Current Landscape of Non-Small Cell Lung Cancer: Epidemiology, Histological Classification, Targeted Therapies, and Immunotherapy

Abstract

Non-small cell lung cancer (NSCLC) is a subtype of the most frequently diagnosed cancer in the world. Its epidemiology depends not only on tobacco exposition but also air quality. While the global trends in NSCLC incidence have started to decline, we can observe region-dependent differences related to the education and the economic level of the patients. Due to an increasing understanding of NSCLC biology, new diagnostic and therapeutic strategies have been developed, such as the reorganization of histopathological classification or tumor genotyping. Precision medicine is focused on the recognition of a genetic mutation in lung cancer cells called "driver mutation" to provide a variety of specific inhibitors of improperly functioning proteins. A rapidly growing group of approved drugs for targeted therapy in NSCLC currently allows the following mutated proteins to be treated: EGFR family (ERBB-1, ERBB-2), ALK, ROS1, MET, RET, NTRK, and RAF. Nevertheless, one of the most frequent NSCLC molecular sub-types remains without successful treatment: the K-Ras protein. In this review, we discuss the current NSCLC landscape treatment focusing on targeted therapy and immunotherapy, including first- and second-line monotherapies, immune checkpoint inhibitors with chemotherapy treatment, and approved predictive biomarkers.

Keywords: cancer biology; epidemiology; histopathology; immunotherapy; lung cancer; non-small cell lung cancer; predictive biomarkers; targeted therapy.

Figure 1

Development of targeted therapy in NSCLC. Over the last decade, there has been an acceleration in the emergence of new inhibitors approved in NSCLC targeted therapy. The approval dates of the inhibitors in the treatment of NSCLC refer to the approvals issued by the Food and Drug Administration (FDA), Silver Spring, MA, USA.

Figure 2

The number of people diagnosed with lung cancer per 100,000 inhabitants. (a) Incidence among women concerning world regions in 2002–2020; (b) Incidence among men concerning world regions in 2002–2020 [1,2,39,40,41].

Figure 3

Genetic basis of neoplastic transformation of lung cells and heterogeneity of NSCLC (non-small cell lung cancer). In normal lung tissue, the cell’s genome is kept in balance between mutation occurrence and repair. When endogenous or exogenous factors disrupt this balance, genetic instability occurs, which initiates the pre-initiation phase. During this time, the increasing instability of epigenetic control and the occurrence of new mutations change the activity of the molecular mechanisms. For neoplastic transformation of the cell, occurring changes need to accumulate and cause defects at the chromosome level (initiation phase). Afterward, the whole genome doubling of clonal cells leads to the development of separate populations with different genotypes. Carcinogenesis enters the progression phase, which results from the formation of cells with increased proliferation and invasiveness, triggering the metastasis formation.

Figure 4

Schematic representation of the leading signaling pathways for which FDA-approved inhibitory substances were developed thus far (EGFR—epidermal growth factor receptor; HER2—human epidermal growth factor receptor 2; ALK—acute lymphoma kinase; ROS1—c-ros1 oncogene; NTRK1—neurotrophic tyrosine kinase receptor type 1; MET—tyrosine-protein kinase Met; RAS—rat sarcoma 2 viral oncogene homologs family; RAF—proto-oncogene c-RAF; MEK—mitogen-activated protein kinase; ERK—extracellular signal-regulated kinases; Pi3K—phosphoinositide 3-kinases; AKT—protein kinase B; mTOR—mechanistic target of rapamycin kinase).