乌鸦传媒

Circulating tumor DNA (ctDNA) was detectable and provided prognostic information in Wilms tumor, according to a preliminary study.

Brian Crompton, MD, of Dana Farber Cancer Institute in Boston, and colleagues used next-generation sequencing to retrospectively analyze banked serum and urine samples from 50 children with stages III or IV Wilms tumor enrolled in the Children's Oncology Group ARENA0533 trial. The researchers compared the results of their analyses with tumor biopsy data.

As shown in the study in the , the team detected ctDNA in the majority of serum (82%) but in less than half (26%) of the urine samples, and identified deletions of chromosomal arms 1p and 16q, and gains of 1q, in the ctDNA. These findings correlated with tumor samples in most, but not all, patients.

All recurrences and deaths occurred in patients who had detectable levels of ctDNA at the time of diagnosis. There was a trend toward worse 4-year event-free survival rates in patients with detectable ctDNA in serum compared with those without (80% vs 100%, P=0.14). There was also a trend toward worse 4-year overall survival (83% vs 100%, P=0.20). The researchers noted similar trends when ctDNA was detected in urine, but with a lower level of discrimination.

"This study demonstrates that ctDNA analysis may improve prognostication and risk-stratified treatment selection for patients with Wilms tumor with advantages of using minimally invasive technology and potential for overcoming challenges of tumor heterogeneity," Crompton and colleagues concluded.

The researchers were not available for an interview to discuss the details of the study; the following responses are taken from the text of the paper.

Why are better risk-stratification techniques needed for patients with Wilms tumors?

The past several decades of clinical trials for patients with WT [Wilms tumor] have resulted in a dramatic improvement in outcomes, with the majority of patients now cured. However, patients who experience relapses have a markedly worse outcome even when treated with intensified regimens.

Furthermore, emerging evidence demonstrates that the use of clinical measures of disease burden alone does not risk stratify as precisely as integration of histopathologic and molecular features of a patient's disease. It also remains unclear how to include molecular prognostic features present in only subclonal populations of tumor cells.

Ongoing efforts to implement these additional prognostic biomarkers of outcome suggest that improved precision of risk stratification could further reduce the rate of disease progression or relapse after initial therapy and mitigate risks of long-term toxicities by facilitating further intensity reduction for some patients without jeopardizing outcomes.

What did you find in terms of ctDNA in serum versus urine, and what are the implications of this?

We found that the majority of these patients shed sufficient levels of ctDNA into their serum to be reliably detectable by a low-sensitivity next-generation sequencing approach that identifies segmental and chromosomal copy-number variants. By contrast, only a minority of patients had detectable levels of ctDNA in their urine, suggesting that more sensitive assays or larger sample volumes may be needed to make urine-based liquid biopsies useful in this disease.

What were the ctDNA results for patients who were found to have anaplasia, and what are the potential implications?

We also found that all patients later found to have localized or diffuse anaplasia in their tumors at the time of surgery shed ctDNA into the serum and urine, further supporting the concept that detection of ctDNA by ULP-WGS [ultra-low-passage whole-genome sequencing] may be associated with more aggressive disease in patients with WT, an important finding to also validate in an expanded cohort.

Correlation between tumor profiling and ctDNA samples was high in your study, but there were also discrepancies. What does that suggest?

Although the level of correlation between tumor profiling and ctDNA samples was high, we also observed discrepancies between samples that suggest the presence of subclonal heterogeneity in these patients, most of whom had metastatic disease. In other cancers, ctDNA has been shown to better capture the presence of subclonal variants than solitary biopsies, especially in patients with metastatic disease.

In five cases from our study, we detected a 1q gain in the serum but not in the matched tumor, and in two cases, 1q gain was detected in the tumor but not the serum, even when samples were profiled by using the same technology, suggesting the possible utility of a more comprehensive profiling strategy for risk stratification at diagnosis. However, it is still unclear how to interpret the detection of these somatic events when present in subclonal fractions.

What are the main clinical implications of this study?

We demonstrated that somatic variants present in the tumor could be detected in the serum and urine of patients with detectable levels of ctDNA. These findings demonstrate the practice-changing potential of liquid biopsies to detect the presence of validated prognostic molecular events in the context of up-front chemotherapy without biopsy.

Read the study here.