Molecular Epidemiology of the Main Druggable Genetic Alterations in Non-Small Cell Lung Cancer.

Sara S Fois,Antonio Cossu,Alessandro G Fois,Angelo Zinellu,Giuseppe Palmieri,Panagiotis Paliogiannis

doi:10.3390/ijms22020612

Abstract

Lung cancer is the leading cause of death for malignancy worldwide. Its molecular profiling has enriched our understanding of cancer initiation and progression and has become fundamental to provide guidance on treatment with targeted therapies. Testing the presence of driver mutations in specific genes in lung tumors has thus radically changed the clinical management and outcomes of the disease. Numerous studies performed with traditional sequencing methods have investigated the occurrence of such mutations in lung cancer, and new insights regarding their frequency and clinical significance are continuously provided with the use of last generation sequencing technologies. In this review, we discuss the molecular epidemiology of the main druggable genetic alterations in non-small cell lung cancer, namely EGFR, KRAS, BRAF, MET, and HER2 mutations or amplification, as well as ALK and ROS1 fusions. Furthermore, we investigated the predictive impact of these alterations on the outcomes of modern targeted therapies, their global prognostic significance, and their mutual interaction in cases of co-occurrence.

Highlights

Lung cancer (LC) is one of the most incident malignancies worldwide
MET-mutated non-small cell lung cancer (NSCLC) has been correlated with an older age at diagnosis compared with epidermal growth factor receptor (EGFR), Kirsten rat sarcoma virus (KRAS), and BRAF-mutant lung cancers, with a median age of 72.5 years; two thirds of patients harboring MET exon 14 mutations have been reported to be current or former smokers, but in a recent Italian study, no differences in MET
Co-occurring driver mutations in BRAF-positive NSCLC have been described with rates up to 13%, including KRAS, EGFR mutations, anaplastic lymphoma kinase (ALK) fusions, ros oncogene 1 (ROS1) fusions, HER2 amplifications, and MET alterations

Summary

Introduction

Lung cancer (LC) is one of the most incident malignancies worldwide. According with the Global Cancer Observatory (GCO), more than 2,200,000 new cases and approximately 1,800,000 deaths were estimated in the world in 2020 [1]. LC has been classically divided in two major classes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) The latter comprises the most common histological subtypes, such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. The discovery of activating mutations of the epidermal growth factor receptor (EGFR) in patients with lung adenocarcinoma led to the development of a new family of biological agents, called tyrosine kinase inhibitors (TKIs) [9]. These medications have revolutionized the clinical management of patients harboring EGFR mutations, whose survival nearly doubled compared to standard chemotherapy [8]. The aim of this review was to summarize the global epidemiology of the main druggable molecular alterations in NSCLC, as well as their correlation with the demographic, anthropometric, pathological, and clinical data of the affected individuals

Molecular Epidemiology of the Main Druggable Genes in LC

Co-Occurrence of Druggable Genetic Alterations in NSCLC

Findings

Conclusions