Molecular characteristics of lung cancer
Lung cancer is a molecularly heterogeneous disease, and several forms of genomic instability can drive its development.A recent report on whole exomegenomic sequencing of 100 NSCLC tumor samples revealed that besides clonal driver mutations, other processes such as chromosomal instability, genome duplications and subclonal mutations cause genetic heterogeneity, all of which have an influence on prognosis [11]. Understanding the biology and molecular characteristics of this disease have been crucial for the development of modern treatment strategies in patients with lung cancer.
The molecular analysis of lung cancers has shown thatEGFR and KRAS and the tumor suppressor genes TP53, KEAP1, STK11 and NF1 are the most commonly mutated genes in lung adenocarcinoma, while in squamous cell lung cancer are tumor suppressor gene TP53, which is present in more than 90% of tumors, and CDKN2A are the most commonly mutated genes[12]. Actionable mutations in receptor tyrosine kinases are rarely observed in squamous cell lung cancers (SCLC) even though EGFR amplification may be found in them [13]. Mutations in KRAS and EGFR genes when detected are usually present in the founder clones, indicating their roles in tumor initiation and can be targets for therapeutic intervention, while mutations in tumor protein TP53 are commonly observed with advancing grade, suggesting a role during tumor progression [14].KRAS and EGFR are mutually exclusive but when they coexist, KRAS mutation can confer resistance to EGFR inhibitors [14].
The genomic profile of smokers is markedly distinct from that of non-smokers [12,15]. Non-smokers have predominant transversionof cytosine to thymine, harbor tumors that have a lower than average mutation load, and have a higher prevalence ofoncogenic drivers such as EGFR mutations, anaplastic lymphoma kinase (ALK) rearrangements , ROS proto-oncogene receptor tyrosine kinase 1 (ROS1) , BRAF V600 E mutations, and neurotrophic receptor tyrosine kinase (NTRK) gene fusions;tumors from smokers contain higher mutation frequency, predominantly cytosine to adenine nucleotide transversions, and non-actionable mutations such as KRAS and TP53 [9,12,15].
An oncogenic driver identified relatively recently in NSCLC is human epidermal growth factor receptor (HER2, also known as ERBB2),a member of the EGFR receptor tyrosine kinase family,which has been added to the growing list of actionable targets [16,17].Early studies observed HER2 overexpression in approximately 1% to 2% of lung cancer cases, whereas results from more current studies show a range of approximately 6% to 30%[18].Data from tumor models and patients expressing HER2 mutations suggest that they tend to be insensitive to EGFR tyrosine kinase inhibitors (TKIs), suggesting the need for specific HER2-directed therapies for these patients. Many clinical trials are being conducted to identify effective and safe targeted treatment for metastatic HER2-mutated NSCLC patients [19].
Due to increasing knowledge of tumor heterogeneity, molecular testing is now performed at the time of metastatic non-small cell lung cancer diagnosis to identify gene mutations or rearrangements for which there are targeted therapies. The molecular targets of non-small cell lung cancer described above are shown in Figure 1.
The use of immune checkpoint inhibitors has become the standard of care for patients with advanced NSCLC. The only predictive biomarker currently available to guide treatment with immunotherapy is programmed death- ligand 1(PD-L1) protein. [19] Studies have shown that PD-L1 tumor proportion score (TPS) measured by immunohistochemical assay is a better predictor of response to immunotherapy as compared to programmed cell death 1 (PD-1). Therefore it is recommended that all patients with advanced NSCLC should get testing for PD-L1 TPS.[20] A PD-L1 TPS score >50% is required for first line treatment with pembrolizumab while patients who have progressed on previous treatment can receive immunotherapy for  PD-L1  negative tumors. [21] In patients with PD-L1 negative tumors, the selection of treatment may be based on tumor mutational burden, disease volume and performance status.[21] The research now is focused on finding a new predictive biomarker for immunotherapy so that it can guide optimal treatment benefit in patients.