Comprehensive Genomic Profiling of Cell-Free DNA in Men With Advanced Prostate Cancer: Differences in Genomic Landscape Based on Race.

Advanced prostate cancer (aPC) in Black men was reported to present with aggressive features and to be associated with poor prognosis. Herein, we compared the cell-free DNA (cfDNA) genomic landscape of aPC in Black vs White men. Patients (pts) with aPC from 6 academic institutions and available cfDNA comprehensive genomic profiling (CGP) were included. Association between mutated genes and race was evaluated using Barnard's test and a Probabilistic Graphical Model (PGM) machine learning approach. Analysis included 743 aPC pts (217 Black, 526 White) with available cfDNA CGP. The frequency of alterations in the androgen receptor gene was significantly higher in Black vs White men (55.3% vs 35% respectively, P < .001). Additionally, alterations in EGFR, MYC, FGFR1, and CTNNB1 were present at higher frequencies in Black men. PGM analysis and Barnard's test were concordant. Findings from the largest cohort of Black men with aPC undergoing cfDNA CGP may guide further drug development in these men.

Multi-institutional Analysis of the Clinical and Genomic Characteristics of Black Patients with Metastatic Hormone-Sensitive Prostate Cancer.

BACKGROUND: The outcomes of metastatic hormone-sensitive prostate cancer (mHSPC) have significantly improved through treatment intensification, yet Black representation in those studies is suboptimal. METHODS: A multi-institutional, retrospective analysis of Black men with mHSPC was conducted, focusing on baseline demographics, treatment patterns, genomic profiles, clinical outcomes including prostate-specific antigen response, time to castrate-resistant prostate cancer (CRPC), and subsequent treatments. RESULTS: A total of 107 patients, median age 64 years, 62% with de novo metastases at diagnosis and 64% with high-volume disease, were included. Twenty-nine patients (27%) were treated with androgen deprivation therapy (ADT) with and without first generation anti-androgens, while 20%, 38% and 5% received chemotherapy, abiraterone, and enzalutamide, respectively. At time of data cut-off, 57 (54%) patients had developed CRPC, with a median time to CRPC of 25.4 months (95% CI 20.3-30.4). The median time to CRPC was 46.3 months (18.9-73.7) and 23.4 months (18.6-28.2) for patients who received ADT with or without first-generation anti-androgens and treatment intensification, respectively. The 2-year survival rate was 93.3%, and estimated median overall survival of was 74.9 months (95% CI, 68.7-81.0). Most patients (90%) underwent germline testing; the most frequent known alterations were found within the DNA repair group of genes. Somatic testing revealed pathogenic alterations of interest, notably TP53 (24%) and CDK12 (12%). CONCLUSION: In our cohort, Black men with mHSPC presented with a high proportion of de novo metastases and high-volume disease. Treatment outcomes were very favorable with ADT-based regimens. The genomic landscape suggests different molecular profile relative to White patients with potential therapeutic implications.

Kidney Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Guidelines for Kidney Cancer focus on the screening, diagnosis, staging, treatment, and management of renal cell carcinoma (RCC). Patients with relapsed or stage IV RCC typically undergo surgery and/or receive systemic therapy. Tumor histology and risk stratification of patients is important in therapy selection. The NCCN Guidelines for Kidney Cancer stratify treatment recommendations by histology; recommendations for first-line treatment of ccRCC are also stratified by risk group. To further guide management of advanced RCC, the NCCN Kidney Cancer Panel has categorized all systemic kidney cancer therapy regimens as "Preferred," "Other Recommended Regimens," or "Useful in Certain Circumstances." This categorization provides guidance on treatment selection by considering the efficacy, safety, evidence, and other factors that play a role in treatment selection. These factors include pre-existing comorbidities, nature of the disease, and in some cases consideration of access to agents. This article summarizes surgical and systemic therapy recommendations for patients with relapsed or stage IV RCC.

NCCN Guidelines® Insights: Bladder Cancer, Version 2.2022.

The NCCN Guidelines for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer and other urinary tract cancers (upper tract tumors, urothelial carcinoma of the prostate, primary carcinoma of the urethra). These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines regarding the treatment of non-muscle-invasive bladder cancer, including how to treat in the event of a bacillus Calmette-Guérin (BCG) shortage; new roles for immune checkpoint inhibitors in non-muscle invasive, muscle-invasive, and metastatic bladder cancer; and the addition of antibody-drug conjugates for metastatic bladder cancer.

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Bladder Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non-muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non-muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org. Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. METHODS: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. RESULTS: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. CONCLUSIONS: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.

Correction to: Immunotherapy Advances in Urothelial Carcinoma.

In the original version of this article, which published in Current Treatment Options in Oncology, Volume 20, Issue 12, December 2018, the surname of the third author was captured incorrectly. The name shown above is correct.

Overview of Current and Future Adjuvant Therapy for High-Risk Localized Renal Cell Carcinoma.

OPINION STATEMENT: High-risk localized renal cell carcinoma represents a therapeutic challenge with high recurrence rates and poor survival with nephrectomy alone. Multiple agents targeting angiogenic and immunologic pathways have demonstrated remarkable efficacy in the metastatic setting but have failed to replicate similar successes in localized disease. Study results with adjuvant anti-angiogenic therapies may have been compromised by the high incidence of treatment discontinuations or dosage reductions secondary to intolerable side effects. Improving patient selection could play a major role in improving outcomes. Multiple models exist to predict survival but require improved accuracy in identifying recurrence to justify exposing patients to therapies that could significantly impair quality of life. Further understanding of pathological and molecular mechanisms of recurrence is required. Novel tools like gene recurrence scores are emerging to improve prognostication for patient selection. Immunotherapeutic approaches using check point inhibition have the potential to achieve sustained remissions with a significantly improved toxicity profile. Amplifying the immune response with a combination of neoadjuvant and adjuvant therapy to exploit the larger antigenic burden prior to nephrectomy has the biologic potential for making significant improvements in efficacy.

Immunotherapy Advances in Urothelial Carcinoma.

OPINION STATEMENT: Checkpoint inhibitors have monumentally transformed the treatment of metastatic urothelial carcinoma. While the efficacy and safety of the different agents are similar in platinum-refractory metastatic urothelial carcinoma, pembrolizumab is the only agent that was superior to chemotherapy in a randomized phase III trial. Pembrolizumab and atezolizumab are also approved as first-line therapies in cisplatin-ineligible metastatic urothelial carcinoma. Several immunotherapy trials are ongoing in non-metastatic setting to maximize responses upfront. Despite the promising responses with immunotherapy, majority of patients do not respond to monotherapy and combination approaches would be the path moving forward to maximize responses. In addition, novel therapies are needed for patients who progress on checkpoint inhibitors. There is still a lot to be done to better understand predictive biomarkers, optimal combination, and sequences to improve clinical outcomes in urothelial carcinoma.

Bronchoscopy can be done safely in patients with thrombocytopenia.

BACKGROUND: Prophylactic platelet (PLT) transfusions are often administered to patients before bronchoscopy or bronchoalveolar lavage (BAL) to prevent bleeding. There is a paucity of data to validate this approach, with a commonly suggested PLT transfusion threshold of fewer than 50 × 10(9) /L, largely based on expert opinion. We conducted a retrospective study on the incidence of bleeding complications in patients with thrombocytopenia undergoing bronchoscopy. STUDY DESIGN AND METHODS: We identified 150 consecutive patients with PLT counts of not more than 100 × 10(9) /L who underwent bronchoscopy and/or BAL from January 2009 to May 2014 at our institution. The British Thoracic Society (BTS) guidelines were used to categorize bleeding associated with bronchoscopy. RESULTS: Infection (40%) was the primary indication for bronchoscopy with BAL. Fifty-eight of 89 (65%) patients with baseline PLT counts of not more than 50 × 10(9) /L received prophylactic transfusions compared to 8% of those with PLT counts of more than 50 × 10(9) /L. The PLT count did not increase to more than 50 × 10(9) /L in many patients who received transfusions. Seventy-two patients had counts of less than 50 × 10(9) /L at the time of bronchoscopy, with 15 patients having counts of less than 20 × 10(9) /L. Only one patient with a PLT count of 61 × 10(9) /L had bleeding that required continuous suctioning but then resolved spontaneously (termed "mild bleeding" by BTS criteria). Bloody lavage that resolved spontaneously without continuous suctioning (termed "no bleeding" by the BTS criteria) was observed in nine (6%) patients. CONCLUSION: The very low incidence of bleeding complications from bronchoscopy with or without BAL even in patients with PLT counts of not more than 30 × 10(9) /L (no episodes of clinically significant bleeding in 35 patients) demonstrates that bronchoscopy can be done safely in patients with severe thrombocytopenia.

Obesity diminishes response to PD-1-based immunotherapies in renal cancer.

BACKGROUND: Obesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes. METHODS: We investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, 'BMI' ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString. RESULTS: With obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1ß in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors. CONCLUSIONS: We find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1ß levels, highlighting the need for continued study of this critical issue.

Investigational MET inhibitors to treat Renal cell carcinoma.

Introduction: Renal cell carcinoma (RCC) consists of distinct clinical and biologic entities, with an urgent need for novel therapies targeting histology-specific molecular drivers of cancer growth. The MET pathway is now being targeted by multiple novel agents in clinical development. This review highlights the upcoming role of MET inhibition in the treatment of RCC. Areas covered: The HGF-MET axis is now recognized as playing a vital role in the growth of papillary histology and in driving VEGF inhibitor resistance. The heterogeneity of MET alterations influences sensitivity to MET inhibition and we need predictive biomarkers for improving patient selection. In this review, we highlight the role of the MET pathway in both clear cell and non-clear cell RCC and  provide a comprehensive review of preclinical and early clinical data on multiple drugs targeting the MET pathway. Expert opinion: MET alterations can act as primary or secondary drivers of tumor growth in RCC and represents a viable therapeutic target. Combination strategies of VEGF and MET inhibitors could lead to sustained and deep responses even in non-MET driven RCC by inhibiting pathways of VEGF resistance. Addition of checkpoint inhibitors to MET inhibition has also demonstrated promising signs of early efficacy.

Correlation between Dt/V derived from ionic dialysance and blood-driven Kt/V of urea in African-American hemodialysis patients, based on body weight and ultrafiltration volume.

BACKGROUND: The Dt/V obtained by using ionic dialysance (D) as a surrogate for urea clearance (K) is a well-validated adjunct measure of hemodialysis adequacy, with a variable level of correlation with urea-based Kt/V. However, this correlation has not been examined based on patients' body size and ultrafiltration (UF) volume during the dialysis session. METHODS: Simultaneous evaluations of online Dt/V and single-pool variable-volume urea Kt/V were made. Patients were categorized into three subgroups based on their weight (<60, 60-80 and ≥80 kg), body mass index (<25, 25-30 and >30 kg/m2) and UF volume (<1.5, 1.5-3 and >3 L). The correlation between Dt/V and Kt/V was evaluated for the entire cohort per dialysis session in each subgroup. RESULTS: Mean Kt/V was greater than the mean Dt/V (1.72 versus 1.50, P < 0.001), with an overall correlation r value of 0.602. This correlation was stronger in the medium weight group versus lower and higher weights. The correlation between Dt/V and Kt/V was inversely related to the UF volume (r = 0.698, 0.621 and 0.558 for those with UF volume of <1.5, 1.5-3.0 and >3 L, respectively). A total of 99.3% of patients with Dt/V of >1.2 also had Kt/V >1.2 and 9.5% of those with Dt/V <1.2 had their Kt/V <1.2. CONCLUSIONS: There is a moderate degree of correlation between Dt/V and Kt/V in African-American hemodialysis patients, which is impacted by body size and UF volume. A Dt/V of >1.2 strongly predicts adequate dialysis as defined by Kt/V of >1.2.

Treatment approaches of hard-to-treat non-Hodgkin lymphomas.

INTRODUCTION: Even after recent advancements with monoclonal antibodies, antibody drug conjugates and immune therapies, relapsed and refractory lymphomas remain challenging to treat; and the definition and treatment approaches of hard-to-treat lymphomas (HTL) continue to evolve. Areas covered: In this review, we will address HTL encompassing diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL) and peripheral T cell lymphomas (PTCL). DLBCL, which comprises 30-40% of non-Hodgkin lymphomas is a highly aggressive and heterogeneous malignancy, with primary refractory or relapsed disease remaining a therapeutic challenge. Similarly, early relapse within 2 years of primary treatment in the more indolent FL is associated with inferior outcomes. Finally, PTCL are universally aggressive and carry a poor prognosis. Expert commentary: Recently, novel antibodies, antibody drug conjugates, immunotherapies and cellular therapy (CAR therapy) have shown promising results in early phase clinical trials. These agents are changing the landscape of treatment of lymphomas and will be extremely important for improving outcomes of HTL. Importantly, revising current strict eligibility criteria for clinical trial participation is needed to help these patients benefit from these novel agents.

Circulating Biomarkers in Bladder Cancer.

Bladder cancer is a molecularly heterogeneous disease characterized by multiple unmet needs in the realm of diagnosis, clinical staging, monitoring and therapy. There is an urgent need to develop precision medicine for advanced urothelial carcinoma. Given the difficulty of serial analyses of metastatic tumor tissue to identify resistance and new therapeutic targets, development of non-invasive monitoring using circulating molecular biomarkers is critically important. Although the development of circulating biomarkers for the management of bladder cancer is in its infancy and may currently suffer from lower sensitivity of detection, they have inherent advantages owing to non-invasiveness. Additionally, circulating molecular alterations may capture tumor heterogeneity without the sampling bias of tissue biopsy. This review describes the accumulating data to support further development of circulating biomarkers including circulating tumor cells, cell-free circulating tumor (ct)-DNA, RNA, micro-RNA and proteomics to improve the management of bladder cancer.