholar 

  54. D’Andrea, D. et al. Association of patients’ sex with treatment outcomes after intravesical bacillus Calmette-Guerin immunotherapy for T1G3/HG bladder cancer. World J. Urol. 39, 3337–3344 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Uhlig, A. et al. Gender-specific differences in recurrence of non-muscle-invasive bladder cancer: a systematic review and meta-analysis. Eur. Urol. Focus. 4, 924–936 (2018).

    Article  PubMed  Google Scholar 

  56. Bree, K. K. et al. Impact of sex on response to BCG in non-muscle invasive bladder cancer patients: a contemporary review from a tertiary care center. World J. Urol. 39, 4143–4149 (2021).

    Article  PubMed  Google Scholar 

  57. Fadel, J. et al. Analysis of sex-based differences to Bacillus Calmette-Guerin for non-muscle invasive bladder cancer. Urol. Oncol. https://doi.org/10.1016/j.urolonc.2022.09.024 (2022).

    Article  PubMed  Google Scholar 

  58. Balar, A. V. et al. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann. Oncol. 34, 289–299 (2023).

    Article  CAS  PubMed  Google Scholar 

  59. Powles, T. et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 22, 931–945 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Galsky, M. D. et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 395, 1547–1557 (2020).

    Article  CAS  PubMed  Google Scholar 

  61. Haines, L. et al. The impact of gender on outcomes in patients with metastatic urothelial carcinoma. Clin. Genitourin. Cancer 11, 346–352 (2013).

    Article  PubMed  Google Scholar 

  62. Hsu, J. W. et al. Decreased tumorigenesis and mortality from bladder cancer in mice lacking urothelial androgen receptor. Am. J. Pathol. 182, 1811–1820 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Miyamoto, H. et al. Promotion of bladder cancer development and progression by androgen receptor signals. J. Natl Cancer Inst. 99, 558–568 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Hsu, I., Vitkus, S., Da, J. & Yeh, S. Role of oestrogen receptors in bladder cancer development. Nat. Rev. Urol. 10, 317–326 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Hsu, I. et al. Estrogen receptor alpha prevents bladder cancer via INPP4B inhibited akt pathway in vitro and in vivo. Oncotarget 5, 7917–7935 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Hsu, I. et al. Suppression of ERβ signaling via ERβ knockout or antagonist protects against bladder cancer development. Carcinogenesis 35, 651–661 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Miyamoto, H. et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 109, 1716–1726 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Nguyen, D. P. et al. Association of aromatase with bladder cancer stage and long-term survival: new insights into the hormonal paradigm in bladder cancer. Clin. Genitourin. Cancer 15, 256–262 e251 (2017).

    Article  PubMed  Google Scholar 

  69. Shen, S. S. et al. Expression of estrogen receptors-α and -β in bladder cancer cell lines and human bladder tumor tissue. Cancer 106, 2610–2616 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Tuygun, C. et al. Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression. Urol. Oncol. 29, 43–51 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Kaneko, S. & Li, X. X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci. Adv. 4, eaar5598 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Huang, A. T. et al. Bladder cancer and reproductive factors among women in Spain. Cancer Causes Control 20, 1907–1913 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bai, Y. et al. Parity and bladder cancer risk: a dose-response meta-analysis. BMC Cancer 17, 31 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Cantwell, M. M., Lacey, J. V. Jr, Schairer, C., Schatzkin, A. & Michaud, D. S. Reproductive factors, exogenous hormone use and bladder cancer risk in a prospective study. Int. J. Cancer 119, 2398–2401 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Daugherty, S. E. et al. Reproductive factors and menopausal hormone therapy and bladder cancer risk in the NIH-AARP diet and health study. Int. J. Cancer 133, 462–472 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. McGrath, M., Michaud, D. S. & De Vivo, I. Hormonal and reproductive factors and the risk of bladder cancer in women. Am. J. Epidemiol. 163, 236–244 (2006).

    Article  PubMed  Google Scholar 

  78. Li, Y.-D., Gao, L., Gou, Y.-Q., Tan, W. & Liu, C. Age of menarche and primary bladder cancer risk: a meta-analysis and systematic review. Urol. Oncol. 40, 346.e17–346.e26 (2022).

    Article  PubMed  Google Scholar 

  79. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

    Article  Google Scholar 

  80. Van, B. J. et al. Bladder cancers arise from distinct urothelial sub-populations. Nat. Cell Biol. 16, 982–991 (2014).

    Article  Google Scholar 

  81. Kamoun, A. et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur. Urol. 77, 420–433 (2020).

    Article  PubMed  Google Scholar 

  82. Lindskrog, S. V. et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat. Commun. 12, 2301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Goel, A. et al. Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes. Genome Med. 14, 59 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Meeks, J. J. et al. Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes. Nat. Rev. Urol. 17, 259–270 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Liu, X. et al. Highly prevalent TERT promoter mutations in bladder cancer and glioblastoma. Cell Cycle 12, 1637–1638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Robertson, A. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171, 540–556 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sfakianos, J. et al. Epithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers. Nat. Commun. 11, 2540 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Soukup, V. et al. Prognostic performance and reproducibility of the 1973 and 2004/2016 World Health Organization grading classification systems in non-muscle-invasive bladder cancer: a European Association of Urology non-muscle invasive bladder cancer guidelines panel systematic review. Eur. Urol. 72, 801–813 (2017).

    Article  PubMed  Google Scholar 

  89. Yuan, Y. et al. Comprehensive characterization of molecular differences in cancer between male and female patients. Cancer Cell 29, 711–722 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hurst, C. D. et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell 32, 701–715 e707 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Ball, K. S., Hounsome, L., Verne, J. & Kockelbergh, R. Non-transitional cell carcinoma only partly explains adverse survival outcomes in females with T1–T4 bladder cancer: a summary of UK epidemiological data. J. Clin. Urol. 10, 14–18 (2017).

    Article  Google Scholar 

  92. de Jong, J. J. et al. Distribution of molecular subtypes in muscle-invasive bladder cancer is driven by sex-specific differences. Eur. Urol. Oncol. 3, 420–423 (2020).

    Article  PubMed  Google Scholar 

  93. Hedegaard, J. et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30, 27–42 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Care, A. et al. Sex disparity in cancer: roles of microRNAs and related functional players. Cell Death Differ. 25, 477–485 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kwon, H. et al. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Sci. Immunol. 7, eabq2630 (2022).

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  96. Toren, P. et al. Androgen receptor and immune cell PD-L1 expression in bladder tumors predicts disease recurrence and survival. World J. Urol. 39, 1549–1558 (2021).

    Article  CAS  PubMed  Google Scholar 

  97. Guan, X. et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature 606, 791–796 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Abdel-Hafiz, H. A. et al. Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature https://doi.org/10.1038/s41586-023-06234-x (2023).

    Article  PubMed  Google Scholar 

  99. Oh, D. Y. et al. Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612–1625 e1613 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Chenard, S. et al. Sexual dimorphism in outcomes of non-muscle-invasive bladder cancer: a role of CD163+ macrophages, B cells, and PD-L1 immune checkpoint. Eur. Urol. Open Sci. 29, 50–58 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Zhang, G. J. et al. Autocrine IL-6 production by human transitional carcinoma cells upregulates expression of the α5β1 fibronectin receptor. J. Urol. 163, 1553–1559 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Guise, A. I., Chen, F., Zhang, G. & See, W. The effects of physiological estrogen concentration on the immune response of urothelial carcinoma cells to bacillus Calmette-Guerin. J. Urol. 185, 298–304 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Shang, Z. et al. Targeting estrogen/estrogen receptor alpha enhances Bacillus Calmette-Guerin efficacy in bladder cancer. Oncotarget 7, 27325–27335 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Piasecka, B. et al. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. Proc. Natl Acad. Sci. USA 115, E488–E497 (2018).

    Article  CAS  PubMed  Google Scholar 

  105. Marquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Hamade, A. et al. Sex differences in the aging murine urinary bladder and influence on the tumor immune microenvironment of a carcinogen-induced model of bladder cancer. Biol. Sex. Differ. 13, 19 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yang, L. et al. Posttranscriptional control of PD-L1 expression by 17β-estradiol via PI3K/Akt signaling pathway in ERα-positive cancer cell lines. Int. J. Gynecol. Cancer 27, 196–205 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Pederzoli, F. et al. Sex-specific alterations in the urinary and tissue microbiome in therapy-naive urothelial bladder cancer patients. Eur. Urol. Oncol. 3, 784–788 (2020).

    Article  PubMed  Google Scholar 

  109. Anzia, L. E. et al. Comprehensive non-invasive analysis of lower urinary tract anatomy using MRI. Abdom. Radiol. 46, 1670–1676 (2021).

    Article  Google Scholar 

  110. Sarrio-Sanz, P. et al. Mortality prediction models after radical cystectomy for bladder tumour: a systematic review and critical appraisal. Eur. J. Clin. Invest. 52, e13822 (2022).

    Article  PubMed  Google Scholar 

  111. Zhou, Y., Funston, G., Lyratzopoulos, G. & Walter, F. M. Improving the timely detection of bladder and kidney cancer in primary care. Adv. Ther. 36, 1778–1785 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Haider, A. et al. Sex and gender in cardiovascular medicine: presentation and outcomes of acute coronary syndrome. Eur. Heart J. 41, 1328–1336 (2020).

    Article  CAS  PubMed  Google Scholar 

  113. Cader, F. A., Banerjee, S. & Gulati, M. Sex differences in acute coronary syndromes: a global perspective. J. Cardiovasc. Dev. Dis. https://doi.org/10.3390/jcdd9080239 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Merriel, S. W. D. et al. A prospective evaluation of the fourth national Be Clear on Cancer ‘Blood in Pee’ campaign in England. Eur. J. Cancer Care 31, e13606 (2022).

    Article  Google Scholar 

  115. Wakefield, M. A., Loken, B. & Hornik, R. C. Use of mass media campaigns to change health behaviour. Lancet 376, 1261–1271 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Arsenault-Lapierre, G. et al. Improving dementia care: insights from audit and feedback in interdisciplinary primary care sites. BMC Health Serv. Res. 22, 353 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Russell, B. et al. A systematic review and meta-analysis of delay in radical cystectomy and the effect on survival in bladder cancer patients. Eur. Urol. Oncol. 3, 239–249 (2020).

    Article  PubMed  Google Scholar 

  118. Bryan, R. T. et al. Comparing an imaging-guided pathway with the standard pathway for staging muscle-invasive bladder cancer: preliminary data from the BladderPath study. Eur. Urol. https://doi.org/10.1016/j.eururo.2021.02.021 (2021).

    Article  PubMed  Google Scholar 

  119. Ward, D. G. et al. Highly sensitive and specific detection of bladder cancer via targeted ultra-deep sequencing of urinary DNA. Eur. Urol. Oncol. https://doi.org/10.1016/j.euo.2022.03.005 (2022).

    Article  PubMed  Google Scholar 

  120. Humayun-Zakaria, N., Ward, D. G., Arnold, R. & Bryan, R. T. Trends in urine biomarker discovery for urothelial bladder cancer: DNA, RNA, or protein? Transl. Androl. Urol. 10, 2787–2808 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Wallace, D. M., Bryan, R. T., Dunn, J. A., Begum, G. & Bathers, S. Delay and survival in bladder cancer. BJU Int. 89, 868–878 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Russell, B. et al. Systematic review of the association between socioeconomic status and bladder cancer survival with hospital type, comorbidities, and treatment delay as mediators. BJUI Compass 2, 140–158 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Esnaola, N. F. & Ford, M. E. Racial differences and disparities in cancer care and outcomes: where’s the rub? Surg. Oncol. Clin. N. Am. 21, 417–437 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Densmore, R., Hajizadeh, M. & Hu, M. Trends in socio-economic inequalities in bladder cancer incidence in Canada: 1992–2010. Can. J. Public Health 110, 722–731 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Sutton, R. T. et al. An overview of clinical decision support systems: benefits, risks, and strategies for success. NPJ Digit. Med. 3, 17 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Walter, F. M. et al. Using the 7-point checklist as a diagnostic aid for pigmented skin lesions in general practice: a diagnostic validation study. Br. J. Gen. Pract. 63, e345–353 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Harrison, H. et al. Risk prediction models for symptomatic patients with bladder and kidney cancer: a systematic review. Br. J. Gen. Pract. 72, e11–e18 (2022).

    Article  PubMed  Google Scholar 

  128. Linder, B. J., Bass, E. J., Mostafid, H. & Boorjian, S. A. Guideline of guidelines: asymptomatic microscopic haematuria. BJU Int. 121, 176–183 (2018).

    Article  PubMed  Google Scholar 

  129. Barocas, D. A. et al. Microhematuria: AUA/SUFU guideline. J. Urol. 204, 778–786 (2020).

    Article  PubMed  Google Scholar 

  130. Sorce, G. et al. Survival trends in chemotherapy exposed metastatic bladder cancer patients and chemotherapy effect across different age, sex, and race/ethnicity. Urol. Oncol. 40, 380.e19–380.e27 (2022).

    Article  CAS  PubMed  Google Scholar 

  131. Fernandez-Gomez, J. et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: multivariate analysis of data from four randomized CUETO trials. Eur. Urol. 53, 992–1001 (2008).

    Article  PubMed  Google Scholar 

  132. Schafer, J. M. et al. Sex-biased adaptive immune regulation in cancer development and therapy. iScience 25, 104717 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kourbanhoussen, K. et al. Switching cancers: a systematic review assessing the role of androgen suppressive therapy in bladder cancer. Eur. Urol. Focus. 7, 1044–1051 (2021).

    Article  PubMed  Google Scholar 

  134. Dekalo, S. et al. 5alpha-reductase inhibitors and the risk of bladder cancer in a large, population-based cohort. Urol. Oncol. https://doi.org/10.1016/j.urolonc.2022.09.004 (2022).

    Article  PubMed  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT05327647 (2022).

  136. Niegisch, G. et al. Treatment patterns, indicators of receiving systemic treatment, and clinical outcomes in metastatic urothelial carcinoma: a retrospective analysis of real-world data in Germany. J. Clin. Oncol. 41, 464 (2023).

    Article  Google Scholar 

  137. Westhofen, T. et al. Gender specific differences in health-related quality of life for patients with bladder cancer following radical cystectomy. J. Clin. Oncol. 41, 437 (2023).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CHU de Québec-Université Laval, Quebec City, Quebec, Canada

    Paul Toren & Typhaine Gris

  2. Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK

    Anna Wilkins & Amy Burley

  3. The Royal Marsden Hospitals NHS Trust, London, UK

    Anna Wilkins

  4. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    Keval Patel

  5. University Hospitals of Leicester NHS Trust, Leicester, UK

    Roger Kockelbergh

  6. Action Bladder Cancer UK, Tetbury, UK

    Roger Kockelbergh & Richard T. Bryan

  7. Division of Cancer Sciences, University of Manchester and The Christie NHS Foundation Trust, Manchester, UK

    Taha Lodhi & Ananya Choudhury

  8. Bladder Cancer Research Centre, Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, UK

    Richard T. Bryan

Authors
  1. Paul Toren
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Wilkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keval Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amy Burley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Typhaine Gris
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roger Kockelbergh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Taha Lodhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ananya Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Richard T. Bryan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article. P.T., R.K. and R.T.B. contributed substantially to discussion of the content. P.T., A.W., K.P., A.B., T.G., T.L., A.C. and R.T.B. wrote the article. P.T., A.W., K.P., T.G., R.K., T.L., A.C. and R.T.B. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Richard T. Bryan.

Ethics declarations

Competing interests

P.T. reports research funding from AstraZeneca, as well as personal fees as a consultant from AbbVie, Bayer, Knight Pharmaceuticals, Tolmar and TerSera. A.W. and A.B. disclose funding received from AstraZeneca for a PhD studentship for A.B. supervised by A.W. A.W. discloses funding from imCORE for RE-ARM trial analysis. A.W. acknowledges funding from the RMH/ICR Cancer Research UK RadNet Centre. R.T.B. discloses research funding from Janssen, QED Therapeutics and UroGen Pharma, and consultancy for Nonacus Limited and Cystotech ApS. A.C. discloses funding from Cancer Research UK, National Institute of Health Research, Prostate Cancer UK, UK Research & Innovation, Elekta AB, honoraria from Bayer PLC, Janssen, AZ, ASTRO, ASCO, Roche and Merck, and is Editor in Chief of BMJ Oncology. A.C. is supported by the NIHR Manchester Biomedical Research Centre. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Ilaria Lucca and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Toren, P., Wilkins, A., Patel, K. et al. The sex gap in bladder cancer survival — a missing link in bladder cancer care?. Nat Rev Urol 21, 181–192 (2024). https://doi.org/10.1038/s41585-023-00806-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-023-00806-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing