Prognostic Factors and Markers in Non-Small Cell Lung Cancer: Recent Progress and Future Challenges

Abstract

Lung cancer is a highly aggressive neoplasm and, despite the development of recent therapies, tumor progression and recurrence following the initial response remains unsolved. Several questions remain unanswered about non-small cell lung cancer (NSCLC): (1) Which patients will actually benefit from therapy? (2) What are the predictive factors of response to MAbs and TKIs? (3) What are the best combination strategies with conventional treatments or new antineoplastic drugs? To answer these questions, an integrative literature review was carried out, searching articles in PUBMED, NCBI-PMC, Google Academic, and others. Here, we will examine the molecular genetics of lung cancer, emphasizing NSCLC, and delineate the primary categories of inhibitors based on their molecular targets, alongside the main treatment alternatives depending on the type of acquired resistance. We highlighted new therapies based on epigenetic information and a single-cell approach as a potential source of new biomarkers. The current and future of NSCLC management hinges upon genotyping correct prognostic markers, as well as on the evolution of precision medicine, which guarantees a tailored drug combination with precise targeting.

Keywords: EGFR mutations; NSCLC; genotyping; lung cancer; prognostic markers.

Figure 1

Global distribution of NSCLC clinical trials. Studies in Europe correspond to 27.6% and the United States correspond to 46% of all clinical trials. Labels give the exact number of studies located in different regions. Studies with no location are not included in the counts or on the map, and studies with multiple locations are included in all corresponding regions. Adapted from https://clinicaltrials.gov, accessed on 20 July 2023.

Figure 2

Driver genes in NSCLC. Driver genes can be classified as oncogenes and tumor suppressor genes and, in NSCLC, the main oncogenes are EGFR, HER2, MET, RET, BRAF, KRAS, NTRK1-3, ROS 1, and ALK. Oncogenes tend to hold mutations that activate proteins, which enhance tumor growth and cell proliferation, and are positively selected in cancer progression; therefore, targeted therapies focused on those genes are promising for the treatment of NSCLC. In contrast, tumor suppressor genes are essential for controlling cell division and replication of genetic material, avoiding imbalances, so they are usually deactivated in tumor selection and the main tumor suppressor gene in NSCLC is TP53, which is also responsible for the survival of several other histological tumor types.

Figure 3

Protein–Protein Interaction Network associating proteins/driver genes in NSCLC. STRING version 12.0 (string-db.org) and Cytoscape version 3.10.1 (cytoscape.org) were used to create this representation. Evidence values were used for protein interaction (percentage values at an evidence level of around 40%) according to experimental, curation, text mining, and predictive computational data. Caption: Driver genes in red (RGB:251,106,74-FB6A4A).