ABSTRACT
BACKGROUND: Lenvatinib is widely used to treat unresectable and advanced thyroid carcinomas. We aimed to determine whether 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) performed 1 week after lenvatinib treatment initiation could predict treatment outcomes. RESULTS: This was a prospective, nonrandomised, multicentre study. Patients with pathologically confirmed differentiated thyroid carcinoma (DTC) and lesions refractory to radioiodine treatment were eligible for inclusion. Patients were treated with 24 mg lenvatinib as the initial dose and underwent PET/CT examination 1 week after treatment initiation. Contrast-enhanced CT was scheduled at least 4 weeks later as the gold standard for evaluation. The primary endpoint was to evaluate the discrimination power of maximum standardised uptake value (SUVmax) obtained by PET/CT compared to that obtained by contrast-enhanced CT. Evaluation was performed using the area under the receiver operating characteristic (ROC-AUC) curve. Twenty-one patients were included in this analysis. Receiver operating characteristic (ROC) curve analysis yielded an AUC of 0.714 for SUVmax after 1 week of lenvatinib treatment. The best cut-off value for the treatment response for SUVmax was 15.211. The sensitivity and specificity of this cut-off value were 0.583 and 0.857, respectively. The median progression-free survival was 26.3 months in patients with an under-cut-off value and 19.7 months in patients with an over-cut-off value (P = 0.078). CONCLUSIONS: The therapeutic effects of lenvatinib were detected earlier than those of CT because of decreased FDG uptake on PET/CT. PET/CT examination 1 week after the initiation of lenvatinib treatment may predict treatment outcomes in patients with DTC. TRIAL REGISTRATION: This trial was registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (number UMIN000022592) on 6 June, 2016.
ABSTRACT
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR-mutant non-small-cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR-mutant cells. Using EGFR-mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR-TKI treatment, we found that EGFR-mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first-generation EGFR-TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre-treatment samples. Monocyte-derived macrophages facilitated antibody-dependent cellular phagocytosis when EGFR-TKI-treated EGFR-mutant cells were incubated with anti-CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR-mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell-free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP-1 monocytes in a stimulator of interferon genes-dependent manner. Our study indicates that EGFR inhibition in EGFR-mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR-mutant NSCLC.
