Extracellular vesicle Tspan8 levels in pretreatment serum from patients with NSCLC predict distant metastasis–free survival.

Exposure to cancer therapies is associated with an increased risk of clonal hematopoiesis (CH). The objective of our study was to investigate the genesis and evolution of CH after cancer therapy. In this prospective study, we undertook error-corrected duplex DNA sequencing in blood samples collected before and at 2 time points after chemoradiation in patients with esophageal or lung cancer recruited from 2013 to 2018. We applied a customized workflow to identify the earliest changes in CH mutation count and clone size and determine their association with clinical outcomes. Our study included 29 patients (87 samples). Their median age was 67 years, and 76% (n = 22) were male; the median follow-up period was 3.9 years. The most mutated genes were DNMT3A, TET2, TP53, and ASXL1. We observed a twofold increase in the number of mutations from before to after treatment in TP53, which differed from all other genes examined (P < .001). Among mutations detected before and after treatment, we observed an increased clone size in 38% and a decreased clone size in 5% of TP53 mutations (odds ratio, 3.7; 95% confidence interval [CI], 1.75-7.84; P < .001). Changes in mutation count and clone size were not observed in other genes. Individuals with an increase in the number of TP53 mutations after chemoradiation experienced shorter overall survival (hazard ratio, 7.07; 95% CI, 1.50-33.46; P = .014). In summary, we found an increase in the number and size of TP53 CH clones after chemoradiation that were associated with adverse clinical outcomes.

The aim of our study is to characterize the risk of radiation-induced esophagitis (RE) in a cohort of Non-Small-Cell Lung Cancer (NSCLC) patients treated with concurrent chemotherapy and photon/proton therapy. For each patient, the RE was graded according to the CTCAE v.3. The esophageal dose-volume histograms (DVHs) were extracted. Voxel-based analyses (VBAs) were performed to assess the spatial patterns of the dose differences between patients with and without RE of grade ≥ 2. Two hierarchical NTCP models were developed by multivariable stepwise logistic regression based on non-dosimetric factors and on the DVH metrics for the whole esophagus and its anatomical subsites identified by the VBA. In the 173 analyzed patients, 76 (44%) developed RE of grade ≥ 2 at a median follow-up time of 31 days. The VBA identified regions of significant association between dose and RE in a region encompassing the thoracic esophagus. We developed two NTCP models, including the RT modality and a dosimetric factor: V_55Gy for the model related to the whole esophagus, and the mean dose for the model designed on the thoracic esophagus. The cross-validated performance showed good predictions for both models (ROC-AUC of 0.70 and 0.73, respectively). The only slight improvement provided by the analysis of the thoracic esophageal subsites might be due to the relevant sparing of cervical and lower thoracic esophagus in the analyzed cohort. Further studies on larger cohorts and a more heterogeneous set of dose distributions are needed to validate these preliminary findings and shed further light on the spatial patterns of RE development.

PURPOSE: Current diagnostic methods to determine programmed death 1 (PD-1) receptor and its ligand (PD-L1)/PD-1 immunotherapy (immune checkpoint inhibitor [ICI]) efficacy in recurrent or metastatic non–small-cell lung carcinoma (rmNSCLC) are imprecise. Although previously shown that patients with high tumor PD-L1 (≥ 50%) demonstrate clinical benefit in the form of disease reduction and improved survival, patients with low PD-L1 (< 50%) sometimes benefit from treatment. Since the PD-L1/PD-1 pathway is dynamic, monitoring PD-L1 levels during treatment may be more accurate than a static baseline tumor biopsy; however, rebiopsying the primary or metastatic disease is rarely feasible. Liquid biopsies that measure the upregulation of PD-L1 on tumor-associated cells (TACs), ie, cancer-associated macrophage-like cells and circulating tumor cells, have been performed, but their predictive value for ICI therapy efficacy is unknown. MATERIALS AND METHODS: We initiated a single-blind prospective study to evaluate TAC PD-L1 expression changes in rmNSCLC from blood samples before (T0) and after (T1) treatment with ICI (ICI, n = 41) or without ICI (no ICI, n = 41). Anonymized blood was filtered to isolate TACs, which were then quantified for high/low PD-L1 expression. Progression-free survival (PFS) or overall survival (OS) hazard ratios (HRs) were evaluated at 18 and 24 months by censored univariate analysis. RESULTS: Increased TAC PD-L1 expression between T0 and T1 in patients who were not treated with ICI had no relationship with PFS or OS. However, increased TAC PD-L1 expression between T0 and T1 in patients treated with ICI had significantly better PFS (HR, 3.49; 95% CI, 1.5 to 8.3; P = .0091) and OS (HR, 3.058; 95% CI, 1.2 to 7.9; P = .0410). CONCLUSION: Blood-based monitoring of dynamic changes in PD-L1 in TACs appears to identify patients with rmNSCLC who may benefit from ICI.