Progress meets resistance

Abstract

A diagnosis of lung cancer at the end of the 20th century was associated with a dismal prognosis, and few targeted treatment options were available beyond the rather blunt instruments of cytotoxic chemotherapy, surgery, or radiotherapy. This situation contrasts with the current status in 2013, where there is a growing list of new and potentially effective biological agents and targets for selected patients, and where improvements in staging and imaging, as well as refinements in surgery and the delivery of radiotherapy have been made. Biological agents have been predominantly effective in patients with the adenocarcinoma subtype of non-small-cell lung cancer (NSCLC). However, this situation might change with the announcement on Aug 13, 2013, by Eli Lilly & Co, that a new biological drug, necitumumab, added to gemcitabine and cisplatin as first-line treatment, has met its primary endpoint of improved overall survival in a phase 3 trial of patients with metastatic squamous NSCLC—an exciting finding because, traditionally, targeted agents have been ineffective in patients with this histology. The company aims to submit its findings to the regulators in 2014. Coincident with this announcement, a preclinical study in Oncogene reported that PARP inhibitors, which target DNA-damaging pathways and are being assessed in trials of breast and ovarian cancers, might add another weapon to the treatment armamentarium for selected patients with lung cancer, provided these findings are confirmed in clinical trials. Despite such progress, prognosis for patients remains grim, with a median overall survival of around 12–18 months in recent clinical trials in advanced disease. Moreover, lung cancer remains the number one cause of cancer mortality in many high-income countries, where several clinical challenges remain, including identifying high-risk groups to screen for earlier diagnosis by CT, selecting patients who might respond to targeted therapy so that the treatment effect is not diluted, and obtaining adequate, sufficient, and serial tissue biopsies. For some new treatments, a large proportion of patients do not have the pertinent treatment target, and assay results identifying the target can vary when completed outside of specialist centres. Thus, the European Society of Medical Oncology has recommended quality assurance procedures are put in place for these assays, and the UK NICE has provided recent guidance on which mutant EGFR tests to use in NSCLC. However, the cost of both the agents and assays can be prohibitive, restricting treatment to those with deep pockets and robust health-care systems. For this reason, The Lancet and The Lancet Respiratory Medicine have devoted a session to lung cancer at the forthcoming ERS 2013 meeting in Barcelona, and have published papers that discuss these issues in detail. Topics include immunotherapy, screening for earlier diagnosis, patient management, and tumour biomarkers and genetics, and we hope that this Series will help to further unpick the disease development pathways involved, identify gaps in research and treatment, and improve clinical outcomes. With the excitement of new therapies comes the new and unwelcome challenge of acquired resistance to treatment, as discussed in two of The Lancet papers. The authors note two main pathways to resistance, one through additional mutation or amplification of the target gene so that the patient no longer responds to treatment, and the other, a so-called bypass mechanism, in which a parallel pathway is activated that affects downstream signalling rendering the initial target redundant. Examples of resistance include secondary EGFR Thr790Met mutation, MET amplification, AXL kinase activation, and loss of the mutant EGFR allele. Recent progress in new drug development has been fuelled by a greater understanding of the pathways of disease development and individual susceptibility, and such knowledge will be key to unlocking and overcoming this new threat of resistance. To this end, in July, 2013, Cancer Research UK announced the funding of a 9-year study in 850 patients looking at the genomics of patients' lung cancers. The multicentre national study, TRACERx (Tracking Cancer Evolution through Therapy), will analyse samples taken before and after surgery, and later in the treatment pathway at disease recurrence, to elucidate changes in the patient's genomic profile over time. Samples will also be taken from different areas of the tumour to try and account for the known heterogeneity that is found within a patient's tumour and which often hampers appropriate treatment choices. Biological resistance is an insidious new enemy for patients with lung cancer. Further research into the mechanisms of resistance is essential to allow progress to continue on its way. Lung cancer: potential targets for immunotherapyLung cancer is the most common cause of cancer-related mortality worldwide and a therapeutic challenge. Recent success with antibodies blocking immune checkpoints in non-small-cell lung cancers (NSCLC) highlights the potential of immunotherapy for lung cancer treatment, and the need for trials of combination regimens of immunotherapy plus chemotherapy that lead to immunogenic cell death. Here, we review the development of immunogenic cytotoxic compounds, vaccines, and antibodies in NSCLC, in view of their integration into personalised oncology. Full-Text PDF Lung cancer: a global scourgeWorldwide, lung cancer killed about 1·5 million people in 2010. Lung cancer has an extremely poor prognosis, with an overall 5 year survival of 16% in the USA and less than 10% in the UK. To achieve a substantial reduction in lung cancer mortality, global action and progress in prevention, early detection, and treatment are crucial. Full-Text PDF Management of non-small-cell lung cancer: recent developmentsNon-small-cell lung cancer is one of the leading causes of deaths from cancer worldwide. Therefore, improvements in diagnostics and treatments are urgently needed. In this review, we will discuss the evolution of lung cancer staging towards more non-invasive, endoscopy-based, and image-based methods, and the development of stage-adapted treatment. A special focus will be placed on the role of novel surgical approaches and modern radiotherapy strategies for early stages of disease, the effect of multimodal treatment in locally advanced disease, and ongoing developments in the treatment of patients with metastatic disease. Full-Text PDF Genetics and biomarkers in personalisation of lung cancer treatmentNon-small-cell lung cancer is often diagnosed at the metastatic stage, with median survival of just 1 year. The identification of driver mutations in the epidermal growth factor receptor (EGFR) as the primary oncogenic event in a subset of lung adenocarcinomas led to a model of targeted treatment and genetic profiling of the disease. EGFR tyrosine kinase inhibitors confer remission in 60% of patients, but responses are short-lived. The pre-existing EGFR Thr790Met mutation could be a subclonal driver responsible for these transient responses. Full-Text PDF Prospects for population screening and diagnosis of lung cancerDeaths from lung cancer exceed those from any other type of malignancy, with 1·5 million deaths in 2010. Prevention and smoking cessation are still the main methods to reduce the death toll. The US National Lung Screening Trial, which compared CT screening with chest radiograph, yielded a mortality advantage of 20% to participants in the CT group. International debate is ongoing about whether sufficient evidence exists to implement CT screening programmes. When questions about effectiveness and cost-effectiveness have been answered, which will await publication of the largest European trial, NELSON, and pooled analysis of European CT screening trials, we discuss the main topics that will need consideration. Full-Text PDF