Thomas A. Longo

Atezolizumab: a PD-L1 blocking antibody for bladder cancer

Atezolizumab (Tecentriq, MPDL3280A; Genentech/Roche) is an FcγR binding–deficient, fully humanized IgG1 mAb designed to interfere with the binding of PD-L1 ligand to its two receptors, PD-1 and B7.1. By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironment and, consequently, increases T-cell–mediated immunity against the tumor. Atezolizumab has been FDA approved as second-line therapy for advanced bladder cancer. This accelerated approval was based on phase II trial data in patients with metastatic bladder cancer that showed unexpected and durable tumor responses. In subjects whose tumors progressed on first-line platinum-based chemotherapy, the objective response rate was 15%, the complete response rate was 5%, and 1-year overall survival was 36%. In subjects that were chemotherapy naïve and cisplatin ineligible, the objective response rate was 24%, the complete response rate was 7%, and 1-year overall survival was 57%. Better responses were associated with higher PD-L1 expression on the tumor-infiltrating leukocytes. These data suggest that patients with advanced bladder cancer treated with atezolizumab have significantly better response rates and survival than historical controls treated with other second-line regimens. The toxicity profile of atezolizumab is also favorable. Trials are currently assessing whether atezolizumab is effective in earlier bladder cancer stages and in the first-line metastatic setting. Clin Cancer Res; 23(8); 1886–90. ©2016 AACR.

A systematic review of regional hyperthermia therapy in bladder cancer

Abstract Context: Bladder cancer therapy remains suboptimal as morbidity and mortality remain high amongst those with non-muscle-invasive and muscle-invasive disease. Regional hyperthermia therapy (RHT) is a promising adjunctive therapy being tested in multiple clinical contexts. Objective: The aim of this study was to systematically review the literature on the efficacy and toxicity of RHT. Evidence acquisition: This systematic review was registered with the PROSPERO database (Registration number: CRD42015025780) and was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. We queried PubMed, EMBASE, and Cochrane libraries. Two reviewers reviewed abstracts independently and a third reviewer arbitrated disagreements. The last search was performed on 28 August 2015. A descriptive analysis was performed and quality assessment was conducted using the Newcastle-Ottawa Quality Assessment Scale for observational studies, and the Cochrane Risk of Bias Assessment Tool for trials. Evidence synthesis: We identified 859 publications in the initial search, of which 24 met inclusion criteria for full-text review. Of these, we were able to obtain data on the outcomes of interest for 15 publications. Conclusions: The review underscores the limited nature of the evidence; definitive conclusions are elusive. However, the promising results of RHT in the setting of intravesical chemotherapy, chemotherapy and radiotherapy show a trend towards legitimate efficacy.

Lifestyle factors and health-related quality of life in bladder cancer survivors: a systematic review

PurposeDiet, physical activity, and smoking cessation are modifiable lifestyle factors that have been shown to improve health-related quality of life (HRQOL) in many cancer survivors. Our objective was to systematically review the literature on the associations between lifestyle factors, namely diet, physical activity, smoking status, and HRQOL in bladder cancer survivors.MethodsWe queried PubMed, EMBASE, and Cochrane libraries. Two reviewers reviewed abstracts independently, and a third reviewer arbitrated disagreements. A descriptive analysis was performed. Quality assessment was conducted using the Newcastle-Ottawa Quality Assessment Scale for observational studies and the Cochrane Risk of Bias Tool for clinical trials.ResultsWe identified 1167 publications in the initial search, of which 9 met inclusion criteria for full-text review. We were able to obtain data on the outcomes of interest for 5 publications. A total of 1288 patients who underwent treatment for bladder cancer were included. Three studies were observational by design and two were randomized controlled trials. Physical activity was addressed by 4 studies, smoking status by 2 studies, and diet by 1 study.ConclusionsThe review highlights the limited evidence around lifestyle factors and quality of life in bladder cancer survivors. There is some evidence for a positive association between HRQOL and physical activity, but insufficient evidence upon which to draw conclusions about the effects of consuming fruits and vegetables or non-smoking.Implications for Cancer SurvivorsThere is limited evidence to support a positive association between health-related quality of life and physical activity, but insufficient evidence upon which to base any conclusions about consumption of fruits and vegetables or smoking cessation in bladder cancer survivors.

Body mass index and the clinicopathological characteristics of clinically localized renal masses—An international retrospective review

OBJECTIVES To investigate the potential association between body mass index (BMI) and clinicopathological features of clinically localized renal masses. MATERIALS AND METHODS An international, multi-institutional retrospective review of patients who underwent surgery for clinically localized renal masses between 2000 and 2010 was undertaken after an institutional review board approval. Patients were divided into 4 absolute BMI groups based on the entire cohort׳s percentiles and 4 relative BMI groups based on their respective population (American or Italian). Renal mass pathological diagnosis, renal cell carcinoma (RCC) subtype, Fuhrman grade (low and high), and clinical stage were compared among groups using Fisher׳s exact test, Kruskal-Wallis test, and the Cochran-Armitage trend test. A multivariate logistic analysis was performed to evaluate independent association between tumor and patient characteristics with tumor pathology (Fuhrman grade). RESULTS A total of 1,748 patients having a median BMI of 28 (interquartile range 25-32) were evaluated. Benign masses and RCC cases had similar proportion across BMI groups (P = 0.4). The most common RCC subtype was clear cell followed by papillary carcinoma, chromophobe, and other subtypes. Their distribution was comparable across BMI groups (P = 0.7). Similarly, clinical stage distribution was comparable with the overall cohort. The distribution of Fuhrman grade in RCC, however, demonstrated an increased proportions of low grade with increasing BMI (P<0.05). This trend was maintained in subgroups according to gender, stage and age (P<0.05 in all subgroup analysis). In a multivariable model that included potential confounders (i.e., age, sex, and tumor size) higher BMI groups had lower odds of presenting a high Fuhrman grade. CONCLUSION In this study, higher BMI was associated with lower grade of RCC in clinically localized renal masses. This may, in part, explain better survival rates in patients with higher BMI and may correlate with a possible link between adipose tissue and RCC biology.

High rates of venous thromboembolic events in patients undergoing systemic therapy for urothelial carcinoma: A systematic review and meta-analysis

BACKGROUND Patients undergoing systemic therapy for urothelial carcinoma (UC) are at increased risk for venous thromboembolic (VTE) events. The objective of the current study was to determine the rate of VTE events in patients undergoing systemic therapy for UC and assess factors affecting this rate. METHODS This study was registered with the PROSPERO database (CRD42015025774). We searched Pubmed, MEDLINE, EMBASE, The Cochrane Library, CINAHL, and Web of Science libraries through August 2014. As per PRISMA guidelines, 2 reviewers independently reviewed titles and abstracts. Disagreements were arbitrated by a third reviewer. After full text review, data were abstracted and pooled using a random effects model. Authors were contacted for clarification of data. To determine VTE risk factors, subgroup analyses and meta-regression were conducted. RESULTS We identified 3,635 publications in the initial search, of which 410 met inclusion criteria for full text review. Of these, we were able to obtain data on the outcome of interest for 62 publications. A total of 5,082 patients, of which 77% were male, underwent systemic therapy for UC, with 373 VTE events. The proportion of patients who had had prior surgery, chemotherapy, or radiation was 55%, 25%, and 9%, respectively. Fixed effects and random effects models were used to estimate the VTE rate, yielding event rates of 6.7% and 5.4%, respectively. CONCLUSIONS VTE occurs frequently in patients undergoing systemic therapy for UC. The VTE rate was affected by the country of origin, history of radiation, as well as by the systemic treatment class. The study was limited by the incomplete reporting of all variables of interest.

Targeted Exome Sequencing of the Cancer Genome in Patients with Very High-risk Bladder Cancer

We completed targeted exome sequencing of the tumors of 50 patients with pTis-pT4b bladder cancer. Mutations were categorized by type, stratified against previously identified cancer loci in the Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas databases, and evaluated in pathway analysis and comutation plots. We analyzed mutation associations with receipt of neoadjuvant chemotherapy, nodal involvement, metastatic disease development, and survival. Compared with The Cancer Genome Atlas, we found higher mutation rates in genes encoding products involved in epigenetic regulation and cell cycle regulation. Of the pathways examined, PI3K/mTOR and Cell Cycle/DNA Repair exhibited the greatest frequencies of mutation. RB1 and TP53, as well as NF1 and PIK3CA were frequently comutated. We identified no association between mutations in specific genes and key clinical outcomes of interest when corrected for multiple testing. Discovery phase analysis of the somatic mutations in 50 high-risk bladder cancer patients revealed novel mutations and mutational patterns, which may be useful for developing targeted therapy regimens or new biomarkers for patients at very high risk of disease metastasis and death. PATIENT SUMMARY In this report we found known, as well as previously unreported, genetic mutations in the tumors of patients with high-risk bladder cancer. These mutations, if validated, may serve as actionable targets for new trials.

MP65-08 HEAT-TARGETED DRUG DELIVERY USING THE COMBAT BRS DEVICE FOR TREATING BLADDER CANCER

resulting in regulation of transcription and cellular processes. HDAC inhibition has been shown to induce genes coding for MHC class I and class II molecules and immunologic activation molecules. Tissue microarray analysis of bladder cancer cell lines has demonstrated high HDAC expression in 40-60% of urothelial tumors. Our objective was to investigate the use of HDAC inhibitors on bladder tumors to stimulate immune mediated tumor cell destruction. METHODS: In vitro human bladder cancer cell lines were cultured with exposure to various HDAC inhibitors and HLA matched human T cells. The murine urothelial cell line, MB49 was also cultured with HDAC inhibitors and activated murine splenocytes. MTT assay was performed to measure cell viability. We transduced the murine tumor line to carry Firefly luciferase to allow for bioluminescence monitoring post implantation and then implanted the cells intra-vesically using a 24Fr angiocatheter delivery method. Following implantation bioluminescence signals were monitored using IVIS Lumina imaging system. Our treatment arm consisted of a single intra-vesical instillation of CI-994 for 60 minutes on post-implantation Day 6 with intraperitoneal injection of PD-1 blockade, appropriate controls were also performed. Total flux was monitored by IVIS in the treatment and control arms. RESULTS: In Vitro analysis showed a statistically significant decrease in viable tumor cells when treated with a short course of CI994 and then exposed to activated human T cells (p 0.0025). There was an even greater response when the T cells had received PD-1 blockade (p 0.0003). MTT assay analysis of MB49 yielded similar positive results with CI-994 treatment and T cell exposure. In vivo mice who received intravesical CI-994 in combination with intraperitoneal PD-1 blockade showed a more immediate and durable response than mice in the control arms. The average bioluminescence signal for our combination treatment arm indicates minimal to no retained tumor burden. CONCLUSIONS: HDACs are widely expressed in urothelial cancer and inhibition of the selective HDAC inhibitor CI-994 has shown promising results in vitro and in an in vivo orthotopic model at reducing tumor burden.

Urinary NID2 and TWIST1 methylation to augment conventional urine cytology for the detection of bladder cancer

BACKGROUND Abnormal methylation of urinary TWIST1 and NID2 conferred high sensitivity and specificity for the detection of urothelial carcinoma. OBJECTIVE We examine the performance of the urine-based TWIST1/NID2 methylation assay with the addition of urine cytology for the detection of urothelial carcinoma. MATERIALS AND METHODS A prospective multi-institutional study was conducted to assess the performance of a methylation assay for patients with hematuria or under surveillance for non-muscle invasive bladder cancer (NMIBC). All patients underwent cystoscopy, a methylation assay, and cytology. Receiver operator characteristic (ROC) curves were constructed for cytology alone, the methylation assay alone, and a combined model. Areas under the curve (AUC) were compared using likelihood ratio tests. RESULTS A total of 172 patients were enrolled (37% for hematuria and 63% NMIBC). The AUC for cytology alone with equivocal cytologies positive was 0.704, and improved to 0.773 with the addition of the DNA methylation assay (p < 0.001). When the equivocal cytologies were considered negative, the AUC improved from 0.558 to 0.697 with the addition of the DNA methylation assay (p = 0.003). CONCLUSIONS Addition of a TWIST1/NID2-based DNA methylation assay adds diagnostic value to urine cytology and the model is sensitive to the classification of equivocal cytology.

Urine Cytology and Existing Urinary Biomarkers for Bladder Cancer

Urine-based testing would seem to be the obvious diagnostic choice for bladder cancer. Conceptually, an ideal diagnostic test would be simple and application of the test would determine if the disease is present or absent. However, like all diagnostic tests for cancer, urine-based tests for bladder cancer suffer from poor performance, limited clinical utility, and the potential for introducing harm. Consequently, none are universally recommended diagnostic tests for use in the evaluation of patients at risk of having bladder cancer [1–3]. Despite this fact, extensive investment into the research and development of urine-based technologies promising to be better bladder cancer tests continues to be made [4].