Biomarkers In Lung Cancer: Overview

May 13,2022
10 Min Read

Lung cancer has shown a decrease in incidence and mortality in recent decades; however, it remains the most common cancer in males.

Despite advances in early detection and standard treatment, most patients are diagnosed at an advanced stage and have a poor prognosis.(1)

GENOMIC BIOMARKERS IN NSCLC

Advances in elucidating the molecular biology of lung cancer have led to the identification of a number of potential biomarkers that could be relevant in the clinical management of patients with non-small cell lung carcinoma (NSCLC).

Epidermal growth factor receptor (EGFR):

Location: The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor member of the ERBB family. The EGFR gene is located on the short arm of chromosome 7 at position 1.(2)
Prevalence in NSCLC: EGFR is overexpressed in 62% of NSCLCs, and its expression has been associated with poor prognosis.(3)
Clinicopathologic features: EGFR mutations are found more often in adenocarcinomas with lepidic features from female never smokers.(4)
Possible targeted therapies: The high response rates (55%-78%) to treatment with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and afatinib, in patients with EGFR-mutant tumors, and the significantly greater progression-free survival (PFS) of these patients, have made EGFR TKIs the standard treatment for patients with these mutations.(5)

Anaplastic lymphoma kinase (ALK):

Location: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor member of the insulin receptor superfamily. The ALK gene is located on the short arm of chromosome 2 at position 23.(6)
Prevalence in NSCLC: The EML4-ALK fusion has been detected in 3.7% to 7% of NSCLCs.(7)
Clinicopathologic features: Seen usually in adenocarcinomas with signet-ring cells or cribriform histology features, and is more common in young patients who have never smoked.(7)
Possible targeted therapies: The ALK fusion defines a distinct subpopulation of patients with lung adenocarcinoma who are highly responsive (57%-74%) to ALK inhibitors such as crizotinib.(8)

Kirsten rat sarcoma viral oncogene homolog (KRAS):

Location: KRAS is an oncogene located on the long arm of chromosome 12 at position 12.1.(9)
Prevalence in NSCLC: KRAS mutations occur in 25% to 35% of patients with NSCLC.(10,11)
Clinicopathologic features: Seen principally in adenocarcinomas with a solid pattern, and are found more often in white patients compared to Asians, in former or current smokers, but without sex predilection.(10,11)
Possible targeted therapies: Although there are no targeted therapies approved for patients with lung cancer and KRAS mutation, several clinical trials aimed at downstream signaling targets are under way. Different phase 2 trials have reported improvements in both PFS and response rate with the combination of selumetinib (MEK1/MEK2 inhibitor) and docetaxel compared to docetaxel alone and promising results with sorafenib (RAS/RAF pathway inhibitor), with a disease control rate of approximately 50%.(12,13)

ROS proto-oncogene 1, receptor tyrosine kinase (ROS1):

Location: ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) is a tyrosine kinase receptor member of the insulin receptor family and is located on the long arm of chromosome 6 at position 22.(14)
Prevalence in NSCLC: Approximately 1% to 2% of NSCLCs.(15)
Clinicopathologic features: ROS1-rearranged NSCLC typically occurs in young, female, never smokers with a histologic diagnosis of adenocarcinoma.(14,15)
Possible targeted therapies: Clinical trials have reported that patients with advanced NSCLC harboring ROS1 rearrangement have benefited from crizotinib treatment, showing response rates up to 80%.(14,16) Ongoing phase 1 and 2 studies are investigating the activity of crizotinib and ceritinib (ALK inhibitor) in ROS1-rearranged NSCLC.(14,16)

Human epidermal growth factor receptor 2 (HER2):

Location: The human epidermal growth factor receptor 2 gene HER2 (ERBB2) is a proto-oncogene located on chromosome 17 at position 12.(17)
Prevalence in NSCLC: Overexpression of HER2 has been reported in 7% to 34.9% of NSCLCs and has been associated with poor prognosis in patients with these tumors.(17) Activating mutations of HER2 have been found in 1.6% to 4% of lung cancers.(17,18)
Clinicopathologic features: More often seen in adenocarcinomas in female, Asian, never or light smokers.(18)
Possible targeted therapies: Different studies reinforce the importance of screening lung adenocarcinomas for HER2 mutation as a method to select patients who could benefit from HER2-targeted therapies (afatinib and trastuzumab), which have shown response rates of approximately 50%.(19)

RET proto-oncogene:

Location: The RET proto-oncogene is located on the long arm of chromosome 10 at position 11.2.(20)
Prevalence in NSCLC: Approximately 1% to 2% of NSCLCs harbor RET fusions, and several fusion partners, including kinesin family member 5B (KIF5B) (90%), coiled-coil domain containing 6 (CCDC6), nuclear receptor coactivator 4 (NCOA4), and tripartite motif-containing 33 (TRIM33), have been described.(21,22)
Clinicopathologic features: RET-rearranged NSCLC typically occurs in adenocarcinomas with more poorly differentiated solid features in young never smokers, and it is mutually exclusive with known driver oncogenes.(21,23)
Possible targeted therapies: In vitro studies showed that RET fusions lead to oncogenic transformation, which can be inhibited by multitargeted kinase inhibitors such as vandetanib, sorafenib, and sunitinib.(23)

MET proto-oncogene:

Location: The MET gene is located on the long arm of chromosome 7 at position 31.(24)
Prevalence in NSCLC & clinicopathologic features: In lung cancer, MET mutations are found in the extracellular semaphorin and juxtamembrane domains, occurring in 3% of squamous cell lung cancers and 8% of lung adenocarcinomas. MET amplifications are found in 4% of lung adenocarcinomas and 1% of squamous cell lung cancers and are associated with sensitivity to MET inhibitors.(25)
Possible targeted therapies: MET inhibitors such as capmatinib and crizotinib (56).

B-RAF proto-oncogene, serine/threonine kinase (BRAF):

Location: The B-RAF proto-oncogene, serine/threonine kinase (BRAF) oncogene is located on the long arm of chromosome 7 at position 34. (26)
Prevalence in NSCLC: BRAF mutations have been reported in 1% to 3% of NSCLCs.(26)
Clinicopathologic features: BRAF-mutated NSCLC has been reported to be mostly adenocarcinoma, and in contrast to patients with EGFR mutations or ALK rearrangements who are mostly never smokers, patients with BRAF mutations are mostly current or former smokers.(27)
Possible targeted therapies: BRAF inhibitors, such as vemurafenib and dabrafenib, have high and selective activity against the V600E-mutant BRAF kinase, with overall responses rates from 33% to 42%.(28,29)

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA):

Location: The PIK3CA gene is located on the long arm of chromosome 3 at position 26.3.(30)
Prevalence in NSCLC: Mutations are found in 1% to 4% of patients with NSCLC, usually affecting exons 9 and 20 (80%).(31-35)
Clinicopathologic features: PIK3CA mutations have not shown association with any clinicopathologic features (65, 68, 69).(32,34,35)
Possible targeted therapies: Studies have shown that PIK3CA mutations in EGFR-mutated lung cancer confer resistance to EGFRTKIs and are a negative prognostic predictor in patients with NSCLC treated with EGFR-TKIs.(36)

Neurotrophic receptor tyrosine kinase 1 (NTRK1):

Location: The neurotrophic receptor tyrosine kinase 1 (NTRK1) proto-oncogene is located on chromosome 1q21-22 and encodes for a receptor tyrosine kinase, also known as tropomyosin-related kinase (TRK) A.(1)
Prevalence in NSCLC: In lung cancer, approximately 3% of adenocarcinomas harbor NTRK1 fusions (73).(37)
Clinicopathologic features: Nil
Possible targeted therapies: In early phase 1 studies, NTRK inhibitors, such as entrectinib and LOXO-101, have shown promising results in patients with solid tumors harboring NTRK fusions.(1)

Fibroblast growth factor receptor (FGFR):

Location: The fibroblast growth factor receptor (FGFR) gene is located on chromosome 8 at position 12 and encodes for a tyrosine kinase receptor belonging to the FGFR family.(1)
Prevalence in NSCLC & clinicopathologic features: Somatic FGFR mutations in lung tumors usually occur in FGFR2 and FGFR3 and have been detected in 6% of lung squamous cell carcinomas.(38) In lung cancer, the incidence of FGFR1 amplification is significantly higher in squamous cell carcinoma (20%) compared to adenocarcinoma (3%) and is more frequent in current smokers compared to former and never smokers.(1)
Possible targeted therapies: Multiple FGFR inhibitors, such as ponatinib, a multitargeted kinase inhibitor that displays potent pan-anti-FGFR activity, are in development, with promising results in cell lines and xenograft models.(39)

Discoidin domain receptor tyrosine kinase 2 (DDR2):

Location: The discoidin domain receptor tyrosine kinase 2 gene (DDR2) is located on the long arm of chromosome 1 at position 23.3 and encodes for a tyrosine kinase receptor that is expressed in mesenchymal tissues and which binds fibrillar collagen as ligand.(40)
Prevalence in NSCLC & clinicopathologic features: In lung cancer, DDR2 mutations occur in 3% to 4% of lung squamous cell carcinomas compared to 0.5% of adenocarcinomas and are only present in smokers.(1)
Possible targeted therapies: DDR2 mutations have been associated with response to dasatinib (a multitargeted kinase inhibitor) in preclinical models.(1)

IMMUNOTHERAPY MARKERS IN LUNG CANCER

Historically, lung cancer has not been considered very immunogenic because of several failed attempts with cytokines and vaccines. Nevertheless, over the past few years, immunotherapy has re-emerged strongly with the development of checkpoint inhibitors as treatments for NSCLC.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)

Monoclonal antibodies that inhibit CTLA-4, such as ipilimumab, are available to prevent the binding of CTLA-4 with its ligands (CD80/CD86), leading to reactivation of the antitumor immune response mediated by specific T cells.(1)

Programmed death-ligand 1 receptor (PD-1)

Several monoclonal antibodies targeting the interaction between PD-1 and its ligands PD-L1 and PD-L2 are available. Clinical trials in NSCLC have shown sustained responses in approximately 20% of unselected patients to treatment with monoclonal antibodies against PD-1, such as nivolumab and pembrolizumab, and with antibodies against PD-L1 such as MPDL3280A. The FDA has approved the use of nivolumab in advanced NSCLC on or after platinum-based chemotherapy and pembrolizumab as second-line treatment for NSCLC after chemotherapy.(41,42)

Furthermore, IHC PD-L1 positivity in NSCLC has been identified as a potential predictor of response to anti- PD-1 and anti-PD-L1 monoclonal antibody therapy and also as a prognostic biomarker.(1)

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