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After a hiatus in November, we resume our Lung Cancer Worldwide series with the twenty-eighth installment focusing on Lung Cancer in South Korea. Dr Park and colleagues provide a comprehensive overview of lung cancer screening, diagnosis and treatment in South Korea.
Although two large phase III studies, the US National Lung Cancer Screening Trial and the Dutch-Belgian Randomized Lung Cancer Screening Trial (Dutch acronym: NELSON), have shown an improved survival with the use of low dose computed tomography screening in high-risk individuals, the uptake of lung cancer screening in high risk individuals has been slow. In this issue of the journal, Quiafe and colleagues report the results of a prospective study evaluating psychological factors associated with screening uptake behavior among participants invited to the Lung Health Check within the SUMMIT lung cancer screening trial, a multi-center screening implementation trial in the UK. Their results indicate that higher odds of uptake were associated with both positive and negative perceptions. These results provide guidance for future interventions to improve screening uptake, which should include addressing participants perceptions and other psychological factors.
Small molecule kinase inhibitors have revolutionized non-small cell lung cancer (NSCLC) care. Objective response (OR) rates after therapy are high and survival has more than tripled. However, with increased efficacy and chronic therapy, a number of organ toxicities continue to emerge. In this context, Waliany and colleagues set out to evaluate cardiac toxicity of kinase inhibitors by using the World Health Organization pharmacovigilance database to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between 4 classes of kinase inhibitors - EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib). Results indicate that ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. As well, osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. These are important safety data and should lead practitioners to monitor for heart failure and arrhythmias with NSCLC targeted therapies, especially osimertinib.
Brigatinib is approved in a number of countries for the first-line therapy of ALK rearranged NSCLC, based on objective response and progression free survival benefit, compared to crizotinib in the ALTA-1L trial. In this issue, Camidge and colleagues present final efficacy and safety results from this trial. After a median follow-up of 40 months brigatinib has significantly better PFS compared with crizotinib, with a 52% reduction in the risk of progression or death (HR: 0.48). Overall response (OS) data are still immature in both arms (HR: 0.81); however, post hoc analyses suggest an OS benefit for brigatinib compared with crizotinib in patients with baseline brain metastases (HR: 0.43). In addition, brigatinib demonstrated better efficacy compared with crizotinib across EML4- ALK fusion variants and in patients with and without the TP53 mutation, which is known to negatively affect treatment outcomes. These results should help investigators with their therapeutic choices in jurisdictions where brigatinib is approved.
A mechanism of MET activation, MET exon 14 skipping (METex14), including base substitutions and insertions/deletions at the splice donor and acceptor sites, and whole exon 14 deletion, have been described. However, due to complexity of MET exon 14 mutations, next‐generation DNA-based sequencing methods as well as next generation RNA-based testing have been applied to detect MET exon 14 genomic variants. In an elegant study with 50 specimens, Teishikata and colleagues analyzed samples with 3 available testing platforms, (Oncomine DxTT, ArcherMET and a laboratory developed test -LDT RT-PCR-) to identify METex14 skipping. Twenty-four cases were negative by all the 3 tests, 18 cases were positive for all tests, whereas in 8 cases ArcherMET and the LDT RT-PCR produced concordant negative results, whereas the third assay (Oncomine Dx TT) showed positivity, discordant with the other results. These results are important and need to be validated, since the implications for patient care could be far-reaching. Until now, most of the caution regarding detection of METex14 skipping has focused on false negatives. This study indicates there could be false positives, leading to an apparent lack of efficacy with available MET inhibitors. Along these lines, clinicians should consider that the clinical characteristics of MET mutant NSCLC can be distinctly different from the other oncogenic drivers. Patients tend to be older, and may be smokers. Occasionally squamous cell lung cancers are also encountered. Drs Buglioni and Marino discuss the implications of these findings in an exceptional accompanying editorial.
Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer, is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies. JTO emphasizes a multidisciplinary approach and includes original research reviews and opinion pieces. The audience includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology. The journal is interested in receiving manuscripts dealing with epidemiology, prevention, screening, early detection, staging, cure, and treatment of thoracic malignancies. More
TME in EGFR-mutated lung cancer. Activation of EGFR leads to the up-regulation of IL-6, IL-10, and VEGF by means of JAK/STAT3 signaling pathway. IL-10 subsequently binds to IL-10RA to induce downstream phosphorylated Src and JAK1 which positively regulate each other to enhance STAT3 activity in EGFR-mutated tumor cell. IL-10 and EGFR regulate each other through positive feedback to promote lung cancer formation. Hypersecretion of IL-6 triggers IL-6/gp130/STAT3 signaling in DC to suppress its maturation and promote IDO production. IDO exerts its suppressive function in multiple ways. IDO could generate tumor-specific Treg cells and maintain the immunosuppressive function of Treg cells. More