Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care

Abstract

The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real‐world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long‐term implementation in clinical workflows.

Targeted Sequencing of Human Satellite 2 Repeat Sequences in Plasma cfDNA Reveals Potential Breast Cancer Biomarkers

“…In CNV analysis of tumor samples, the relationship between the observed copy ratios and the true copy number is not linear, as bulk tumor samples are mixtures of billions of cells, including normal ones [ 49 ]. The same is true for plasma, as the fraction of DNA derived from tumor cells is low, sometimes less than 0.01% [ 50 , 51 ]. Thus, the total cfDNA concentration measured in the blood is not a reliable biomarker for tumor burden and is subject to significant technical and biological variability [ 52 ].…”

Diagnostic value of liquid biopsy in the era of precision medicine: 10 years of clinical evidence in cancer

“…Despite the tissue biopsy is a gold standard technique for cancer diagnosis and molecular characterization, the liquid biopsy can be a complementary and even an alternative tool, considering a good concordance between the two methods and the high specificity and the moderate sensitivity of the latest one [174,[219][220][221][222][223][224][225]. For these reasons, the companion diagnostic tests have spread in the routinely clinical practice, particularly when the tissue is unavailable or insufficient (to search clonal alterations) and to detect acquired resistance mechanisms to therapy (to search clonal and subclonal alterations) [199,226].…”

Circulating Tumor DNA: An Emerging Tool in Gastrointestinal Cancers

“…153 ctDNA reportedly has a 10-month lead time to imaging progression in CRC 154 ; however, in the real-world setting this seems to be anecdotal, mainly owing to a lack of consensus on optimal ctDNA sampling time. 155 Moreover, the use of variant allele frequency for specific mutations used for disease monitoring will be limited by assay sensitivity (especially in poor DNA shedding) or simply not feasible (for patients with "true-negative" results per tissue sequencing). To overcome this, other methods that are not dependent on somatic mutations (analysis of DNA fragments) are being explored.…”