Predictive Value of Dynamic Changes in ctDNA, Baseline Biomarkers for MIBC

A team of researchers led by Matthew Nicholas Young, MD, BSc, performed an exploratory biomarker analysis using different definitions of circulating tumor DNA (ctDNA) response and assessed correlation with tissue response at time of cystectomy for patients receiving neoadjuvant atezolizumab in the ABACUS trial.

Results of this investigation were presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Multiple prospective clinical trials are exploring the prognostic significance of ctDNA in the neoadjuvant setting. Dynamic changes in ctDNA may be a surrogate marker of pathological complete response (pCR).

The ABACUS trial was a multicenter, single-arm, phase 2 examination of 2 cycles of atezolizumab before cystectomy in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or refused neoadjuvant cisplatin-based chemotherapy. Primary and secondary end point data were previously published.

Dr. Young and colleagues conducted an exploratory biomarker analysis of the ABACUS trial of different definitions of ctDNA response, assessed correlation with tissue response at time of cystectomy, and assessed how these definitions of response correlate with baseline biomarker expression. Patients with PD-L1, CD8, TMB, and sequential ctDNA measurements—at baseline and at cystectomy—were included.

Researchers performed ctDNA analysis using the Signatera assay, defined PD-L1 positivity as ≥5% of immune cell staining, assessed TMB using the FoundationOne CDx assay, and measured CD8 via immunohistochemistry analyses. Two definitions of ctDNA response were used: ctDNA clearance and a ≥50% reduction in ctDNA variant allele frequency (VAF).

Among the 40 patients who had sequential DNA analysis, 43% had pCR and 20% experienced relapse. Sixty-three percent of patients were ctDNA-positive at baseline, with 40% having a ctDNA response of 50% VAF reduction and 8% achieving ctDNA clearance.

Researchers further reported that 30% of patients who had VAF reduction experienced relapse and 40% achieved pCR. All patients with ctDNA clearance achieved pCR and none relapsed. There was no noted association between VAF reduction of 50% and tissue response (P=.24).

Additional analysis showed no association between a ctDNA reduction of 75% and pCR (P=.24). Baseline PD-L1 and TMB were not predictive of pCR or ctDNA response to neoadjuvant atezolizumab.

“ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response and relapse,” they concluded, adding that “combining immune tissue-based biomarkers with ctDNA does not appear to improve biomarker accuracy.”