**Abstract**

Lung cancer patients have the highest mortality among patients with solid tumors worldwide and their prognosis is strictly stage-associated. However, only 15–20% of patients are diagnosed in stage I, since these early tumors are frequently asymptomatic. Early detection of lung cancer, which allows effective therapeutic intervention, is a promising approach to lowering its mortality rate. However, conventional diagnostic methods for lung cancer, such as chest X-ray and CT of the chest, produce high costs and potentially false-positive results. Thus, the discovery of highly sensitive, specific, noninvasive, and cost-effective lung cancer biomarkers combined with conventional approaches, such as X-rays, may improve the sensitivity of lung cancer screening. Herein, we summarize the most recent studies about the molecular pathology of lung cancer and discuss the advancements expected in the near future, including the potential biomarkers and liquid biopsy approaches for the detection of lung cancer in populations at risk of developing this disease.

**Keywords:** lung cancer, CT, biomarkers, lung cancer screening, liquid biopsy, cfDNA, CTCs

## **1. Introduction**

Despite multimodality treatment strategies including surgery, radiotherapy, chemotherapy, and targeted therapy, lung cancer is still the first leading cause of cancer-related death in the world with the 5-year lung cancer survival rate remaining as low as 15% [1–3]. The most common histologies are summarized as non-small cell lung cancer (NSCLC) and account for 80–85% of newly diagnosed cases. Surgery is the standard of care for functionally operable early stage NSCLC and resectable stage IIIA disease and possesses a potential for cure. However, only 20% of NSCLC are resectable at diagnosis [4]. Histology and cytology of thoracic biopsies are currently the gold standard that asserts early diagnosis of lung cancers detected by thoracic imagery. Nevertheless this approach is costly and often detects false positive nodules that turn out not to be cancers. Therefore, early detection approaches—especially directed toward the population at high risk for the development of this disease—remain an unmet clinical need. Several studies have been performed to define the ideal approach that should be sensitive, specific, reliable, and reproducible for early diagnosis of lung cancer or for prediction of the development of this disease in subjects at risk. This review summarizes the molecular

biology of lung cancer and conventional diagnostic methods currently used, with a particular attention on the development of new screening approaches such as liquid biopsy to improve the early detection of this disease.
