Handbook of Targeted Cancer Therapy and Immunotherapy

104 coupled with low levels of ctDNA related to tumor burden, particularly for the early de tection of disease. Approximately 6,000 diploid genomic molecules are present in 4 mL of plasma, providing a sensitivity limit of 0.01%. Improvements in assay sensitivity with ultradeep sequencing techniques and use of NGS panels that enable use of large num bers of epigenetic and genetic markers are facilitating improvements in sensitivity. Preanalytical considerations for ctDNA analysis have been described previously (34). Other practical considerations of selecting and developing liquid biopsy platforms with high sensitivities ( > 95%) in order to detect very low tumor burden in the context of surveillance or MRD with maintaining high specificity ( > 99%) would be important to avoid false negatives and under treatment of patients. On the other hand, DNA aberrations from hematopoietic stem cells released into circulation increase with increasing age and can give rise to alterations in genes such as KRAS and TP53 , which are also found in CRC and thereby can contribute to false positives. The concomi tant use of bioinformatics tools to parse ctDNA-based genomic profiling can assist in limiting these incidences. Controlling for lead-time bias in these studies would be an important factor as well. These and other important practical considerations are discussed in greater detail in the recent whitepaper set forth by the National Cancer Institute colon and rectal-anal task forces (13).

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