Bladder Cancer: Androgen receptor activation a potential therapeutic target

Byron H. Lee, MD, PhDMultiple studies on exosomes, data from the IMvigor 210 trial of atezolizumab (TECENTRIQ), and research on prehabilitation for cystectomy were among the highlights in bladder cancer from the 2016 AUA annual meeting. The take-home messages for bladder cancer were presented by Byron H. Lee, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York.   

Exosomes, which are membrane-enclosed, 30- to 100-nanometer vesicles found in bodily fluids, can modulate the immune system, alter target cell behavior, promote angiogenesis, and facilitate migration of cancer cells. Four studies found: Exosomes from invasive and noninvasive bladder cancer cell lines have distinct microRNA signatures and can be taken up by naïve fibroblasts. A 38-gene panel from urinary exosomes may be used to develop a new assay for urothelial carcinoma detection. Increased levels of tumor-associated mRNA and long non-coding RNA such as HOTAIR were found in exosomes isolated from patients with invasive bladder cancer. Bladder cancer cell lines shed exosomes at much higher quantities than non-transformed urothelial cell lines and have distinct mRNA expression profiles.

Atezolizumab (TECENTRIQ), an anti-PD-L1 antibody indicated for patients with platinum-treated locally advanced or metastatic urothelial carcinoma, showed significantly improved objective response rate versus historical controls in the IMvigor 210 trial. There was a 27% response rate in high expressers of PD-L1 and a 15% objective response rate in all comers. Responses were durable, poor prognostic factors did not preclude response, and the drug was well tolerated.

Androgen receptor activation may play a role in bladder carcinogenesis and potentially serve as a therapeutic target. Analysis of gene expression data found that expression of 5-alpha-reductase isozyme subtype and genes involved in androgen signaling are associated with bladder cancer cluster type. Also, anti-androgens can inhibit colony formation in vitro and growth in a xenograft model of a carcinogen-transformed, androgen receptor-expressing urothelial cell line.

In one new model of bladder cancer, a tet-inducible UPII-CRE was used to delete P53 and/or PTEN in mice; knockout of both genes led to development of invasive tumors with squamous differentiation and expression of high levels of basal cell markers. In a second, study authors successfully cultured organoids derived from surgical specimens with similar mutation profiles as the parental tissue.

Prehabilitation for cystectomy was feasible and safe in two presentations. Both groups used a 2- to 3-week program, reported good patient compliance (75%-80%), and demonstrated measurable improvement in postoperative fitness and endurance.

• Robotic cystectomy utilization has increased over time to 20% to 30%. Perioperative and short-term outcomes (length of stay, complications, and readmission rates) are similar to open cystectomy. No significant differences in long-term oncologic outcomes were seen between robotic and open cystectomy, but studies are needed to compare late postoperative complications such as ureterointestinal and urethrointestinal anastomotic strictures, and renal function deterioration.

• A study on the potential of tumor dissemination under pneumoperitoneum, which examined mRNA expression and epithelial cell markers from intravesical and pelvic washes in patients undergoing robotic cystectomy, found intravesical washes were positive for bladder cancer markers but pelvic irrigations were typically not positive for these markers. However, epithelial markers were detected in the pelvis in one patient with node-positive disease.

• A subset of patients with metastatic bladder cancer who undergo surgery will achieve long-term cancer control, but it’s still unclear whether this is due to patient selection. Further studies are warranted to identify who would benefit from surgery.

• An oncolytic adenovirus, CG0070, was studied in nonmuscle-invasive bladder cancer. In 22 patients who were given this drug or standard intravesical therapy, 53% of those receiving the adenovirus had initial complete response and six had a durable complete response at 6 and 9 months, comparable to the 57% initial complete response in the control patients. Toxicities were similar between the two groups.

• OGX-427, a second-generation antisense oligonucleotide, was administered intravesically prior to surgery in 23 patients with nonmuscle-invasive and bladder cancer one with muscle-invasive disease that was treated by transuretheral resection and radical cystectomy. OGX-427 decreased Hsp27 expression in the tumors when compared with pre-treatment. Eight patients had initial complete responses.

More AUA 2016 take-home messages:

Kidney Ca: Cytoreductive nephrectomy appears to be protective

BPH: Current, forthcoming modalities show efficacy

Stone Disease: New AUA guide discusses SWL vs. URS

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