Genetic Mutations May Predict Chemo Response in Bladder Cancer

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Certain genetic mutations were associated with better responses to presurgical chemotherapy in muscle-invasive bladder cancer.

Image of DNA strands and a person touching one with a surgical instrument.

Three specific genetic mutations associated with DNA damage repair may help prevent unnecessary surgeries from occurring.

A genetic mutation in one of three genes associated with DNA damage repair was associated with improved outcomes to presurgical chemotherapy in localized muscle-invasive bladder cancer, according to recent research published in the journal, European Urology.

These findings, if validated, may one day help prevent patients with bladder cancer from undergoing unnecessary surgeries, according to the researchers.

More specifically, the study findings showed that patients whose tumors had mutations in the ERCC2, ATM or RB1 genes were five times more likely to achieve a pathologic complete response (meaning that tissue samples showed no signs of cancer) to presurgical chemotherapy than those without mutations in any of the genes.

The researchers on the study analyzed 105 tumor samples collected during the S1314 trial — the primary results of which were published in Clinical Cancer Research in 2021 — that had not yet undergone neoadjuvant (presurgical) cisplatin-based chemotherapy. Patients then underwent chemotherapy (gemcitabine and cisplatin) followed by surgery. The researchers analyzed the tissue that was surgically removed, too.

“We found that a mutation in any one of these four genes predicted for pT0 at surgery,” the researchers wrote in their findings. Of note, pT0 can be synonymous with pathologic complete response.

The researchers decided to conduct this trial to validate findings from the previous SWOG S8710 trial, which showed similar results, though not quite as strong of an association.

“The SWOG S8710 randomized trial provided Level 1 evidence supporting the use of neoadjuvant chemotherapy in eligible patients with muscle-invasive bladder cancer, but uptake was disappointing because the magnitude of the effect was considered modest,” David James McConkey, of Johns Hopkins Greenberg Bladder Cancer Institute, senior author on the European Urology article, said in a press release about the findings.

McConkey continued, “So we designed the S1314 COXEN trial to test whether a tumor biomarker known as the COXEN score could predict which patients had tumors that were likely to respond to neoadjuvant chemotherapy.”

According to the earlier S1314 trial, COXEN is a certain model of gene expression.

Researchers are hoping that these findings — which will be further studied in the RETAIN trial — can one day be useful in determining which patients need to undergo cystectomy (surgical removal of the bladder) and which patients can skip the surgery.

“The evolution of more effective systemic neoadjuvant therapies in conjunction with innovative tools such as urine-based tests for detection and monitoring patients on bladder surveillance will build on this work toward a goal of avoiding cystectomy in cases where radical surgery is not required to achieve [a] cure,” Dr. Elizabeth R. Plimack, of Fox Chase Cancer Center, lead author of the new work, said in the press release.

“We conclude that this biomarker test, when combined with careful clinical assessment, can be used to allocate patients to careful bladder surveillance instead of surgery,” the researchers wrote.

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