Men are more frequently diagnosed with kidney cancer than women, with a more aggressive histology, larger tumors, a higher grade and stage, and worse oncological outcomes. Smoking habits and sex steroid hormones seem to have a possible role in explaining these gender disparities. Moreover, the expression of genes involved in tumor growth and immune response in kidney cancer varies between men and women, having an impact on the gender-related response to oncological therapy, such as anti-angiogenic drugs and immunotherapy. Recent advances have been made in our understanding of the molecular and genetic mechanisms involved in kidney cancer, which could partially explain the gender differences, and they are summarized in this paper. However, other key mechanisms, which fully clarify the striking clinical gender-related differences observed in kidney cancer, are not completely understood at present. We reviewed and summarized the most relevant publications about the relationship between gender and kidney cancer. Efforts should be made to progress in bench and clinical research on gender-related signatures and disparities, and their impact on the clinical management of kidney cancer.

Recently, there has been a great effort to develop tests based on non-invasive urinary biomarkers (NMIBCs). These tests are based on the fact that NMIBCs are heterogeneous at the molecular level and can be divided into different molecular groups useful to predict prognosis and response to treatment. The assessment of epigenetic alterations, such as DNA methylation, represents a promising cancer biomarker. DNA methylation is an epigenetic modification that affects gene expression without modifying the DNA sequence. Several studies have highlighted the presence of methylated loci in the context of bladder cancer, indicating its potential application as a diagnostic and prognostic biomarker. One of the novel assays based on a DNA methylation profile, the Bladder EpiCheck, analyzes DNA from spontaneous urine, detecting disease-specific DNA methylation patterns in bladder cancer patients. This test, due to its non-invasive nature and highly promising performance could, in future, become an invaluable tool in the follow-up of bladder cancer patients. Potential new applications could include diagnosis and surveillance of upper-tract disease, for the replacement of invasive testing and ureteroscopy.

Men are at a higher risk of developing bladder cancer, but women present with more advanced disease and have more unfavourable outcomes. Although epidemiologic and genetical studies have underlined the multifactorial aetiology and gender-related differences of bladder cancer, there is lack of evidence-based recommendation for gender-specific management of bladder cancer. We summarize the evidence and most recent findings on gender-specific differences in bladder cancer incidence, diagnosis, treatment and outcome, spotlighting the gender disparities in genetic and hormonal risk factors, pelvic anatomy, diagnostic setting and surgical choices. We reviewed the literature published on PubMed between 1981 and 2018. Males have a threefold to fourfold higher risk of bladder cancer as compared to females; however, women have higher stage-for-stage mortality, being diagnosed with more advanced disease, mostly due to a delay in haematuria evaluation. Numerous studies indicate an increased risk of disease recurrence or progression in women with non-muscle-invasive bladder cancer treated with trans-urethral resection, with or without intravesical chemotherapy or immunotherapy, compared to males. In particular, recent molecular evidence show that there is an excess of female Ta mutant tumours. At the time of radical cystectomy, women have a significantly longer length of hospital stay, operative time, higher blood loss and higher 90-day mortality and perioperative complication rate. Moreover, females are less likely to receive a continent diversion. Future research should guarantee greater inclusion of women in trials and focus on improving the effectiveness of therapies in women, perhaps exploring different therapeutic approaches in men and women. Specific data on functional and oncological outcomes can be analysed to define predictive factors able to guide the surgeon in decisions based on evidence. It is urgently needed to limit gender-related discrepancies in early diagnosis and treatment of bladder cancer. Public awareness and bladder cancer female patients’ consciousness on gender inequalities must be similarly uprisen.

In contrast with other strategies, immunotherapy is the only treatment aimed at empowering the immune system to increase the response against tumor growth. Immunotherapy has a role in the treatment of bladder cancer (BC) due to these tumors’ high tumor mutational burden (TMB) and mostly prominent immune infiltrate. The therapy or combination has to be adjusted to the tumor’s immunobiology. Recently, a new class of immunotherapeutic agents, immune checkpoint inhibitors (ICI), has shown potential in increasing treatment chances for patients with genitourinary cancers, improving their oncological outcomes. The clinical efficacy of ICI has been shown in both the first-line treatment of cisplatin-ineligible patients, with programmed death ligand 1 (PD-L1)-positive tumors (atezolizumab, pembrolizumab), and in second-line settings, for progression after platinum-based chemotherapy (atezolizumab, pembrolizumab, and nivolumab for FDA and EMA; durvalumab and avelumab for FDA alone). Predicting the response to ICI is important since only a subset of patients undergoing ICI therapy develop a concrete and lasting response. Most of the patients require a different therapy or therapy combination to achieve tumor control. The cancer immunity cycle provides a conceptual framework to assist therapy selection. Biomarkers to predict response to ICI must identify where the cancer immunity cycle is disrupted. We reviewed the current knowledge on ICI treatment in BC, going from basic science to current data and available clinical evidence. Secondly, a critical analysis of published data is provided, and an original panel of biomarkers able to predict response to ICI treatment, based on tumor-specific immune profiling, is proposed.

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