Clinical Utility of Circulating Tumor DNA in Cancer

Liquid biopsy is detection of cell-free DNA (cfDNA) fragments in a patient’s blood that has several potential clinical applications, such as diagnosis, surveillance, and assessment of treatment response; a small fraction of cfDNA originating from tumor cells is known as circulating tumor DNA (ctDNA). At the 5th annual CCA Summit meeting, Pashtoon Kasi, MD, MS, discussed the different clinical applications of liquid biopsies including opportunities for precision medicine.¹

Cancer-related features such as mutations in ctDNA can be directly detected in blood independent of tumor alterations; however, only a small fraction of ctDNA contains mutations. The NILE study demonstrated the noninferiority of noninvasive liquid biopsy to conventional tissue biopsy for identifying targetable biomarkers in metastatic non–small cell lung cancer.² Dr Kasi noted that “cfDNA analysis as the first genomic testing approach would have identified 87% of the 89 biomarker-positive participants, compared with a rate of 67% using tissue testing first.”¹ Other advantages of using ctDNA to assess actionable mutations is quicker turnaround time and lower proportion of insufficient samples.¹ Comparing ctDNA sequencing (GOZILA, n=1687) versus tumor tissue sequencing (GI-SCREEN, n=5621), median time from receiving samples to reporting results was 7 days versus 19 days.³ Mutational burden on ctDNA testing may represent a surrogate marker of mismatch repair deficiency or microsatellite instability in patients.

Characterization of genomic alterations in patients with advanced cholangiocarcinoma (CCA; n=137) by ctDNA testing and tissue-based next-generation sequencing profiling found actionable alterations in CCA represents approximately 30% of total alterations.⁴ Of these, actionable mutations were found in 33.1% of patients in the ctDNA liquid biopsy cohort and 23.2% of the tissue biopsy cohort.⁴ The alterations included FGFR2 fusions, IDH1/2, BRAF-V600E, HER2, MET, BRCA1/2/ATM, PIK3CA, and ERRFI1. Moreover, well-designed hybrid capture-based ctDNA sequencing can detect a diverse array of potentially actionable and disease-relevant rearrangements across cancer types. Among 11% of liquid biopsies, 4553 predicted pathogenic rearrangements were detected in 61 genes, which may be targetable with existing or emerging therapies.

ctDNA may be used for the assessment of minimal residual disease (MRD) in patients with biliary tract cancer. ctDNA detection was shown to be significantly associated with the stage of disease. Therefore, assessment of MRD or ctDNA clearance during treatment would help identify patients at high risk for recurrence/metastasis.¹

ctDNA may be utilized to predict response to treatment. In contrast to protein markers that have a half-life of days, the half-life of ctDNA in circulation is measured in minutes/hours, allowing quicker readouts and correlations with treatment response. ctDNA levels have been shown to decrease >90% in 2 weeks in responding patients.¹

Shedding and amount of detectable ctDNA varies between different tumors, between different stages of the tumor, and by location of metastatic site. For example, liver metastases appear to shed the most DNA followed by the peritoneum and lung.¹ Moreover, surgical trauma was associated with elevated cfDNA levels that persist for up to 6 weeks, which masks ctDNA detection.⁵

These data support the use of liquid biopsy molecular profiling to identify actionable alterations and guide therapy selection in patients with advanced CCA, and suggest that liquid biopsy can identify additional patients who are missed by conventional tissue biopsy testing. As for future directions, research efforts are focused on refining current methods or developing novel methodologies, such as a targeted methylation-based multicancer early detection test, to move this field forward.¹

Sources:

1. Kasi PM. ctDNA. Presented at: 5th Annual CCA Summit Meeting, October 19-21, 2023; Scottsdale, AZ.
2. Page RD, Drusbosky LM, Dada H, et al. Clinical outcomes for plasma-based comprehensive genomic profiling versus standard-of-care tissue testing in advanced non-small cell lung cancer. Clin Lung Cancer. 2022;23(1):72-81.
3. Nakamura Y, Taniguchi H, Ikeda M, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26:1859-1864.
4. Kasi PM, Le AD, Barret A. Comparative landscape of actionable somatic alterations in advanced cholangiocarcinoma from circulating tumor and tissue-based DNA profiling. J Clin Oncol. 2021;39(suppl 3):abstr 342.
5. Henriksen TV, Reinert T, Christensen E, et al. The effect of surgical trauma on circulating free DNA levels in cancer patients-implications for studies of circulating tumor DNA. Mol Oncol. 2020;14(8):1670-1679.