Chapter 7 244 as OS across two validation cohorts. In pooled analysis, a trend in better PFS was observed, and a significantly improved OS was demonstrated for patients categorized as “sensitive” compared to those categorized as “not sensitive”. For “resistant” versus “not resistant” patients, both PFS and OS were significant independent predictors. In contrast, our test did not show the ability to stratify patients based on treatment outcome within a historical cohort of patients treated with chemotherapy. Recently, Roder and colleagues conducted a blind and retrospective validation of our protein signature, now referred as the ‘Primary Immune Response’ (PIR) test, in the POPLAR and OAK trials60. This study also showed prolonged PFS and OS in the “not resistant” group compared to the “resistant” group in both cohorts. When comparing the “sensitive” and “not sensitive” groups, both PFS and OS demonstrated superiority in the POPLAR cohort. In the OAK cohort, only OS showed improvement, and these findings remained consistent even after adjusting for PD-L1 expression60. As previously described, it is of interest to assess the performance of the test in the present clinical setting, particularly considering that the standard first-line treatment for advanced NSCLC patients lacking targetable driver mutations now involves dual therapy comprising chemotherapy and pembrolizumab. Advanced-stage NSCLC patients harboring tumors with molecular alterations such as EGFR mutations, ALK and ROS1 rearrangements, or the BRAFV600E mutation are eligible for specific targeted therapies. Therefore, it is imperative that all newly diagnosed patients receive comprehensive molecular tumor profiling. Also, the detection of resistance mechanisms during treatment with tyrosine kinase inhibitors (TKI) can guide the next line of therapy. In chapter 6, we emphasize the utility of cell-free DNA (cfDNA) in the supernatant of pleural effusion as an alternative bio-source, rather than relying on the cell pellet. In this study, driver and resistance mutations were detected with high accuracy in patients with NSCLC, colon and appendiceal cancer using droplet digital PCR. Notably, the supernatant showed a consistently high level of concordance with the cell pellet. Interestingly, its sensitivity surpassed that of the cell pellet, as mutations could still be detected in the supernatant even tumor purity was very low. As a result, the analysis of cfDNA in the supernatant has been institutionally implemented at the Netherlands Cancer Institute.
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