Integrated circulating tumour DNA and cytokine analysis for therapy monitoring of ALK-rearranged lung adenocarcinoma

Abstract

Background Detection of circulating tumour DNA (ctDNA) in biological fluids is a minimally invasive alternative to tissue biopsy for therapy monitoring. Cytokines are released in the tumour microenvironment to influence inflammation and tumorigenic mechanisms. Here, we investigated the potential biomarker utility of circulating cytokines vis-à-vis ctDNA in ALK-rearranged+ lung adenocarcinoma (ALK + NSCLC) and explored the optimal combination of molecular parameters that could indicate disease progression. Methods Longitudinal serum samples (n = 296) were collected from ALK + NSCLC patients (n = 38) under tyrosine kinase inhibitor (TKI) therapy and assayed to quantify eight cytokines: IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12p70, MCP1 and TNF-α. Generalised linear mixed-effect modelling was performed to test the performance of different combinations of cytokines and previously determined ctDNA parameters in identifying progressive disease. Results Serum IL-6, IL-8 and IL-10 were elevated at progressive disease, with IL-8 having the most significant impact as a biomarker. Integrating changes in IL-8 with ctDNA parameters maximised the performance of the classifiers in identifying disease progression, but this did not significantly outperform the model based on ctDNA alone. Conclusions Serum cytokine levels are potential disease progression markers in ALK + NSCLC. Further validation in a larger and prospective cohort is necessary to determine whether the addition of cytokine evaluation could improve current tumour monitoring modalities in the clinical setting.

Unraveling the Potential of ALK-Targeted Therapies in Non-Small Cell Lung Cancer: Comprehensive Insights and Future Directions

“…Although the combination of alterations in IL-8 alongside circulating tumor DNA parameters enhanced the ability to detect disease progression, it did not exceed the accuracy achieved by using circulating tumor DNA alone. This study suggested that serum cytokine levels might indicate disease progression in ALK+ NSCLC, potentially enhancing current monitoring methods pending further confirmation in more extensive studies (Figure 6) [112].…”

NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia

“…These cytokines were selected because their secretion is influenced by NF-κB activation and they were linked to cancer cell propagation and survival [24,[98][99][100]. Furthermore, their secretion in A549 cells is wellcharacterized and their serum levels can be used as biomarkers of progression in lung cancer patients [101][102][103]. Recently, many studies tie the release of pro-inflammatory cytokines such as IL-6 and IL-8 with the activation of the cGAS-STING pathway in response to DNA double-strand breaks such as those induced by ionizing radiation [104][105][106][107].…”

Changes in serum CXCL13 levels are associated with outcomes of Colorectal Cancer Patients Undergoing First-Line Oxaliplatin-Based Treatment

“…This subsequently results in heightened expression and secretion of CXCL8 10 . Furthermore, other studies have reported increased levels of CXCL8 in blood samples from NSCLC patients that do not respond to tyrosine kinase inhibitors or anti-PD1 therapy and in blood samples from melanoma patients that do not respond to anti-PD1 therapy 30,31 . These findings may be related to the fact that patients with liver and lung metastases had higher baseline levels of CXCL8 in comparison to those with metastases only in liver, lung or in other sites.…”