Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer.

Background: Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.

Methods: Defective mismatch repair (dMMR) status was determined by either loss of mismatch repair protein expression on IHC or microsatellite instability (MSI) by PCR in 127 APC biopsies from 124 patients (Royal Marsden [RMH] cohort); MSI by targeted panel next-generation sequencing (MSINGS) was then evaluated in the same cohort and in 254 APC samples from the Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF). Whole exome sequencing (WES) data from this latter cohort were analyzed for pathogenic MMR gene variants, mutational load, and mutational signatures.

Nomogram to Assess the Survival Benefit of New Salvage Agents for Metastatic Urothelial Carcinoma in the Era of Immunotherapy.

Introduction: Optimal end points in phase 2 trials evaluating salvage therapy for metastatic urothelial carcinoma are necessary to identify promising drugs, particularly immunotherapeutics, where response and progression-free survival may be unreliable. We developed a nomogram using data from phase 2 trials of historical agents to estimate the 12-month overall survival (OS) for patients to which observed survival of nonrandomized data sets receiving immunotherapies could be compared.

Patients And Methods: Survival and data for major prognostic factors were obtained from phase 2 trials: hemoglobin, performance status, liver metastasis, treatment-free interval, and albumin.

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function Mutations.

African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing ( = 102) and targeted validation ( = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in , an ETS transcriptional repressor, in 5% of cases.

DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma.

Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified.

Outcomes in patients with advanced urothelial carcinoma after discontinuation of programmed death (PD)-1 or PD ligand 1 inhibitor therapy.

Objective: To study the subsequent therapy and disease outcomes of patients with advanced urothelial carcinoma (UC) after discontinuation of programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors.

Patients And Methods: We performed a retrospective analysis to examine outcomes and systemic therapy administration after PD-1/PD-L1 inhibitor therapy in patients with advanced UC. Data on demographics and therapy administered were collected from the institutions involved in the study.

Cancer immunotherapy: new applications in urologic oncology.

Purpose Of Review: Immunotherapy in urological cancer has made substantial progress during the last 20 years, but recent advances in immunotherapy have completely transformed the present treatment landscape. In this review, we summarize major clinical achievements of immunotherapy in genitourinary cancers, as well as address potential new directions for these therapies, including new agents, combinations, and biomarkers.

Recent Findings: Recently, nivolumab and atezolizumab have joined sipuleucel-T as Food and Drug Administration-approved therapies in urological malignancies.

Association of tumour microRNA profiling with outcomes in patients with advanced urothelial carcinoma receiving first-line platinum-based chemotherapy.

Background: Tumour expression of selected microRNAs (miRs) correlates with cisplatin efficacy in multiple cancers. We investigated the role of selected miRs in patients receiving cisplatin-based therapy for advanced urothelial carcinoma (UC).

Methods: RNA was extracted from formalin-fixed paraffin-embedded tumour from 83 advanced UC patients who received cisplatin.

Correlation of Apobec Mrna Expression with overall Survival and pd-l1 Expression in Urothelial Carcinoma.

Metastatic urothelial carcinoma (mUC) has a very high mutational rate and is associated with an APOBEC mutation signature. We examined the correlation of APOBEC expression with overall survival (OS) and PD-L1 expression in a cohort of 73 mUC patients. mRNA expression of APOBEC3 family of genes (A3A, A3B, A3C, A3F_a, A3F_b, A3G, A3H) was measured using Nanostring.

Chromatin immunoprecipitation from fixed clinical tissues reveals tumor-specific enhancer profiles.

Extensive cross-linking introduced during routine tissue fixation of clinical pathology specimens severely hampers chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) analysis from archived tissue samples. This limits the ability to study the epigenomes of valuable, clinically annotated tissue resources. Here we describe fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq), a method that enables reliable extraction of soluble chromatin from formalin-fixed paraffin-embedded (FFPE) tissue samples for accurate detection of histone marks.

Precision medicine for advanced prostate cancer.

Purpose Of Review: Precision cancer medicine, the use of genomic profiling of patient tumors at the point-of-care to inform treatment decisions, is rapidly changing treatment strategies across cancer types. Precision medicine for advanced prostate cancer may identify new treatment strategies and change clinical practice. In this review, we discuss the potential and challenges of precision medicine in advanced prostate cancer.

Expression Levels of DNA Damage Repair Proteins Are Associated With Overall Survival in Platinum-Treated Advanced Urothelial Carcinoma.

Background: Combination platinum chemotherapy is standard first-line therapy for metastatic urothelial carcinoma (mUC). Defining the platinum response biomarkers for patients with mUC could establish personalize medicine and provide insights into mUC biology. Although DNA repair mechanisms have been hypothesized to mediate the platinum response, we sought to analyze whether increased expression of DNA damage genes would correlate with worse overall survival (OS) in patients with mUC.

Temporal trends in receipt of adequate lymphadenectomy in bladder cancer 1988 to 2010.

Introduction And Objective: The importance of pelvic lymphadenectomy (LND) for diagnostic and therapeutic purposes at the time of radical cystectomy (RC) for bladder cancer is well documented. Although some debate remains on the optimal number of lymph nodes removed, 10 nodes has been proposed as constituting an adequate LND. We used data from the Surveillance, Epidemiology, and End Results database to examine predictors and temporal trends in the receipt of an adequate LND at the time of RC for bladder cancer.

Single-agent Taxane Versus Taxane-containing Combination Chemotherapy as Salvage Therapy for Advanced Urothelial Carcinoma.

Background: Single-agent taxanes are commonly used as salvage systemic therapy for patients with advanced urothelial carcinoma (UC).

Objective: To study the impact of combination chemotherapy delivering a taxane plus other chemotherapeutic agents compared with single-agent taxane as salvage therapy.

Design, Setting, And Participants: Individual patient-level data from phase 2 trials of salvage systemic therapy were used.

Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors.

Background: An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS) in patients with advanced urothelial carcinoma (UC) treated with platinum-based chemotherapy.

Patients And Methods: DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE) invasive high-grade UC samples and were screened for mutations, copy number variation (CNV) and gene expression analysis. Clinical data were available from 85 cases.

Perioperative therapy for muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) is an aggressive disease associated with poor survival rates. High rates of relapse, despite radical cystectomy, suggest that administration of systemic therapy in the perioperative period may improve clinical outcomes. Neoadjuvant treatment with cisplatin-based combination regimens is an established standard of care and has improved long-term survival in MIBC.

HER2 as a target in invasive urothelial carcinoma.

We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥ 2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival.

Incomplete Cross-Resistance Between Taxanes for Advanced Urothelial Carcinoma: Implications for Clinical Practice and Trial Design.

Background: Taxanes such as paclitaxel and docetaxel are commonly used for second- or third-line salvage systemic therapy for metastatic UC. Although trials have generally excluded previous exposure to taxanes when using a taxane in a salvage therapy trial, taxanes might not be completely cross-resistant. Hence, we aimed to study outcomes with docetaxel after previous paclitaxel and the reverse sequence, to identify the level of cross-resistance between these taxanes.

Identification of ALK gene alterations in urothelial carcinoma.

Background: Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome.

Methods: Samples from patients with advanced UC and correlative clinical data were collected.