Lung cancer, as the malignant tumor with the highest mortality rate worldwide, causes more than 1 million deaths per year and is one of the most important health problems in our society [1]. Of these, non-small cell lung cancer (NSCLC) is the most common type of pathology[2]. Radiotherapy is used in all stages of lung cancer treatment, with more than half of patients requiring at least one radical or palliative radiotherapy session [3]. However, rates of tumor regression and local control after radiotherapy may vary significantly between patients. Just as individual with the same disease diagnosis responds differently to drugs, the response to radiotherapy varies according to inherent genetic characteristics that are closely related to the hypoxic microenvironment, apoptosis and proliferation, and DNA damage repair4, 5, 6, 7.

A recent study found that non-synonymous mutations in several genes (including MET, FGFR family, and NOTCH2), deleterious mutations in PTEN, and dysfunction of the KEAP1-NRF2 pathway (including KEAP1, NFE2L2, and CUL3) are high-risk factors for recurrence of locally advanced NSCLC after radiotherapy[8]. However, the genetic variants in this study were detected based on tumor tissue samples. In clinical practice, tissue sampling is traumatic and the collection, preparation, and fixation of specimens are difficult and unstable. Moreover, biopsy tissue from different sites in the same patient may be heterogeneous, and it is difficult to capture all tumor mutations in one biopsy sampling [9]. "Liquid biopsy is a test method that uses blood as the test specimen to obtain tumor-related information. It has the advantages of low heterogeneity, good patient compliance, convenient sampling, and dynamic monitoring. Taus[10] et al. performed circulating tumor DNA（ctDNA） testing on the peripheral blood of 35 lung adenocarcinoma patients with histopathologically confirmed KRAS mutations before treatment, and the results showed that there was a strong consistency between tumor tissue-based detection of common mutated genes in lung cancer and plasma-based ctDNA. Therefore, plasma ctDNA can not only qualitatively and quantitatively, but also specifically detect common mutant genes, TMB, and other indicators.

This study aimed to explore the potential association of gene mutations or pathway mutations with radiotherapy response based on peripheral blood specimens using next-generation sequencing (NGS).