Hereditary and Familial Traits in Urological Cancers and Their Underlying Genes

Early recognition of hereditary urological cancers may influence diagnostic and therapeutic decision-making, and potentially alter the fate of patients and family members. Here, we introduce readers to the current knowledge on germline genetic testing and clinical practice in prostate, bladder, renal, and testicular carcinoma. Considering all urological cancer patients, routine inquiries about familial cancer history should become a standard practice in clinical settings. If suspicion arises, patients can opt for two avenues: referral to genetic counseling or undergoing genetic tests after consultation with the treating urologist. Patient summary: Tumors of the urogenital tract (prostate, kidney, bladder, and testes) can sometimes be related to genetic mutations that are present in all the cells of the body. Such mutations can be inherited and run in families. Therefore, it is relevant to obtain information on the incidence of all cancers in the family history. The information obtained may initiate genetic testing, leading to the identification of mutations that are related to cancer in the current or next generation. In addition, these mutations may offer alternative treatment options for patients.</p

Genome-wide association study for tumour stage, grade, size, and age at diagnosis of non-muscle-invasive bladder cancer

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade. OBJECTIVE: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables). RESULTS AND LIMITATIONS: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ss=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis. CONCLUSIONS: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding. PATIENT SUMMARY: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity

The present and future burden of urinary bladder cancer in the world

Urinary bladder cancer (UBC) is a common disease worldwide. At any point in time 2.7 million people have a history of UBC. The incidence of UBC varies over the world with highest rates in developed communities. But the burden of UBC will increase in less developed areas of the world. These changes can be attributed to global changes in exposure to risk factors for UBC and growth and aging of the world population

Low adherence to recommended use of neoadjuvant chemotherapy for muscle-invasive bladder cancer

Purpose: To evaluate guideline adherence and variation in the recommended use of neoadjuvant chemotherapy (NAC) and the effects of this variation on survival in patients with non-metastatic muscle-invasive bladder cancer (MIBC). Patients and methods: In this nationwide, Netherlands Cancer Registry-based study, we identified 1025 patients newly diagnosed with non-metastatic MIBC between November 2017 and November 2019 who underwent radical cystectomy. Patients with ECOG performance status 0–1 and creatinine clearance ≥ 50 mL/min/1.73 m2 were considered NAC-eligible. Interhospital variation was assessed using case-mix adjusted multilevel analysis. A Cox proportional hazards model was used to evaluate the association between hospital specific probability of using NAC and survival. All analyses were stratified by disease stage (cT2 versus cT3-4a). Results: In total, of 809 NAC-eligible patients, only 34% (n = 277) received NAC. Guideline adherence for NAC in cT2 was 26% versus 55% in cT3-4a disease. Interhospital variation was 7–57% and 31–62%, respectively. A higher hospital specific probability of NAC might be associated with a better survival, but results were not statistically significant (HRcT2 = 0.59, 95% CI 0.33–1.05 and HRcT3-4a = 0.71, 95% CI 0.25–2.04). Conclusion: Guideline adherence regarding NAC use is low and interhospital variation is large, especially for patients with cT2-disease. Although not significant, our data suggest that survival of patients diagnosed in hospitals more inclined to give NAC might be better. Further research is warranted to elucidate the underlying mechanism. As literature clearly shows the potential survival benefit of NAC in patients with cT3-4a disease, better guideline adherence might be pursued.</p

Low adherence to recommended use of neoadjuvant chemotherapy for muscle-invasive bladder cancer

Purpose: To evaluate guideline adherence and variation in the recommended use of neoadjuvant chemotherapy (NAC) and the effects of this variation on survival in patients with non-metastatic muscle-invasive bladder cancer (MIBC). Patients and methods: In this nationwide, Netherlands Cancer Registry-based study, we identified 1025 patients newly diagnosed with non-metastatic MIBC between November 2017 and November 2019 who underwent radical cystectomy. Patients with ECOG performance status 0–1 and creatinine clearance ≥ 50 mL/min/1.73 m2 were considered NAC-eligible. Interhospital variation was assessed using case-mix adjusted multilevel analysis. A Cox proportional hazards model was used to evaluate the association between hospital specific probability of using NAC and survival. All analyses were stratified by disease stage (cT2 versus cT3-4a). Results: In total, of 809 NAC-eligible patients, only 34% (n = 277) received NAC. Guideline adherence for NAC in cT2 was 26% versus 55% in cT3-4a disease. Interhospital variation was 7–57% and 31–62%, respectively. A higher hospital specific probability of NAC might be associated with a better survival, but results were not statistically significant (HRcT2 = 0.59, 95% CI 0.33–1.05 and HRcT3-4a = 0.71, 95% CI 0.25–2.04). Conclusion: Guideline adherence regarding NAC use is low and interhospital variation is large, especially for patients with cT2-disease. Although not significant, our data suggest that survival of patients diagnosed in hospitals more inclined to give NAC might be better. Further research is warranted to elucidate the underlying mechanism. As literature clearly shows the potential survival benefit of NAC in patients with cT3-4a disease, better guideline adherence might be pursued.</p

Iron and hepcidin as risk factors in atherosclerosis: what do the genes say?

BACKGROUND: Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. RESULTS: Analyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [-0.27 (SE 0.34) and -0.22 (SE 0.35), respectively] and ABI after exercise [-0.29 (SE 0.34) and -0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations. CONCLUSIONS: Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women

Minimum Volume Standards: An Incentive To Perform More Radical Cystectomies?

Background: Minimum volume standards (MVS) for hospitals and/or surgeons remain a subject of debate. Opponents of MVS emphasize the possible negative effects of centralization, such as an unwanted incentive to perform surgery. Objective: To evaluate whether the introduction of MVS for radical cystectomy (RC) in the Netherlands resulted in more RCs outside guideline-recommended indications. Design, setting, and participants: All RCs performed for bladder cancer in the Netherlands between January 1, 2006 and December 31, 2017 were identified in the Netherlands Cancer Registry. During this period, two MVS were sequentially implemented for RC. RCs in intermediate-volume hospitals (hospitals that approximated the MVS) were compared with RCs in high-volume hospitals (hospitals exceeding the MVS by ≥5 RCs/yr) in a period before and a period after implementation of each of the two MVS. Outcomes measurements and statistical analysis: Descriptive analyses were performed to evaluate whether hospitals performed more RCs outside the recommended indication (cT2–4a N0 M0) and whether an increase in the number of RCs towards the end of the year could be observed. Results and limitations: After MVS implementation, no clear shift towards disease stages outside the recommended indication for RC was observed in comparison to the period before the MVS. Results for high-volume and intermediate-volume hospitals were similar. In addition, no increase in RCs towards the end of the year was evident. Conclusions: We did not find evidence indicating an unwanted incentive to perform more RCs as a result of MVS in the Netherlands. Our results further strengthen the case for MVS implementation. Patient summary: We evaluated whether criteria for the minimum number of radical cystectomies (surgical removal of the bladder) that hospitals have to perform caused urologists to perform more of these operations than necessary in order to meet the minimum level. We found no evidence that minimum criteria led to such an unwanted incentive

Treatment Patterns and Use of Immune Checkpoint Inhibitors Among Patients with Metastatic Bladder Cancer in a Dutch Nationwide Cohort

Since 2017, two immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of metastatic urothelial carcinoma in Europe: pembrolizumab as second-line therapy and avelumab as maintenance therapy. Our aim was to describe the use of ICIs as first and later lines of treatment in patients with metastatic bladder cancer (mBC) in the Netherlands. We identified all patients diagnosed with primary mBC between 2018 and 2021 in the Netherlands from the Netherlands Cancer Registry (NCR). NCR data were supplemented with data from the Dutch nationwide Prospective Bladder Cancer Infrastructure (ProBCI) collected from medical files, with follow-up until death or end of data collection on January 1, 2023. A total of 1525 patients were diagnosed with primary mBC between 2018 and 2021 in the Netherlands. Of these, 34.7% received at least one line of systemic treatment with chemotherapy or ICI. After first-line platinum-based chemotherapy, 34.1% received second-line ICI and 3.9% received maintenance ICI. Among patients who completed or discontinued first-line cisplatin- or carboplatin-based chemotherapy after approval of maintenance ICI in the Netherlands, 40.7% and 19.7% received second-line ICI, and 9.3% and 14.1% received maintenance ICI, respectively. ICI use for mBC treatment has not increased considerably since their introduction in 2017. Future research should assess whether the introduction of maintenance avelumab (available since April 2021 in the Netherlands) has led to increases in the proportion of patients with mBC patients receiving systemic treatment and the proportion receiving ICI. Patient summary: We assessed the rate of immunotherapy use for patients with metastatic bladder cancer in the Netherlands. Since its introduction, immunotherapy has been used in a minority of patients, mostly as second-line treatment after platinum-based chemotherapy.</p

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes:disclosure of genetic test results to relatives

Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives’ medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden.</p