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While immune checkpoint inhibitors (ICI) have revolutionized treatment for bladder cancer patients, studies have shown that not all patients achieve a response. To identify potential genetic predictors of ICI treatment response, Sarfaty et al. investigated the link between specific subtypes based on genomic alterations in ICI-treated patients with advanced urothelial carcinoma and survival outcomes.
Published May 12, 2023
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Tumor mutation burden (TMB) is a measure of the number of genetic mutations within a tumor. High TMB levels are associated with better patient prognosis and enhanced sensitivity to immune checkpoint inhibitors. Biologically, TMB levels are linked to increased expression of neoantigens on cancer cells, which facilitates their recognition and subsequent elimination by tumor-infiltrating lymphocytes (TILs). Various studies have revealed the possibility of using automated models to quantify and characterize TILs in whole-slide images (WSIs). Xu et al. developed a computational model to analyze patient WSI data and trained a deep learning model to detect TILs and quantify their densities within tumor regions to characterize the spatial organization of immune cells in tumors. The investigators tested the performance of these methods in predicting TMB, TIL status, and patient survival.
Published December 6, 2022
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Accurate risk stratification of patients with non-muscle invasive bladder cancer (NMIBC) is essential for proper treatment selection and optimal clinical outcomes. The American Urological Association (AUA) recommends pathology review by an experienced genitourinary pathologist in patients who meet specific risk criteria. There have been limited studies on the effect of pathologic re-review of patient specimens from transurethral resection of bladder tumor (TURBT) procedures. Campbell et al. recently investigated the link between pathologic re-review on grade, staging, and risk stratification.
Published August 8, 2024
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For patients with muscle-invasive bladder cancer (MIBC), the gold standard for treatment is cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy. However, the response to neoadjuvant chemotherapy varies significantly, and additional regimens that enhance the efficacy of neoadjuvant chemotherapy are needed.
Published December 15, 2022
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Neoadjuvant chemotherapy followed by radical cystectomy (RC) with lymph node dissection is the standard of care in patients with muscle-invasive urothelial bladder carcinoma (MIBC). Unfortunately, many patients are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy.
Published March 6, 2019
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Platinum-based chemotherapy is the cornerstone of initial treatment for most patients with advanced urothelial cancer (UC). EGFR is a promising target given its high expression levels in UC and the availability of anti-EGFRs inhibitors. However, it is unclear if adding an anti-EGFR inhibitor to platinum-based chemotherapy will lead to better clinical outcomes.
Published October 26, 2021
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Detection of upper tract carcinoma in situ (UTcis) is challenging. There is a growing interest in effective renal-sparing treatment options for these patients. Instillation of Bacillus Calmette-Guérin (BCG) has proven effective in bladder carcinoma in situ, and a few studies have reported its use in patients with UTcis. Fontanet et al. studied BCG treatment in patients with UTcis and a systematic review of previous literature.
Published August 23, 2023
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The standard treatment for patients with high-risk non-muscle invasive bladder cancer (NMIBC) includes transurethral resection of bladder tumor (TURBT) followed by intravesical bacillus Calmette-Guérin (BCG). Radical cystectomy (RC) is recommended in patients with BCG-unresponsive NMIBC. However, due to the high morbidity and risk associated with RC, identifying alternative treatment options for this subgroup of patients is crucial. Cretostimogene grenadenorepvec (CG0070), an oncolytic adenovirus, has been investigated for its potential efficacy in patients unresponsive to BCG. Li et al. recently reported the results of the CORE-001 trial testing cretostimogene in combination with the PD-1 inhibitor pembrolizumab.
Published July 19, 2024
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While intravesical Bacillus Calmette-Guérin has been effective in patients with non-muscle invasive bladder cancer (NMIBC), recurrence rates are high. A recent study by Li et al. described the responses to durvalumab treatment among patients with BCG-unresponsive carcinoma in situ (CIS)-containing NMIBC.
Published August 31, 2023
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There have been significant advancements in treatment options for patients with metastatic urothelial carcinoma (mUC) in recent years, including immune checkpoint inhibitors (ICIs), antibody-drug conjugates, and fibroblast growth factor receptor (FGFR) inhibitors. FGFR alterations are present in 15-20% of patients with mUC and inhibitors, such as erdafitinib, derazantinib, and atezolizumab have therefore been approved for use in patients harboring selected alterations. The aim of this study was to analyze findings from a phase 1b/2 clinical trial (FIDES-02) in which patients with mUC and FGFR alterations were treated with derazantinib alone or in combination with atezolizumab.
Published July 8, 2024
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Optimal treatment regimens for histologic variants of non-muscle invasive bladder cancer (NMIBC) are not well established. Accordingly, patients with variant cases exhibit worse clinical outcomes. Micropapillary urothelial carcinoma (MPUC) is the most common variant of urothelial carcinoma. A recent study by Abou Chakra et al. examined the efficacy of Intravesical gemcitabine/docetaxel (Gem/Doce) and intravesical valrubicin and docetaxel (Val/Doce) in patients with MPUC.
Published August 6, 2024
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The standard of care first-line treatment for advanced urothelial carcinoma (aUC) is platinum-based chemotherapy, followed by avelumab (anti-PD-L1), for maintenance treatment in patients without progression. The JAVELIN trial confirmed that maintenance avelumab was associated with significantly prolonged overall survival (OS) and progression-free survival (PFS). Bakaloudi et al. set out to characterize clinical outcomes of switch maintenance avelumab in a real-world cohort of patients with aUC.
Published September 5, 2023
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Neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is a standard of care in patients with muscle-invasive bladder cancer (MIBC). However, the role of NAC remains controversial for patients undergoing bladder preservation with radiation therapy (RT). Kool et al. recently investigated the effect of NAC on survival outcomes in MIBC patients treated with curative RT.
Published July 3, 2024
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Bacillus Calmette-Guérin (BCG) has long been considered a standard of care in treating intermediate-risk or high-risk non-muscle invasive bladder cancer (NMIBC). For maintenance, recommendations stipulate a 1-year treatment for intermediate-risk patients and up to 3 years for high-risk patients.
Published November 22, 2022
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Sarcomatoid urothelial bladder cancer (SARC) is an aggressive histological variant of bladder cancer. It is associated with early distant metastasis and poor survival rates. Understanding the molecular characteristics of SARC will lead to improved clinical outcomes.
Published January 20, 2020
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Patients with advanced urothelial carcinoma (UC) still have low 5-year survival rates. Most patients experience disease progression after treatment with chemotherapy or PD-1 inhibitors. Enfortumab vedotin (EV) is an antibody-drug conjugate that targets Nectin-4, a protein highly expressed in UC. A recent study by Rosenberg et al. reports long-term outcomes from EV-301, an open-label phase III trial for EV versus chemotherapy in previously treated patients with advanced UC.
Published October 26, 2023
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CD19-directed chimeric antigen receptor (CAR) T cells are now used to treat B-cell malignancies. Extending their use to solid tumors requires optimizing the interactions between CAR-T cells and specific cancer cell types. A recent study by Grunewald et al. examined the role of DNA methyltransferases inhibitors (DNMTi) and histone deacetylases inhibitors (HDACi) to optimize improving CAR-T cell-mediated tumor-specific cytotoxicity against bladder cancer cells.
Published January 24, 2022
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The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) are approved for metastatic bladder cancer treatment. However, little is known about their efficacy in earlier stages and whether they can be combined with radiation for bladder preservation approaches.
Published June 20, 2024
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Immense resources have been dedicated to identifying innate biological differences between Black and White men that could explain the disparities in prostate cancer with the results being equivocal at best. Prostate cancer, the most commonly diagnosed solid organ cancer in men, represents perhaps the greatest disparity in outcomes in oncology.1 Few studies, if any, have attempted to evaluate the association between prostate cancer outcomes and social determinants of health (SDOH). The Department of Health and Human Services (HHS) defines SDOH as "the conditions in the environments where people are born, live, learn, work, play, worship and age that affect a wide range of health, functioning, and quality-of-life outcomes and risks".2 With the historical and continued oppression of Black people that transcends income and educational level, evaluating the association between SDOH and disparities in healthcare outcomes is crucial to determine initiatives to mitigate these continued inequities.
Published March 31, 2023
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Olaparib is a poly(ADP-ribose) polymerase inhibitor approved for metastatic castration-resistant prostate cancer (mCRPC). Olaparib is approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone
Published December 6, 2021
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Primary carcinoma in situ (P-CIS) of the bladder is rare. Adjuvant intravesical Bacillus Calmette-Guérin (BCG) immunotherapy has been reported to be effective in reducing recurrence rates in CIS and P-CIS patients but the clinical factors associated with the recurrence of P-CIS are not well-defined.
Published November 5, 2018
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Genetic alterations in fibroblast growth factor receptors (FGFRs) are common in patients with urothelial carcinoma. Erdafitinib, a kinase inhibitor, is the current standard of care for patients with FGFR3 or FGFR2 genetic alterations. Guercio et al. investigated how different genetic alterations affect treatment response and their variation across primary and metastatic sites.
Published November 2, 2023
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The administration of bacillus Calmette-Guérin (BCG) as an adjuvant is recommended in the context of high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection of bladder tumor (TURBT). However, there have been production shortages of BCG. Moreover, efficacy is suboptimal and clinical tolerance of BCG has been problematic.
Published November 9, 2022
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Therapeutic blockade of PD-1, a receptor on T cells that inhibits tumor suppressive activity, has been highly effective in treating many different types of cancer. Pembrolizumab is a monoclonal antibody that targets PD-1. This type of treatment is particularly valuable for patients who are ineligible for chemotherapy, including patients with muscle-invasive bladder cancer (MIBC).
Published February 21, 2023
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The oncogene addiction model occurs when cancer cells become dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype. Withdrawal of the oncogenic signal leads to the regression of cancer. The role of oncogenic addiction in precursor lesions such as hyperplasia is not well understood. A recent study by Yee et al. in Scientific Reports examined the interaction between Forkhead box A1 (FOXA1), a transcriptional activator of the Upk2-promoter in controlling the expression of oncogenic HRAS to induce urothelial hyperplasia in transgenic mice.1 By knocking out FOXA1, the investigators simulated oncogenic HRAS withdrawal. This resulted in a significant reduction of urothelial proliferation consistent oncogenic addiction to HRAS.
Interestingly, the investigators found that reduced proliferation did not affect basal cells indicating that the regulation of oncogenic HRAS by Upk2 occurs mainly in luminal cells. These results demonstrate the dependence of urothelial hyperplasia on the continuous expression of Foxa1 and activated HRAS in this model.
This important study adds to our understanding of the events that result in oncogenic addiction in urothelial hyperplasia. Additional studies characterizing the molecular events that occur in normal urothelium and precursor lesions such as hyperplasia have the potential for improving early-detection and for designing strategies to prevent progression.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
Reference: 1. Yee CH, Zheng Z, Shuman L, Yamashita H, Warrick JI, Wu XR, Raman JD, DeGraff DJ. Maintenance of the bladder cancer precursor urothelial hyperplasia requires FOXA1 and persistent expression of oncogenic HRAS. Sci Rep. 2019 Jan 22;9(1):270. doi: 10.1038/s41598-018-36720-6.
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Published October 15, 2019
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The treatment of metastatic prostate cancer has seen a paradigm shift, particularly in the management of metastatic hormone sensitive prostate cancer (mHSPC). The developments come not only on the fronts of systemic agents but also in the area of therapy to primary tumour and metastases. The consistent survival benefit seen in landmark trials of androgen receptor inhibitors (ARIs) have collectively put forth a strong argument for early intensification of treatment. Together with level 1 evidence from CHAARTED and STAMPEDE, docetaxel or ARIs in combination with ADT are now established as the new standard of care for de novo mHSPC.
Published September 9, 2022
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Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) neoadjuvant chemotherapy is a standard of care for muscle-invasive urothelial bladder cancer. However, gemcitabine-cisplatin (GC) is equally effective and associated with less toxicity in the metastatic setting. This has been extrapolated to the neoadjuvant setting in clinical practice. A recent study by Niedersüss-Beke et al. in the journal Oncologyprospectively evaluated the clinical outcomes of neoadjuvant GC in patients with locally advanced urothelial cancer.
Published April 28, 2017
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The optimal treatment for cisplatin-ineligible patients with metastatic urothelial cancer is unknown. A recent study published by Sadeghi et al. in the Journal of Clinical Oncology1 examined the efficacy of the gemcitabine-eribulin combination in this patient population.
Cisplatin-ineligibility was defined as a creatinine clearance <60 ml/min and ≥30ml/min, grade 2 or above hearing loss and grade 2 or higher neuropathy. The study enrolled twenty-four patients between 2015 and 2017. Subjects received 1,000 mg/m2 of gemcitabine intravenously 30 minutes before 1.4 mg/m2 eribulin on day 1 and 8 in 21-day cycles until progression or unacceptable toxicity. The median age of enrolled patients was 73 years (range 62-88 years). Most patients had a performance status of 0 or 1. The majority of patients (16/24) had lymph node metastases, and several patients had visceral metastases.
The observed objective response rate was 50% (95% CI, 29% to 71%) in 12/24 patients. The median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). Common toxicities included fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), constipation, nausea, and thrombocytopenia (42% each).
This study demonstrated the efficacy of the combination of gemcitabine-eribulin in cisplatin-ineligible metastatic urothelial cancer patients. Prospective trials comparing the efficacy of carboplatin-based regimens, immunotherapy, and gemcitabine-eribulin combinations are needed to determine the optimal treatment regimen.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
Reference:
1. Sadeghi, Sarmad, Susan G. Groshen, Denice D. Tsao-Wei, Rahul Parikh, Amir Mortazavi, Tanya B. Dorff, Cheryl Kefauver et al. "Phase II California Cancer Consortium Trial of Gemcitabine-Eribulin Combination in Cisplatin-Ineligible Patients With Metastatic Urothelial Carcinoma: Final Report (NCI-9653)." Journal of Clinical Oncology (2019): JCO-19.
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Published September 9, 2019
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Understanding the demographic factors which affect clinical outcomes following radical cystectomy (RC) is critical for improving oncologic outcomes for all patients. A recent study published in European Urology Oncology examined intraoperative and postoperative differences in outcomes between male and female patients who underwent radical cystectomy.
Published January 23, 2020
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Currently, intermediate or high-risk non-muscle-invasive bladder cancer patients (NMIBC) require intensive follow-up. This usually consists of urethrocystoscopy (gold standard) and urine cytology to monitor the recurrence of NMIBC. The current methods are expensive and invasive and have low sensitivity.
Published July 23, 2018
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Muscle-invasive bladder cancer (MIBC) tumors can be divided into luminal and non-luminal subtypes. The establishment of the six molecular subtypes represents gene regulatory networks that integrate changes at the level of the genome, the epigenome, and the transcriptome. Moreover, highly active enhancers, known as super-enhancers (SEs), play a significant role in cell identity changes and oncogenic transformation.
Published May 15, 2023
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The recommended treatment for patients with muscle-invasive bladder cancer (MIBC) is neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy. However, many patients do not respond to NAC, and extensive research is therefore being undertaken to identify biomarkers that predict response to treatment.
Published November 28, 2022
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Germline DNA damage repair (gDDR) alterations are common in men with prostate cancer (PCa). Men with PCa and gDDR alterations showed poor clinical outcomes. It is unclear if men with high-risk PCa and gDDR alterations would respond differently to neoadjuvant androgen deprivation therapy (ADT) than men without gDDR alterations.
Published July 22, 2021
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Renal cell carcinoma (RCC) accounts for approximately 2% of all cancers. The predisposing risk factors for RCC are still not well-defined. Understanding germline genetic predisposition for RCC in different ethnic groups is an area of unmet need.
Published June 17, 2021
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Recent studies have highlighted emerging associations between the urinary microbiome and bladder cancer. Bukavina et al. conducted an in-depth survey of differences in the urinary microbiome between patients with bladder cancer and healthy controls using a new urinary microbiome dataset and existing datasets across three other countries.
Published September 27, 2023
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Bladder cancer affects 550,000 new cases every year. Understanding the gender-specific incidence and mortality patterns and trends of bladder cancer is critical for reducing the global impact of this disease.
Published October 26, 2020
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Treatment options for bladder cancer are expanding but finite. Identifying novel potential therapeutic agents for patients with bladder cancer is a key research priority. In a recent study, Ertl et al. recently performed a drug screening study to examine the effects of novel and repurposed compounds on bladder cancer cell lines.
Published June 22, 2022
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On June 22, 2023, the Oversight and Investigations Subcommittee of the House Energy and Commerce Committee hosted a hearing entitled, “MARCA Checkup: Assessing Implementation and Challenges that Remain for Patients and Doctors.”
Published June 26, 2023
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Squamous cell carcinoma represents 5% of lower urinary tract tumors in the U.S. Several factors are linked to squamous cell carcinoma of the bladder (BSCC), such as Schistosoma infection, recurrent urinary tract infections (UTIs), bladder calculi, pelvic radiation, antecedent intravesical Bacillus Calmette-Guérin (BCG), and indwelling catheters. Human papillomavirus (HPV) is also known to contribute to SCC, but there has been limited data on the association between HPV and advanced BSCC (aBSCC). Ghelani et al. conducted a retrospective study to determine whether patient outcomes correlated with HPV status.
Published February 6, 2024
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Bladder cancers (BC) are among tumor types with a high mutation load. Somatic mutations can encode mutant peptides that can be recognized by T-cells as neoantigens triggering an anti-tumor immune response. T cells can identify mutant epitopes when presented by human leukocyte antigen (HLA) class I molecules. The HLA-1 profile in a cancer patient is a crucial determinant of the immunoreactivity against cancer neoepitopes.
Published January 20, 2021
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Incorporating neoadjuvant chemotherapy (NAC) into the management of patients with localized muscle-invasive bladder cancer (MIBC) improves survival. However, due to multiple factors, NAC is still not effectively used in real-life settings. Moreover, there is are established predictor biomarkers to guide clinicians to choose the most beneficial treatment with the least possible toxicities.
Published January 28, 2022
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Potentially actionable genomic alterations are common in advanced urothelial cancers (aUC). However, it is unclear if personalized treatment strategies based on each patient’s genomic profile will be effective in the clinic.
Published December 20, 2021
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Treating patients who received immune checkpoint inhibition (ICI) and experienced treatment-related toxicities, remains complicated due to the high risk of Immune-relate adverse events (irAEs) with the reintroduction of ICIs.
Published July 20, 2020
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Non-muscle-invasive bladder cancer (NMIBC) has a high recurrence rate. Although the BCG therapy is recommended as an immune targeting treatment in high-risk NMIBC tumors, the BCG’s role in the eliciting a response by the innate and adaptive immunity is unclear. A recent study by Audenet et al. published recently in the World Journal of Urology, investigated the immune phenotype of peripheral blood mononuclear cells (PBMC) in patients with NMIBC treated with intravesical BCG.
Published July 31, 2018
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Despite initial responses, a significant limitation of immunotherapy is the development of resistance that is thought to be related to immune exhaustion, suppression of T-cell activity, and loss of neoantigens. Previous studies detected high expression of E2F and EZH2 in a subset of patients with high-risk non-muscle invasive bladder cancer (NMIBC) in association with immune suppression.
Published November 16, 2022
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The relationship between the expression of GATA3, cytokeratin (CK) 20, CK 5/6, and p53 and survival in patients with muscle-invasive bladder cancer (MIBC) is not well characterized.
Published January 9, 2020
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Early-phase clinical trials are a treatment option for patients with metastatic bladder cancer (mBC). However, Patients enrolled in these trials have already been exposed to toxicity from prior therapies and developed a poor performance status making it challenging to identify patients who are likely to benefit.
Published August 23, 2021
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Transurethral resection of bladder tumor (TURBT) is therapeutic in non-muscle invasive bladder cancer (NMIBC), but the role of repeat TURBT (reTURBT) in MIBC patients remains poorly understood. TURBT with concurrent radiotherapy and chemotherapy can contribute to bladder preservation. It has also been shown to improve patient outcomes when performed before the administration of neoadjuvant chemotherapy, although some findings have been contradictory. Bree et al., therefore, sought to identify the effects of reTURBT before radical cystectomy in MIBC patients.
Published February 2, 2023
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The effect of restaging transurethral resection (Re-TUR) timing after initial transurethral resection of bladder tumor (TURBT) on survival rates is not well studied. A recent study published by Calò et al. in the World Journal of Urologyinvestigated the appropriate time frame for patients with high-grade T1 bladder cancer (BC) to undergo Re-TUR.
Published June 16, 2020
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With the expanding therapeutic arsenal for metastatic castration-resistant prostate cancer (mCRPC), clinical decision-making has become increasingly complex. The optimal drug choice or sequence remains debated, and the resulting challenge for treatment planning is particularly nuanced for older men who are disproportionately underrepresented in clinical trials. As a result, their illness experience remains poorly understood.
Published August 4, 2023
