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.