麻豆传媒

A next-generation sequencing–based molecular assay using urine holds promise for improving the clinical staging of non-metastatic muscle-invasive bladder cancer (MIBC). The assay, the Noninvasive Test for Assessment of Cancerous Tumors (NTACT), is designed to help identify patients with a clinical complete response to standard neoadjuvant chemotherapy (NAC), said Philip H. Abbosh, MD, PhD, of Fox Chase Cancer Center and Albert Einstein Medical Center in Philadelphia, and co-authors.

"By incorporating NTACT alongside conventional clinical staging, we can potentially identify suitable candidates to avoid radical cystectomy," the researchers wrote in . "Biomarkers such as NTACT could ultimately enhance bladder cancer patient outcomes and herald novel personalized treatment strategies."

The approximate $150,000 cost for cancer care for patients with bladder cancer in the first year after radical cystectomy eclipses the first-year costs associated with all other cancers, the team noted. In addition, radical cystectomy is associated with significant morbidity that includes "life-changing" . The fact that up to 70% of patients with MIBC achieve complete clinical response to standard NAC and have good long-term "bladder-intact survival" suggests that "radical cystectomy might be safely avoided in properly selected patients," the authors said.

Urinary DNA sequencing was evaluated for the detection of mutations derived from tumor that correlated with the presence of residual bladder cancer at the time of surgery. Known mutations identified in the pre-NAC urine of 20 patients were cross referenced against whole exome sequencing mutation profiles from urine. These benchmark results were then validated through analyses of the correlation between mutation profiles from urine and pre-surgery residual disease in 44 radical cystectomy candidates from a second prospective clinical trial.

The residual mutation profile status correlated strongly with residual disease status (P=0.0092). NTACT had a sensitivity and specificity of 91% and 50%, respectively, with a positive predictive value of 86% and a negative predictive value of 63%.

Although the assay demonstrated 82% accuracy in detecting the presence or absence of disease, however, this didn't correlate with disease stage or tumor size. In addition, the greater sensitivity of the assay for residual disease compared with conventional clinical staging was accompanied by a higher false-negative rate, and a 7% false-positive rate.

The researchers noted that current are plagued with "inherent inaccuracies" and that the level of biomarker performance needed to make safe avoidance of radical cystectomy feasible is not known.

Retrospective studies indicate that 30-50% of patients with MIBC thought to have a (based on cystoscopy/biopsy, examination under anesthesia, and cross sectional-imaging) have disease recurrence or metastatic disease, or die from bladder cancer. Findings such as these underscore "the of clinical staging as currently practised," Abbosh and co-authors said.

"We propose tandem NTACT as a noninvasive urinary biomarker test to prospectively distinguish residual disease states in patients with bladder cancer after clinical intervention to be used as a clinical decision-making guide in SaRCA [safe radical cystectomy avoidance] algorithms. NTACT could also be used in conjunction with systematic endoscopic evaluation to detect residual urothelial carcinoma," the team suggested.

In the following interview, Abbosh, who works in the Nuclear Dynamics and Cancer Program, discussed the need to improve residual disease detection in post-NAC radical cystectomy candidates, and some of the work currently underway.

What events led to the development of this novel urine biopsy?

Abbosh: As an intern on morning rounds, I saw a patient with bladder cancer who had undergone radical cystectomy and was experiencing severe postop complications. The chief resident tried to reassure the patient by telling him that at least his resected bladder showed no evidence of cancer, and that he was cured. When the patient realized, perhaps correctly, that he would have been fine without the surgery, he became quite upset. That stuck with me.

Did your study produce any unexpected findings?

Abbosh: Only one result surprised me initially. In several patients whose radical cystectomy specimens showed no pathological evidence of disease, mutations were still detected in urine. The specificity was lower than expected, and we are now exploring possible reasons for this.

What's needed to further optimize NTACT, and what are the clinical implications of doing so?

Abbosh: The test needs to be more specific. If we can improve the accuracy of this test or similar tests, and validate it as a tool for clinical decision-making, it could be used as a way to identify prospective candidates for radical cystectomy who can safely avoid surgery.

What's next for your research?

Abbosh: In addition to looking at ways to increase the test's accuracy, we are working to identify optimal preservatives, and determine the test's potential in patients who have undergone different types of neoadjuvant therapy. We are also exploring how best to translate the test for clinical use. If we can do all this, we can potentially apply it to patients in a clinical trial setting.

Read the study here and expert commentary about it here.