Liquid biopsy has been developed as a non-invasive tool to detect circulating free DNA (cfDNA), circulating tumour DNA (ctDNA) [1] and circulating tumour cells (CTCs) [2] in patient blood to diagnose early-stage cancer and monitor treatment progression in advanced-stage cancers. The November issue of Molecular Oncology includes research on the clinical application of liquid biopsies in monitoringimmunotherapy responses of patients with advanced-stage non-small-cell lung cancer (NSCLC), which accounts for over 80% of all diagnosed lung cancers.  

Tumour cells often show dysregulation of immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1). PD-L1 binding to programmed death 1 (PD1) on T cells prevents immune responses against cancerous cells. Immune checkpoint inhibitors (ICIs), such as the PD-L1-specific Pembrolizumab and the PD1-specific Nivolumab, have proven to be valuable immunotherapy drugs for the treatment of NSCLC, but only a subset of patients with advanced NSCLC benefit from their use. So far, patients have been selected for treatment with ICIs based on the tumour PD-L1 expression levels, but new, non-invasive biomarkers are needed.

In their studies, Mondelo-Macía et al., [3] and van der Leest et al., [4] used liquid biopsy to assess the cfDNA and CTCs levels in patients before and during ICI treatment with Pembrolizumab or Nivolumab. The authors further applied this information to predict patient responsiveness to ICI.

Mondelo-Macía et al., [3] analyzed liquid biopsy samples from patients with advanced NSCLC prior to immunotherapy, as well as at weeks 6 and 12 after initiation of treatment with Pembrolizumab. Patients who experienced progression-free survival (PFS) had low baseline levels of CTCs Moreover, using quantitative PCR, the authors quantified cfDNA through the detection of the single-copy gene telomerase reverse transcriptase (hTERT) in the blood. Subsequently, they identified a subgroup of patients, where cfDNA levels were initially low, or decreased over treatment, and who were most likely to respond to pembrolizumab with a longer PFS.

van der Leest et al., [4] screened for ctDNA based on clinically relevant mutations of the primary tumours in a cohort of 100 patients with advanced NSCLC. After analyzing samples collected prior to or 4-6 weeks after initiation of ICI immunotherapy, the authors found that decreasing ctDNA levels, as identified by detecting tumour-specific KRAS mutations with highly sensitive droplet digital PCR (ddPCR), were associated with PFS.

Taken together, the results from these studies are a significant step forward in developing non-invasive techniques to predict which patients are most likely to respond positively to treatment.

 References

1 Filipska, M. and Rosell, R. (2021), Mutated circulating tumour DNA as a liquid biopsy in lung cancer detection and treatment. Mol Oncol, 15: 1667-1682

2 Labib, M. and Kelley, S.O. (2021), Circulating tumour cell profiling for precision oncology. Mol Oncol, 15: 1622-1646

3 Mondelo-Macía, P., García-González, J., León-Mateos, L., Anido, U., Aguín, S., Abdulkader, I., Sánchez-Ares, M., Abalo, A., Rodríguez-Casanova, A., Díaz-Lagares, Á., Lago-Lestón, R.M., Muinelo-Romay, L., López-López, R. and Díaz-Peña, R. (2021), Clinical potential of circulating free DNA and circulating tumour cells in patients with metastatic non-small-cell lung cancer treated with pembrolizumab. Mol Oncol.

4 van der Leest, P., Hiddinga, B., Miedema, A., Aguirre Azpurua, M.L., Rifaela, N., ter Elst, A., Timens, W., Groen, H.J.M., van Kempen, L.C., Hiltermann, T.J.N. and Schuuring, E. (2021), Circulating tumor DNA as a biomarker for monitoring early treatment responses of patients with advanced lung adenocarcinoma receiving immune checkpoint inhibitors. Mol Oncol.