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Accurate prediction of bladder-cancer response to neoadjuvant chemotherapy remains elusive

European Urology
Reuters Health - 10/09/2020 - Clinical restaging and tumor sequencing do not accurately indicate the response of muscle-invasive bladder cancer (MIBC) to neoadjuvant chemotherapy (NAC), according to a database study.

Many institutions undertake restaging evaluations after NAC and prior to consolidation therapy with radical cystectomy in patients with MIBC. Whether such evaluations accurately reflect individual patient responses to NAC remains unclear.

Dr. Russell E. N. Becker of Johns Hopkins Medicine, in Baltimore, Maryland, and colleagues evaluated the accuracy of endoscopic visual and tissue restaging after NAC and explored the prognostic value of tumor mutation analysis as an adjunct to post-NAC restaging protocols in their study of 114 patients with MIBC who underwent NAC followed by radical cystectomy.

The presence of residual MIBC on restaging transurethral resection (TUR) was only 27% sensitive (but 95% specific) for predicting residual MIBC at radical cystectomy, the researchers report in European Urology.

Ultimately, 41 patients (36%) were found to have been downstaged falsely on post-NAC restaging TUR.

Tumor sequencing identified mutations in 22 of 49 patients (45%) using the RETAIN gene panel and in 26 of 49 patients (53%) using the Alliance gene panel.

The distribution of pathologic staging at cystectomy was not associated with tumor mutation status, regardless of which gene panel was used.

Moreover, tumor mutational burden and mutation status were not associated with NAC response, and there was no association between tumor mutation status and overall survival.

"This study highlights the current inadequacy of molecular and clinical restaging after NAC, namely, the inability of post-NAC TUR, even when combined with knowledge of tumor mutation status, to accurately assess for residual muscle-invasive disease," the researchers conclude.

They add, "Caution must be taken when determining whether a patient has truly achieved a complete or a favorable response to NAC, and more accurate diagnostic and disease staging tools, including urine and tissue biomarkers, are needed to guide clinical trial design and facilitate safe selection of patients for post-NAC active surveillance versus standard consolidative therapy."

Dr. Peter C. Black of the University of British Columbia, in Vancouver, Canada, who previously found that molecular subtypes of MIBC could affect patient responses to NAC, told Reuters Health by email, "The new finding here, and the most interesting, is the fact that the rate of 'false downstaging' was the same in patients whose tumors contained a DNA damage repair (DDR) gene mutation. In other words, the risk of the cystectomy specimen harboring residual muscle-invasive disease (MIBC) when the restaging evaluation was negative did not differ between patients with or without DDR gene mutations."

"As highlighted in the manuscript, three clinical trials are using similar gene panels to determine that patients retain their bladder after neoadjuvant chemotherapy if they have a DDR mutation and demonstrate a complete clinical response," he explained. "The results of this study would indicate that there is a 17-19% risk that those patients will harbor MIBC, which would lead to failure of these trials if true."

"The trials have very strict stopping rules, and it is important that they be completed, but this type of study is important in informing the risk associated with that type of approach," said Dr. Black, who was not involved in the study.

Dr. Becker did not respond to a request for comments.

By Will Boggs MD

SOURCE: https://bit.ly/31R8XmE European Urology, online August 17, 2020.

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