Background
Delays from the diagnosis of muscle‐invasive bladder cancer (MIBC) to radical cystectomy (RC) longer than 12 weeks result in higher mortality and shorter progression‐free survival. This ...study sought to identify factors associated with RC delays and to determine whether delays in care in the current treatment paradigm, which includes neoadjuvant chemotherapy (NAC), affect survival.
Methods
Subjects with American Joint Committee on Cancer stage II urothelial carcinoma of the bladder who underwent RC from 2004 to 2012 were identified from the linked Surveillance, Epidemiology, and End Results national cancer registry and the Medicare claims database and were stratified into RC groups with or without NAC. Cox multivariable proportional hazard models and multivariable logistic regression models assessed the significance of delays in RC for survival and identified independent characteristics associated with RC delays, respectively.
Results
This study identified 1509 patients with MIBC who underwent RC during the study period. In comparison with timely surgery, delays in RC increased overall mortality, regardless of the use of NAC (hazard ratio HR without NAC, 1.34; 95% confidence interval CI, 1.03‐1.76; HR after NAC, 1.63; 95% CI, 1.06‐2.52). Patients proceeding to RC without NAC had higher odds of delayed care if they lived in a high‐poverty neighborhood (odds ratio OR, 1.37; 95% CI, 1.01‐2.08) or nonmetropolitan area (OR, 1.61; 95% CI, 1.01‐2.55), were men (OR, 2.22; 95% CI, 1.25‐4.00), or required a provider transfer for bladder cancer care (OR, 1.82; 95% CI, 1.10‐3.03).
Conclusions
Delays in care from the time of either the initial diagnosis or the completion of NAC to RC are associated with worse overall survival among patients with MIBC. Timely surgery is fundamental in the treatment of MIBC, and this necessitates attention to disparities in access to complex surgical care and care coordination.
Delays from either the initial diagnosis or the completion of neoadjuvant chemotherapy to definitive local treatment with radical cystectomy are associated with decreased survival among patients with muscle‐invasive bladder cancer. Timely surgery is a fundamental part of treatment, and this necessitates attention to disparities in access to complex surgical care.
Purpose
Diet may play an essential role in the aetiology of bladder cancer (BC). The B group complex vitamins involve diverse biological functions that could be influential in cancer prevention. The ...aim of the present study was to investigate the association between various components of the B group vitamin complex and BC risk.
Methods
Dietary data were pooled from four cohort studies. Food item intake was converted to daily intakes of B group vitamins and pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using Cox-regression models. Dose–response relationships were examined using a nonparametric test for trend.
Results
In total, 2915 BC cases and 530,012 non-cases were included in the analyses. The present study showed an increased BC risk for moderate intake of vitamin B1 (HR
B1
: 1.13, 95% CI: 1.00–1.20). In men, moderate intake of the vitamins B1, B2, energy-related vitamins and high intake of vitamin B1 were associated with an increased BC risk (HR (95% CI): 1.13 (1.02–1.26), 1.14 (1.02–1.26), 1.13 (1.02–1.26; 1.13 (1.02–1.26), respectively). In women, high intake of all vitamins and vitamin combinations, except for the entire complex, showed an inverse association (HR (95% CI): 0.80 (0.67–0.97), 0.83 (0.70–1.00); 0.77 (0.63–0.93), 0.73 (0.61–0.88), 0.82 (0.68–0.99), 0.79 (0.66–0.95), 0.80 (0.66–0.96), 0.74 (0.62–0.89), 0.76 (0.63–0.92), respectively). Dose–response analyses showed an increased BC risk for higher intake of vitamin B1 and B12.
Conclusion
Our findings highlight the importance of future research on the food sources of B group vitamins in the context of the overall and sex-stratified diet.
Background
Immune checkpoint inhibitors (ICIs) represent an appealing treatment for patients with advanced urothelial cancer (aUC) and a poor performance status (PS). However, the benefit of ICIs for ...patients with a poor PS remains unknown. It was hypothesized that a poor Eastern Cooperative Oncology Group (ECOG) PS (≥2 vs 0‐1) would correlate with shorter overall survival (OS) in patients receiving ICIs.
Methods
In this retrospective cohort study, clinicopathologic, treatment, and outcome data were collected for patients with aUC who were treated with ICIs at 18 institutions (2013‐2019). The overall response rate (ORR) and OS were compared for patients with an ECOG PS of 0 to 1 and patients with an ECOG PS ≥ 2 at ICI initiation. The association between a new ICI in the last 30 and 90 days of life (DOL) and death location was also tested.
Results
Of the 519 patients treated with ICIs, 395 and 384 were included in OS and ORR analyses, respectively, with 26% and 24% having a PS ≥ 2. OS was higher in those with a PS of 0 to 1 than those with a PS ≥ 2 who were treated in the first line (median, 15.2 vs 7.2 months; hazard ratio HR, 0.62; P = .01) but not in subsequent lines (median, 9.8 vs 8.2 months; HR, 0.78; P = .27). ORRs were similar for patients with a PS of 0 to 1 and patients with a PS ≥ 2 in both lines. Of the 288 patients who died, 10% and 32% started ICIs in the last 30 and 90 DOL, respectively. ICI initiation in the last 30 DOL was associated with increased odds of death in a hospital (odds ratio, 2.89; P = .04).
Conclusions
Despite comparable ORRs, ICIs may not overcome the negative prognostic role of a poor PS, particularly in the first‐line setting, and the initiation of ICIs in the last 30 DOL was associated with hospital death location.
This multi‐institution, retrospective cohort study shows that patients with an Eastern Cooperative Oncology Group performance status ≥2 (versus a performance status of 0‐1) have a comparable overall response rate but worse overall survival with treatment with an immune checkpoint inhibitor as first‐line therapy, whereas treatment initiation in the last 30 days of life is associated with increased odds of hospital death.
It is now understood that persistent activation of the androgen receptor (AR) signaling pathway often underlies the development of castration-resistant prostate cancer (CRPC). This realization led to ...renewed interest in targeting the AR and ultimately to the development of the potent next-generation AR-directed agents abiraterone and enzalutamide. While these drugs prolong survival in men with CRPC, they are unfortunately not curative. Perhaps not surprisingly, evidence points to persistent AR signaling as one of the key drivers by which resistances to these agents develops. In this context, activation of the AR signaling program can occur through a number of molecular adaptations, including alterations leading to persistent canonical AR signaling (e.g., AR amplification/overexpression, elucidations/concentration of intratumoral androgens), activation of the AR program via feedback pathways (e.g., AKT/mTOR/Pi3K, HER2/Neu), and activation of the AR program via mutation or substitution (e.g., AR ligand binding domain mutation; AR splice variants; glucocorticoid receptor signaling). This review will provide an overview of the more clinical relevant (i.e., druggable) pathways that have been implicated in the emergence of drug resistance in men with CRPC and highlight some of the ongoing efforts towards developing therapeutics to impair these mechanisms.
A significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor mutations in homologous recombination (HR) repair genes, with some of these mutations ...associating with increased tumor susceptibility to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. While mutations in some HR repair genes (e.g., BRCA1/2) have been associated with a more aggressive clinical course, prior studies correlating HR mutational status with treatment response to androgen receptor (AR) signaling inhibitors (ARSIs) or taxane-based chemotherapy have yielded conflicting results.
We conducted a single-center retrospective analysis to assess clinical outcomes to conventional, regulatory-approved therapies in mCRPC patients with somatic (monoallelic and biallelic) and/or germline HR repair mutations compared to patients without alterations as determined by clinical-grade next-generation sequencing assays. The primary endpoint was PSA30/PSA50 response, defined as ≥30%/≥50% prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints of PSA progression-free survival (pPFS) and clinical/radiographic progression-free survival (crPFS) were estimated using Kaplan-Meier methods.
A total of 90 consecutively selected patients were included in this analysis, of which 33 (37%) were identified to have HR repair gene mutations. Age, race, Gleason score, prior surgery, and receipt of prior radiation therapy were comparable between carriers and non-carriers. There was no evidence that PSA30/PSA50 differed by HR gene mutational status. Median pPFS and crPFS ranged 3-14 months across treatment modalities, but there was no evidence either differed by HR gene mutational status (all p>0.05). There was also no difference in outcomes between those with BRCA2 or PALB2 mutations (n = 17) compared to those without HR repair mutations.
HR gene mutational status was associated with comparable clinical outcomes following treatment with ARSIs or taxane-based chemotherapy. Additional prospective studies are needed to confirm these findings.
Abstract
Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic ...metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.
Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients ...develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.
Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.
A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in
(mutations, amplifications) and tumor suppression genes (
, and
), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased
amplifications (64.7% at progression vs. 53.9% at baseline) and
alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression.
Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of
alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.
The effects of fat intake from different dietary sources on bladder cancer (BC) risk remains unidentified. Therefore, the present study aimed to investigate the association between fat intakes and BC ...risk by merging world data on this topic. Data from 11 cohort studies in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study, provided sufficient information on fat intake for a total of 2731 BC cases and 544 452 noncases, which yielded 5 400 168 person‐years of follow‐up. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox‐regression models stratified on cohort. Analyses were adjusted for total energy intake in kilocalories, gender, smoking status (model‐1) and additionally for sugar and sugar products, beers, wine, dressing and plant‐based and fruits intakes (model‐2). Among women, an inverse association was observed between mono‐unsaturated fatty acids (MUFAs) and BC risk (HR comparing the highest with the lowest tertile: 0.73, 95% CI: 0.58‐0.93, P‐trend = .01). Overall, this preventative effect of MUFAs on BC risk was only observed for the nonmuscle invasive bladder cancer (NMIBC) subtype (HR: 0.69, 95% CI: 0.53‐0.91, P‐trend = .004). Among men, a higher intake of total cholesterol was associated with an increased BC risk (HR: 1.37, 95% CI: 1.16‐1.61, P‐trend = .01). No other significant associations were observed. This large prospective study adds new insights into the role of fat and oils in BC carcinogenesis, showing an inverse association between consumption of MUFAs and the development of BC among women and a direct association between higher intakes of dietary cholesterol and BC risk among men.
What's new?
The association between bladder cancer risk and fat intake from different dietary sources remains inconclusive. Here, Dianatinasab et al. investigated associations using pooled data from prospective 11 cohort studies in the Bladder Cancer Epidemiology and Nutritional Determinants consortium. Analyses show that while higher intake of monounsaturated fatty acids and plant‐based oils was associated with decreased bladder cancer risk, greater intake of cholesterol and animals fats was associated with increased risk, particularly in men. The findings offer insight into the role of fats and oils in the development of bladder cancer and lay the foundation for new dietary strategies in bladder cancer prevention.
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