In ongoing efforts to better understand the predictive value of circulating tumor DNA (ctDNA) in cancer treatment response, new research shows ctDNA clearance following neoadjuvant treatment of muscle-invasive urothelial cancer is a better predictor of the risk of relapse than a 50% reduction in ctDNA variant allele frequency (VAF).
The combination of ctDNA with other baseline biomarkers shows further accuracy in predicting treatment response, the study also shows.
Matthew Nicholas Young, MD, of Barts Cancer Institute, London, presented the research at the ASCO Genitourinary Cancers Symposium.
“We found that ctDNA and tissue-based biomarkers improved biomarker accuracy,” Dr Young, first author of the study, said at the meeting.
Furthermore, “ctDNA clearance is rare but appears more accurate than 50% reduction in VAF to predict response/relapse,” the authors said in their abstract.
“This is relevant for ongoing neoadjuvant trials planning to use this as an endpoint,” they wrote.
Dr Young and his colleagues have previously shown ctDNA clearance to be an important predictive marker of treatment response or relapse.
To better understand the predictive value in combination with other biomarkers, as well as whether a reduction in ctDNA variant allele frequency could be used as a surrogate predictor of relapse compared with ctDNA clearance, the authors conducted an exploratory biomarker analysis of the phase 2, multicenter ABACUS trial.
Methods and Results
In the study, 95 patients with inoperable, muscle-invasive urothelial cancer who were either not eligible for or refused neoadjuvant cisplatin-based chemotherapy, each received two cycles of atezolizumab, followed by radical cystectomy.
Previously published results show the study met its primary endpoint of a pathological complete response (pCR) of 31%, and the 2-year disease-free survival and overall survival rates were 68% and 77%, respectively.
Of the 95 patients, 40 had sequential DNA analysis that could be evaluated in the current analysis; 43% of those patients achieved a pCR, while 20% experienced a relapse.
At baseline, 63% of patients were ctDNA-positive, and after treatment, 8% achieved ctDNA clearance, while 40% had a ctDNA response of a 50% VAF reduction.
All patients who had ctDNA clearance achieved pCR and none relapsed. In comparison, 30% of patients with a 50% VAF reduction experienced relapse and only 40% achieved pCR.
In terms of correlations with baseline biomarkers, the combination of ctDNA with activated T cells was significantly associated with outcomes (P = .02), as was the combination with PDL-1 status (P = .004).
However, combination with tumor mutation burden, already weak as a predictive biomarker, remained weak when combined with ctDNA status (P = .2), Dr Young reported.
In terms of baseline expression of ctDNA, patients who were positive at baseline showed an increase in innate and adaptive immune signaling, in a profile aligning with increased PD-L1 at baseline in ctDNA-positive patients.
In addition, decreased immune signaling was observed in ctDNA-positive patients who relapsed.
Results May Be ‘Hypothesis-Generating’
Asked during the session whether the results imply that patients with no detectable ctDNA prior to the start of therapy may not need or benefit from neoadjuvant therapy, Dr Young said the small sample size of ctDNA patients in the study was an important limitation.
“I think [the results] are hypothesis-generating, as we know that some patients will not benefit from neoadjuvant therapy and the goal of this work is to try to identify patterns among those who may not need treatment,” he said.
Of the patients with ctDNA analysis, “only those who were ctDNA-positive at baseline relapsed, [as well as] those who were ctDNA-positive following cystectomy, so I think [the possibility that a lack of detectable ctDNA prior to the start of therapy could suggest that the patient may not need or benefit from neoadjuvant therapy] is an interesting hypothesis that has come from this work,” Dr Young said.
Overall, the findings show that, “in ctDNA-positive patients, increased immune signals appear to be associated with better outcomes with atezolizumab,” he concluded.
“Combining immune and circulating biomarkers may be required to accurately predict response to therapy,” Dr Young added.
The ABACUS trial was supported by Roche.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
Source link : https://www.medscape.com/s/viewarticle/ctdna-clearance-strong-predictor-relapse-risk-therapy-2024a1000222?src=rss
Publish date : 2024-01-30 12:18:19
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