Luis M. Montuenga, PhD, Centro de Investigación Médica Aplicada (CIMA); Department of Pathology, Anatomy and Physiology, Schools of Medicine and Sciences; University of Navarra, Pamplona, Spain. IdisNa, Pamplona Spain. CIBERONC, Madrid, Spain
Which factors are impeding the implementation of low-dose computed tomography (LDCT) lung cancer screening at the global level?
All of us agree that LDCT is effective and should be widely implemented. I would say that cost and awareness are the two major issues that are impeding the implementation of LDCT all over the world. Cost-effectiveness of LDCT has been demonstrated by many publications; and there are even other arguments in favor of the cost-effectiveness of this technology. We are screening for lung cancer, but we can also simultaneously identify patients with other conditions, such as cardiovascular disease (through coronary artery calcification determination) and emphysema. The awareness issue is probably due to the fact that LDCT-based lung cancer screening has been a seemingly controversial topic for decades. It still has some remnants of a controversial label, although current evidence clearly supports screening of patients who fit the National Lung Screening Trial (NLST) and other criteria [1-3]. In addition, the stigma associated with lung cancer may have had some role in the slow implementation of LDCT.
How can new biomarkers improve the effectiveness of screening?
We must distinguish two concepts here. One is the concept of prognostic biomarkers that enable determination of the patient outcome after a diagnosis of lung cancer. The staging committee of the International Association for the Study of Lung Cancer (IASLC) has a subcommittee that focuses on identifying molecular markers for prognostication to improve the efficacy of TNM staging. In my laboratory, we are also working on finding molecular prognostic markers for early lung cancer.
The other area relates to biomarkers that can help in the process of LDCT screening. Firstly, they can improve the selection of high-risk individuals who should be advised to participate in a screening program. These markers might refine the risk models that are already in use. We have genetic biomarkers and others based on environmental exposure and smoking habits, as well as phenotypic circulating biomarkers. The other aspect regarding biomarkers that can help in the process of screening relates to nodules of indeterminate risk. LDCT identifies nodules that clearly belong to the low-risk category, while others are clearly high-risk lesions and call for quick intervention. However, in approximately 70 % of cases, nodules are not clearly characterizable in terms of risk. Biomarkers can help here by providing information to improve risk stratification, thus contributing to avoiding unnecessary interventions such as PET scan or biopsy.
Which biomarkers are promising with respect to early detection of lung cancer?
This is a difficult question, as there are many biomarkers. Numerous publications reporting the discovery of markers have been released. Promising molecular candidates include autoantibodies, blood protein profiling, complement fragments, microRNAs, circulating tumor DNA methylation, and RNA airway or nasal signatures . Other emerging biomarkers or new technologies to follow are exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies or the integration of next generation sequencing in circulating DNA.
However, these biomarkers need to be validated. Validation is the key issue. The most promising markers will be the ones that reach clinical utility validation, and this has not been achieved in the screening context by any of these yet. A number of them have undergone some type of validation in the clinical setting, such as case control studies including samples obtained from screening cohorts. However, we need to design trials showing that these biomarkers work and improve the management of high-risk individuals or not otherwise specified patients in the setting of screening cohorts. This is a bottle neck which is very difficult to solve, because not many screening programs are collecting biospecimens. Moreover, we need collaboration between all of these programs, as well as standardization and good trial design. This is the course of action that will tell us which markers are the most promising ones. At this point, we even have commercially available biomarkers that work well for a variety of questions, but the key will be to have something that improves the gold standard management in the context of screening.