NEW YORK – The European Society for Medical Oncology released new recommendations Thursday on the use of circulating tumor DNA assays in cancer patients.
Developed by the society's Precision Medicine Working Group and published in the ESMO journal Annals of Oncology, the new recommendations endorse liquid biopsies as a standard of care for genotyping and treatment selection for many patients with advanced cancer.
Tests that are validated and properly sensitive "may be used in routine clinical practice, provided the limitations of the assays are taken into account," the authors wrote. According to the group, tissue-based testing should remain a first choice for many, due to limitations of ctDNA assays in detecting fusion events and copy number changes. However, ctDNA assays become preferable when faster results will be clinically important or when tissue biopsies are either inappropriate or impossible.
For oncologists, ESMO said the choice between PCR and NGS assays should be defined by availability, reimbursement status, and the number of "tier I actionable genetic aberrations" for each individual tumor type.
As leaders have cautioned from the first inception of liquid biopsy profiling tests, the ESMO guidelines endorse taking a negative ctDNA result with caution and reflexing, if possible, to a tumor tissue analysis. However, the authors said that alternative confirmation methods — based on analysis of overall ctDNA levels or the allele frequency of detected variants — can be employed by expert users to confirm true negatives.
Although the authors called it an active area of research, ESMO currently recommends against using blood-based calculations of tumor mutational burden on their own to select patients for immunotherapy, due to the sensitivity of this measure to the amount of ctDNA present and the presence of subclonal and hematopoietic variants.
For more recent applications of liquid biopsy, ESMO's recommendations include a nod to molecular testing of minimal residual disease in early-stage cancer patients, which authors wrote has "high evidence of clinical validity," for predicting relapse but cannot yet be recommended in routine clinical practice due to a lack of clinical utility data regarding specific treatment interventions.
Citing data from recent studies in early-stage lung and bladder cancer, the ESMO group noted that the most obvious potential utility for ctDNA MRD assays is in personalizing adjuvant treatment in the MRD-positive patients who might derive the most benefit. Definitive proof of this will require randomized trials, several of which are now underway.
In their publication, the authors outlined a number of specific recommendations for these and other liquid biopsy utility studies in early-stage, surgically resected cancer patients.
ESMO also recommended against using ctDNA assays to track patients' treatment responses, identify non-responders, monitor emerging resistance mutations, or screen asymptomatic populations for incipient cancer.
According to the working group authors, "randomized interventional studies are required to assess whether changes of treatment on the basis of ctDNA dynamics assessment can improve outcome."
Further studies are also needed "to define the optimal timing of ctDNA dynamic assessment and the most accurate threshold for response prediction," as well as to define the frequency of monitoring in the case of serial testing.
"Data are awaited from large studies conducted in true screening populations to assess ctDNA assays as a multi-cancer screening tool, but at this point screening cannot be considered as a validated use for ctDNA assays," the group added.