ESMO issues guidance on liquid biopsy testing in clinical practice 

Circulating tumour DNA (ctDNA) assays are recommended in routine clinical practice in patients with advanced cancer provided their limitations are taken into account, new guidelines from ESMO state. 

Issued by the ESMO Precision Medicine Working Group the guidelines highlight the main aspects medical oncologists should consider before testing, when reading a report and then translating the findings into action. 

Published in the Annals of Oncology, the guidelines note that ctDNA assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. 

“Circulating tumour DNA (ctDNA) can theoretically give more information on the spatial and temporal heterogeneity of a tumour than traditional tissue genotyping, [but]  its use in routine clinical practice requires a careful attention to pre-analytical processing and the selection of the appropriate technology which may influence the results obtained,” the group cautions.

The clinical utility of validated and adequately sensitive ctDNA assays was most established in patients with advanced cancer where testing could identify actionable mutations to direct targeted therapy.

“The level of evidence for the clinical validity of ctDNA assays is such that validated and adequately sensitive ctDNA testing can be used in routine practice for advanced disease genotyping, provided that limitations are understood and taken into account,” the group wrote. 

One such limitation was incomplete sensitivity, with risk of false-negative results, the expert group noted.

“If an assay is used when interrogating for an actionable genetic aberration and shows an undetected result, this should be considered a ‘non-informative’ result and confirmation with tissue testing (reflex tissue testing) is advised,” they said.

For many cancer patients tissue-based testing was preferred because of the limitations of ctDNA assays detecting fusion events and copy number changes. 

However, they noted that ctDNA assays “may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate.”

In early-stage cancers the detection of molecular residual disease (MRD) or molecular relapse has high evidence of clinical validity in anticipating future relapse. Nevertheless, the clinical sensitivity of MRD detection with current assays shortly after completion of therapy was suboptimal and often ≤ 50%, the group said. 

“Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment,” they advised. 

Additional potential applications of ctDNA assays currently not recommended for routine practice include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. 

“New technologies currently in development, such as methylation pattern based sequencing, fragmentation pattern-based sequencing or novel ultra-sensitive mutation detection methods, have the potential to optimise utility in these new settings,” they wrote.

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