ctDNA predicts relapse and response in bladder cancer
medwireNews: Ultra-deep sequencing of circulating tumor (ct)DNA is highly sensitive and specific for early risk stratification in patients with bladder cancer, predicting treatment response and identifying patients with early metastatic relapse, indicate findings reported in the Journal of Clinical Oncology.
“On the basis of these findings, new paradigms for ctDNA-guided patient management should be investigated in future clinical trials,” say Lars Dyrskjøt (Aarhus University Hospital, Denmark) and colleagues.
They assessed ctDNA in 68 patients with localized muscle-invasive urothelial bladder carcinoma from 656 plasma samples taken at diagnosis, during chemotherapy, before cystectomy, and during a median surveillance follow-up of 21 months.
They found that 24 patients testing positive for ctDNA, based on the presence of at least two out of 16 prespecified patient-specific somatic variants, before chemotherapy had a 46% rate of recurrence. This compared with a low rate of 3% in 35 patients testing negative, which the team suggests may make these patients “eligible for cystectomy without neoadjuvant chemotherapy.”
Patients testing positive for ctDNA after chemotherapy had a 75% rate of recurrence, compared with 11% for patients testing negative, while the corresponding rates after cystectomy were 76% and 0%.
In fact, ctDNA status after cystectomy was the strongest predictor of recurrence-free survival, even above lymph node status before cystectomy and pathologic downstaging, with a hazard ratio of 129.6.
“Detection of ctDNA after cystectomy serves as direct evidence of occult carcinoma cells and thus remnant disease,” propose the researchers.
In addition, analysis of serial ctDNA measurements as part of disease surveillance correctly identified patients with metastatic relapse with 100% sensitivity and 98% specificity, and at a median lead time of 96 days over that of conventional imaging.
This “provides a window of opportunity for earlier initiation of therapy, which could improve treatment efficacy and thereby survival,” say Dyrskjøt and colleagues.
The findings also suggest that ctDNA might have a role in measuring response to therapy, with its presence and dynamics correlated with pathologic downstaging. In total, 85% (35/41) of ctDNA-negative patients showed pathologic downstaging and among patients initially ctDNA positive but with subsequent clearance the response rate was 53% (9/17), compared with 0% (0/8) among patients without ctDNA clearance.
“[A]lthough pathologic downstaging is a strong predictor of outcome, ctDNA informs chemotherapy response and outcome during treatment and before cystectomy,” the researchers note.
They conclude: “Patients with ctDNA clearance, which suggests responsiveness to chemotherapy, may be offered additional cycles of chemotherapy before cystectomy. For patients without clearance of ctDNA, the potential benefits of other therapeutic strategies can be explored.”
By Catherine Booth
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