Muscle-invasive urothelial bladder cancer: an update on systemic therapy

Knollman, Hayley; Godwin, James Luke; Jain, Rishi; Wong, Yu‐Ning; Plimack, Elizabeth R.; Geynisman, Daniel M.

doi:10.1177/1756287215607418

Cited by 33 publications

(28 citation statements)

References 124 publications

(152 reference statements)

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“…Metastatic UC is almost uniformly fatal (1). However, progress in systemic therapies for muscle-invasive bladder carcinoma (MIBC) has been stagnant for decades, with few new systemic therapies being evaluated, until recently (2). Therefore, there is an urgent requirement for new potential therapeutic targets in UC.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

et al. 2017

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Abstract. Bladder cancer, the majority of which is urothelial carcinoma (UC), is a common malignancy worldwide. Genes encoding transmembrane/secretory proteins expressed specifically in certain cancers may be ideal biomarkers for cancer diagnosis and may represent therapeutic targets. In the present study, the expression and function of the bone marrow stromal cell antigen 2 (BST2) gene was analyzed in UC. Reverse transcription-quantitative polymerase chain reaction demonstrated that expression of BST2 in normal tissue samples was the highest in liver tissue. However, expression of BST2 in UC tissue samples was higher than in normal liver. Immunohistochemical analysis revealed weak or no staining of BST-2 in non-neoplastic mucosa, whereas UC tissue exhibited stronger and more extensive staining compared with non-neoplastic mucosa. BST-2 staining was observed mainly on UC cell membranes. In total, 28 (41%) of 69 UC cases were positive for BST-2. UC cases positive for BST-2 were more frequently T2/3/4 cases [so-called muscle-invasive bladder cancer (MIBC)] than Ta/is/1 cases (P=0.0001). However, Kaplan-Meier analysis demonstrated no association between BST-2 expression and survival. BST2 small interfering RNA (siRNA)-transfected T24 cells exhibited significantly reduced cell growth relative to negative control siRNA-transfected T24 cells. The levels of phosphorylated Akt and extracellular signal-regulated kinase were lower in BST2 siRNA-transfected T24 cells than in control cells. These results suggest the involvement of BST-2 in the pathogenesis of UC. Since BST-2 is expressed on the cell membrane, BST-2 may be a good therapeutic target for MIBC.

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Section: Introductionmentioning

confidence: 99%

Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

et al. 2017

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“…49 Additionally, the role of immune checkpoint inhibitors, such as PD-1 and PDL-1, is being actively explored in in phase I-III clinical trials in the neoadjuvant, adjuvant and metastatic settings. 50 Specifically, these inhibitors are hypothesized to prevent immune system tumor evasion and maximizing the body's immune response to malignant urothelial cells via regulation of T-cell activity. 50 Although no trials have been performed in the BPT setting, future studies may elucidate the role genetic or molecular markers in predicting response to BPT and the use of immunotherapy in this domain.…”

Section: Future Researchmentioning

confidence: 99%

Bladder Preservation Therapy: A Review of the Literature and Future Directions

Cahn

Ristau

Ghiraldi

et al. 2016

Urology

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“…While this holds promise particularly in tumor types that have established sensitivity to a given TT, its utility in mUC is purely investigational. Currently, no TTs are approved for use in patients with mUC, although several drugs and targets are being investigated in clinical trials [13,74]. The advantage of this strategy in tumors that are identified to have certain driver mutations for which a specific drug is available is compelling, as it theoretically allows for target-directed tumor cell killing with release of neoantigens followed by the capacity to generate a durable antitumor response.…”

Section: • Immunotherapymentioning

confidence: 99%

“…Despite this recommendation, retrospective studies in the USA and Europe have reported that the majority of patients do not ultimately receive this potentially life-preserving therapy [10][11][12]. Reasons cited for this have varied, but include concerns about the toxicities of chemotherapy leading to worsening performance status and treatment delays, ultimately contributing to worse perioperative outcomes, though many of these concerns have proved to be unfounded [12,13]. Fortunately, there is some evidence that practice patterns may be changing, increasing the proportion of MIBC patients offered NAC [11,14].…”

mentioning

confidence: 99%

Systemic Therapy for Bladder Cancer Finally Comes into a New Age

Zibelman

Plimack

2016

Future Oncol.

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Systemic therapy for bladder cancer, both localized muscle-invasive disease and metastatic disease, has seen minimal progress over the past two decades. Current approaches rely upon cytotoxic chemotherapy combinations aimed at increasing cure rates or achieving palliation and disease control, but these regimens are fraught with short-and long-term toxicities and outcomes remain suboptimal. The emergence of systemic immunotherapies that can provide durable remissions in subsets of patients with other malignancies has the potential to transform the field, and early phase trials have begun to demonstrate activity in some patients with metastatic bladder cancer. In this article, we review the current state of systemic therapy for bladder cancer and discuss the current literature and ongoing trials utilizing various immunotherapies. KEYWORDS• bladder cancerCancers of the urinary bladder are the sixth most commonly diagnosed malignancy in the USA and the most prevalent malignancy of the GI tract, with 74,000 new cases estimated from 2015 [1]. The predominant histologic subtype is urothelial carcinoma (UC), which accounts for more than 90% of diagnoses in the western world. For patients with muscle-invasive bladder cancer (MIBC) confined to the bladder and deemed surgical candidates, radical cystectomy (RC) with pelvic lymphadenectomy remains the gold standard, with bladder preservation techniques using combinations of radiation therapy (RT) and systemic therapy receiving increased attention [2][3][4][5]. Local therapy with surgery or radiation alone is suboptimal, with median overall survival (OS) ranging from 1.8 to 3.8 years and 5-year survival of only 43% after RC and less than 40% with RT, with the majority of deaths related to distant disease [6,7]. The addition of neoadjuvant chemotherapy (NAC) has significantly improved outcomes. For patients who present with metastatic disease, systemic chemotherapy with cisplatin-based regimens, long recognized as an active drug in this disease, is accepted as the standard of care. Thus, systemic therapy is an integral component of treatment for patients with UC, yet despite tremendous advances across a multitude of malignant conditions, no new therapies have entered the armamentarium in over decade. Fortunately, recent and ongoing research in the burgeoning field of cancer immunotherapy (IT) offers hope that new agents will finally demonstrate survival benefits in clinical trials. In this article, we review the definitive studies that have established the current standards of care for systemic treatment in UC, then focus on new and future trials aiming to bring the systemic treatment of UC into the IT age.For reprint orders, please contact: reprints@futuremedicine.com

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Muscle-invasive urothelial bladder cancer: an update on systemic therapy

Cited by 33 publications

References 124 publications

Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

Overexpression of the transmembrane protein BST-2 induces Akt and Erk phosphorylation in bladder cancer

Bladder Preservation Therapy: A Review of the Literature and Future Directions

Systemic Therapy for Bladder Cancer Finally Comes into a New Age

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