Project description:Liquid biopsy has emerged as a minimally invasive alternative to tumor tissue analysis for the management of lung cancer patients, especially for epidermal growth factor receptor (EGFR) oncogene addicted tumor. In these patients, despite the clear benefits of tyrosine kinase inhibitors therapy, the development of acquired resistance and progressive disease is inevitable in most cases and liquid biopsy is important for molecular characterization at resistance and, being non-invasive, may be useful for disease monitoring. In this review, the authors will focus on the applications of liquid biopsy in EGFR-mutated non small cells lung cancer at diagnosis, during treatment and at progression, describing available data and possible future scenarios.

| S-EPMC9400718 | biostudies-literature

Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC.

Project description:The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2-7% of lung adenocarcinomas, with higher incidence (17-20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms.

| S-EPMC7563786 | biostudies-literature

Perioperative Chemo-Immunotherapy in Non-Oncogene-Addicted Resectable Non-Small Cell Lung Cancer (NSCLC): Italian Expert Panel Meeting.

Project description:BackgroundImmunotherapy (IO)-based strategies have been demonstrated to significantly prolong survival in the perioperative setting of non-oncogene-addicted non-small cell lung cancer (NSCLC). The adoption of such strategies in clinical practice depends on heterogeneous regulatory approvals and on the agreement between medical oncologists and thoracic surgeons on patients' selection.MethodsAn Expert Panel Meeting of medical oncologists and thoracic surgeons was held virtually by the Italian Association of Thoracic Oncology (AIOT) to discuss results of pivotal clinical trials with perioperative chemo-immunotherapy and reach agreement on open issues for the topic, formulating specific statements based on initially proposed discussion questions.ResultsOverall, panelists found agreement on seven statements. With regard to tissue and biomarker analysis, the role of increasing PD-L1 expression in predicting IO efficacy was recognized, whereas ctDNA and pCR were mainly attributed a prognostic role, in the absence of dedicated studies. The panelists acknowledged direct relationship between the benefit of neoadjuvant chemo-immunotherapy approaches and the local burden of disease/mediastinal node involvement, supporting the inclusion of these factors, together with PD-L1, in selecting upfront surgery or induction treatment. The panelists agreed that the current literature data do not answer the issue of assessing the role of the adjuvant phase within a perioperative treatment strategy. Surgical considerations on the role of pneumonectomy and other approaches were also discussed.ConclusionsThis experience highlights the importance of a synergistic approach between oncologists and surgeons to leverage the unmet needs in translating results of IO-perioperative clinical trials into clinical practice in patients with resectable NSCLC.

| S-EPMC11854886 | biostudies-literature

Oncogene Overdose: Too Much of a Bad Thing for Oncogene-Addicted Cancer Cells.

Project description:Acquired resistance to targeted inhibitors remains a major, and inevitable, obstacle in the treatment of oncogene-addicted cancers. Newer-generation inhibitors may help overcome resistance mutations, and inhibitor combinations can target parallel pathways, but durable benefit to patients remains elusive in most clinical scenarios. Now, recent studies suggest a third approach may be available in some cases-exploitation of oncogene overexpression that may arise to promote resistance. Here, we discuss the importance of maintaining oncogenic signaling at "just-right" levels in cells, with too much signaling, or oncogene overdose, being potentially as detrimental as too little. This is highlighted in particular by recent studies of mutant-BRAF in melanoma and the fusion kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) in anaplastic large cell lymphoma. Oncogene overdose may be exploitable to prolong tumor control through intermittent dosing in some cases, and studies of acute lymphoid leukemias suggest that it may be specifically pharmacologically inducible.

| S-EPMC4681422 | biostudies-literature

Immunotherapy in oncogene addicted non-small cell lung cancer.

Project description:The use of immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) has led to notable changes in treatment strategies for patients with advanced non-small cell lung cancer (NSCLC) and now forms a part of standard of care treatment in patients with advanced disease. However, most patients do not respond to ICI monotherapy, which may be explained by significant variations in efficacy according to different immune and molecular profiles in tumours. Improved response rates have been observed in smokers and are associated with tumors that have high mutation loads, with a higher tendency to form neoantigens. This premise itself defies the eventual significance of ICIs for oncogene-driven NSCLC, which in general are more common in never smokers and potentially have reduced capacity for neoantigen formation. Furthermore, pivotal trials investigating ICIs in advanced NSCLC have usually excluded patients with oncogenic drivers, hence the outcome of these agents in this population is poorly characterized. In this article, we aim to review the most current evidence, encompassing clinical and preclinical data focused on a wide range of oncogene-addicted NSCLCs.

| S-EPMC8264320 | biostudies-literature

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