Abstract Urothelial bladder cancer is one of the first cancers recognized to be immunogenic since 40 years ago when the use of bacillus Calmette–Guerin was shown to prevent recurrence. Since that ...time, our knowledge of immune biology of cancer has expanded tremendously, and patients with bladder cancer finally have new active immunotherapeutic drugs on the horizon. Anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) therapy has shown impressively durable responses in urothelial bladder cancer (UBC), but the reported response rates warrant improvement. To outline potential strategies to overcome tumor immune resistance, herein, we summarize current models of tumor immunology with a specific focus on bladder cancer. Recognition of tumor-specific antigens through cross-presentation, T-cell priming and activation, and trafficking of immune cells to the tumor microenvironment are some of the critical steps we now understand to be necessary for an effective antitumor immune response. Many of the involved steps are important targets for therapeutic interventions. As new immunotherapies are developed, predictive biomarkers would also be important to select patients most likely to respond and to better understand tumor biology. Several potential biomarkers are reviewed including PD-L1 expression, identification of T-cell-inflamed/non–T-cell-inflamed tumors based on immune gene expression, intrinsic molecular subtyping based on luminal/basal or the cancer genome atlas (TCGA) groups, T-cell receptor sequencing, and somatic mutational density. Even within the past few years, our current knowledge of immune biology has exploded, and we are highly optimistic about the future of UBC therapy that will be available to patients.
Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized ...muscle-invasive bladder cancer.
To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy.
A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included.
Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti–PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti–PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%.
Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting.
Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.
Neoadjuvant immunotherapy has demonstrated effective antitumor efficacy in patients with resectable muscle-invasive bladder cancer. Whether pathological complete response predict long-term survival benefit after neoadjuvant immune checkpoint inhibitors remains to be demonstrated. Phase III trials are currently investigating this strategy in the presurgical setting before radical cystectomy.
The number and diversity of cancer therapeutics in the pipeline has increased over the past decade due to an enhanced understanding of cancer biology and the identification of novel therapeutic ...targets. At the same time, the cost of bringing new drugs to market and the regulatory burdens associated with clinical drug development have progressively increased. The finite number of eligible patients and limited financial resources available to evaluate promising new therapeutics represent rate-limiting factors in the effort to translate preclinical discoveries into the next generation of standard therapeutic approaches. Optimal use of resources requires understanding and ultimately addressing inefficiencies in the cancer clinical trials system. Prior analyses have demonstrated that a large proportion of trials initiated by the National Cancer Institute (NCI) Cooperative Group system are never completed. While NCI Cooperative Group trials are important, they represent only a small proportion of all cancer clinical trials performed. Herein, we explore the problem of cancer clinical trials that fail to complete within the broader cancer clinical trials enterprise. Among 7776 phase II-III adult cancer clinical trials initiated between 2005-2011, we found a seven-year cumulative incidence of failure to complete of approximately 20% (95% confidence interval = 18% to 22%). Nearly 48000 patients were enrolled in trials that failed to complete. These trials likely contribute little to the scientific knowledge base, divert resources and patients from answering other critical questions, and represent a barrier to progress.
Patient stratification based on molecular subtypes is an important strategy for cancer precision medicine. Deriving clinically informative cancer molecular subtypes from transcriptomic data generated ...on whole tumor tissue samples is a non-trivial task, especially given the various non-cancer cellular elements intertwined with cancer cells in the tumor microenvironment.
We developed a computational deconvolution method, DeClust, that stratifies patients into subtypes based on cancer cell-intrinsic signals identified by distinguishing cancer-type-specific signals from non-cancer signals in bulk tumor transcriptomic data. DeClust differs from most existing methods by directly incorporating molecular subtyping of solid tumors into the deconvolution process and outputting molecular subtype-specific tumor reference profiles for the cohort rather than individual tumor profiles. In addition, DeClust does not require reference expression profiles or signature matrices as inputs and estimates cancer-type-specific microenvironment signals from bulk tumor transcriptomic data.
DeClust was evaluated on both simulated data and 13 solid tumor datasets from The Cancer Genome Atlas (TCGA). DeClust performed among the best, relative to existing methods, for estimation of cellular composition. Compared to molecular subtypes reported by TCGA or other similar approaches, the subtypes generated by DeClust had higher correlations with cancer-intrinsic genomic alterations (e.g., somatic mutations and copy number variations) and lower correlations with tumor purity. While DeClust-identified subtypes were not more significantly associated with survival in general, DeClust identified a poor prognosis subtype of clear cell renal cancer, papillary renal cancer, and lung adenocarcinoma, all of which were characterized by CDKN2A deletions. As a reference profile-free deconvolution method, the tumor-type-specific stromal profiles and cancer cell-intrinsic subtypes generated by DeClust were supported by single-cell RNA sequencing data.
DeClust is a useful tool for cancer cell-intrinsic molecular subtyping of solid tumors. DeClust subtypes, together with the tumor-type-specific stromal profiles generated by this pan-cancer study, may lead to mechanistic and clinical insights across multiple tumor types.
We investigated the characteristics and outcomes of patients with muscle invasive bladder cancer treated with transurethral resection plus chemotherapy alone in a large observational cohort ...reflecting the continuum of practice settings in the United States.
In the National Cancer Database from 2004 to 2015 we identified 1,538 patients treated with transurethral resection plus multi-agent chemotherapy as definitive treatment of cT2-T4aN0M0 urothelial carcinoma of the bladder. For comparison purposes we included in study 17,866 patients treated with radical cystectomy with or without perioperative chemotherapy. Baseline characteristics were compared between the 2 groups by multivariable logistic regression. Treatment outcomes were assessed using Kaplan-Meier analysis and a Cox regression model.
On multivariate analysis several variables, including patient demography (older age, African American race, prior malignancy and lack of insurance), tumor characteristics (higher cT stage) and facility type (nonacademic facilities and lower radical cystectomy volume) were associated with a higher probability of transurethral resection plus chemotherapy for muscle invasive bladder cancer compared to the standard of care. Two and 5-year survival rates in all patients treated with transurethral resection plus chemotherapy were 49.0% and 32.9%, and in patients with cT2 disease the rates were 52.6% and 36.2%, respectively.
This large population level cohort of unselected patients shows that long-term survival can be achieved in a subset of patients treated with transurethral resection plus chemotherapy alone for muscle invasive bladder cancer. However, the best candidates for this approach remain to be defined. Ongoing clinical trials are now being launched to evaluate the ability of biomarkers to accurately select patients who could be treated with this bladder sparing strategy.
C-reactive protein (CRP) may reflect a pro-inflammatory tumor microenvironment and could represent a biomarker to select patients with urothelial carcinoma more likely to benefit from therapies ...directed at modulating tumor-promoting inflammation. We performed a systematic review to evaluate survival outcomes based on pre-treatment CRP values in urothelial carcinoma. The hazard ratios (HRs) of survival such as overall survival (OS) and progression-free survival (PFS) between groups with high versus low CRP values were pooled by the random-effect model meta-analyses. Overall, 28 studies comprising 6789 patients were identified for meta-analyses. High CRP levels were associated with shorter OS (HR=1.96 95% CI: 1.64–2.33, p < 0.01), particularly in advanced disease treated with immune checkpoint blockade (ICB, HR=1.78 1.47–2.15, p < 0.01). Similar findings were observed in ICB-treated patients with PFS. These findings suggest that CRP could be an attractive biomarker to select patients with urothelial carcinoma for strategies seeking to modulate tumor-promoting inflammation.
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•C-reactive protein (CRP) is an acute phase reactant may reflect a pro-inflammatory tumor microenvironment.•A systematic review found 28 studies reporting clinical outcomes based on pre-treatment CRP values in urothelial carcinoma.•High CRP levels were associated with shorter overall survival in patients with urothelial carcinoma.•This association was particularly seen in advanced urothelial carcinoma treated with immune checkpoint blockade.•CRP could be a biomarker to select patients for strategies seeking to modulate tumor-promoting inflammation.
Take Home Message First-line docetaxel treatment for metastatic castration-sensitive prostate cancer is associated with higher rates of neutropenic fever compared with those with castration-resistant ...disease, and prophylactic granulocyte colony-stimulating factor should be considered in those harboring risk factors for developing neutropenia.
Abstract Background The incidence and risk of unique toxicities associated with a multi-targeted tyrosine kinase inhibitor sunitinib, such as hypertension and thromboembolic events, have been ...previously reported. However, the incidence and risk of hematologic toxicities have been less well characterized. We performed an up-to-date meta-analysis of trials to evaluate the risk of sunitinib-related hematologic toxicities. Methods We searched Medline and the American Society of Clinical Oncology online database of meeting abstracts up to July 2012 for relevant clinical trials. Eligible studies included phase II and III trials and expanded access programs of sunitinib that reported adequate safety data profile reporting neutropenia, thrombocytopenia or anemia. The summary incidence, relative risk (RR) and 95% confidence intervals (CIs) were calculated. Results A total of 8,526 patients from 60 trials of sunitinib as a single agent revealed that the incidence of sunitinib-associated all-grade and high-grade (Grades 3 and 4) hematologic toxicities were, respectively: neutropenia: 42.1% and 12.8%; thrombocytopenia: 44.7% and 10.7% and anemia: 50.4% and 6.2%. Sunitinib-treated patients (2667 subjects from 10 randomized trials) had a significantly increased risk of all-grade (RR = 3.58; 95% CI, 1.71–7.49) and high-grade (RR = 3.32; 95% CI, 1.60–6.90) neutropenia, all-grade (RR = 4.59; 95% CI, 2.76–7.63) and high-grade (RR = 5.84; 95% CI, 2.22–15.41) thrombocytopenia and all-grade anemia (RR = 1.15; 95% CI, 1.00–1.31). Conclusions Sunitinib is associated with a significant increase in the risk of developing all-grade and high-grade neutropenia and thrombocytopenia and all-grade anemia compared with control.
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