4. Discussion
NSCLC, tumor, cancers, tumor-related, tumors
TUMOR, CANCERS, NSCLC, TUMORS, SOMATIC MUTATIONS
This study was a single-arm, prospective, observational study and a comprehensive analysis of blood samples as predictive biomarkers for atezolizumab response in previously treated patients with advanced NSCLC. In this study, baseline cfDNA concentration and dynamic change in the hVAF and VAFSD were significant predictors of DCB. Furthermore, a high level of cfDNA concentration at the baseline, an increased level of bTMB from the baseline to the first response assessment or EOT and a high VAFSD at the baseline were significant risk factors for decreased PFS and OS.Pretreatment ctDNA level, especially bTMB, is known as a surrogate marker of tumor load, and the identification of tumor-related mutations using ctDNA can assist in predicting the ICI response in metastatic solid cancers [In contrast, monitoring dynamic changes in ctDNA could be an alternative for enhancing the utility of the bTMB. In a meta-analysis of ten previous studies, early reduction of ctDNA was associated with improved PFS, OS, and ORR in advanced NSCLC patients treated with ICIs; however, the baseline level of ctDNA was irrelevant to the clinical outcomes [In a recent biomarker study using POPLAR, OAK and other validation cohorts, the maximum somatic allele frequency (MSAF), defined as the maximum allele frequency (AF) of all the somatic mutations identified per sample by NGS, was adopted in the study to adjust the bTMB for MSAF interference [Intratumoral heterogeneity (ITH) is a major cause of anticancer treatment failure, including resistance to ICIs [This study had several limitations. First, compared with the baseline, there were limited numbers of paired C4/EOT samples. The insufficient number of on-treatment samples might have affected the predictive power of the dynamic changes in the novel biomarkers. Second, the timing of the on-treatment sampling varied but was mainly from eight to nine weeks, and blood sampling from three to six weeks was not mandatory in this study. Validation of the reproducibility of the biomarker candidates might be necessary for the earlier phase of treatment before the first imaging study. Finally, the mutation profiling in the ctDNA BEP did not reveal any specific mutations related to the efficacy of the ICI treatment. The genetic ITH or compound mutations developed after a previous anticancer treatment may have affected the indistinct distribution of mutations. A comprehensive mutational profiling comparing tumor tissue and plasma is warranted in a larger prospective cohort. Furthermore, larger clinical trials, including different types of tumors and ICIs, are needed to validate the utility and versatility of these blood-based biomarkers.