Presently, two categories of biomarkers are employed to refine the treatment strategy for lung cancer patients:
- driver mutations within the cancer’s DNA to assess suitability for targeted therapy
- the expression level of a specific protein, PD-L1, within the patient’s tumor to evaluate sensitivity to immunotherapy.
Driver Mutations
All organs and tissues are made of cells, each containing numerous genes. Genes consist of DNA, which carries precise instructions for producing proteins that fulfill distinct functions within the cell. It is crucial for each gene to possess accurate DNA coding to enable proper protein functionality.
When a gene undergoes a change in its DNA, a mutation occurs. Mutations can be classified as either acquired (or somatic), present only in the tumor and not transmitted to children, or inherited (or germline), present in all body cells and inherited by children. The majority of biomarkers which help in treatment decisions for lung cancer are acquired, while research into inherited biomarkers is ongoing. This section focuses only on acquired mutations.
Mutations occur frequently, and typically, the body can rectify them. However, depending on the location within a gene, a minor alteration may escape detection by the body and become integrated into the cell’s genetic makeup. Over time, a buildup of mutations can lead to tumor formation. Mutations responsible for triggering cancer are referred to as driver mutations.
Different types of mutations can cause cancer.
Activating Mutation
One type is called an activating mutation. This mutation changes the DNA sequence, which in turn changes the protein made by the gene. This alteration causes the protein to be always active, leading to uncontrolled cell growth.
In lung adenocarcinoma – a type of non-small cell lung cancer (NSCLC) – an example of an activating mutation is called BRAF V600E.
Fusion
Fusion, also known as rearrangement, happens when one part of a gene attaches to another gene. This combination creates a new protein that causes abnormal and uncontrolled cell growth. Another term for gene rearrangement is translocation.
In lung adenocarcinoma, some fusion genes are EML4-ALK and CD74-ROS1.
Amplification
Amplification means there are a lot more copies of a gene than usual. This results in too much protein overexpression, which causes excessive activity and uncontrolled cell growth.
In lung adenocarcinoma, some genes are amplified, like HER2 (also known as ERBB2) and MET.
Deletion
Deletion happens when part or all of a gene is missing in cancer cells. This results in lower levels of normal protein produced by the cancer cell, leading to uncontrolled cell growth.
In small cell lung cancer (SCLC) examples of deleted genes include TP53 and RB1.
Over 20 different driver mutations have been identified in NSCLC and SCLC, serving as biomarkers in lung cancer testing. These mutations may determine eligibility for targeted therapies or clinical trials.
Currently, more information is available on driver mutations in the NSCLC subtype lung adenocarcinoma, with ΕΜΑ-approved targeted therapies for mutations like ALK, BRAF V600E, EGFR, KRAS G12C, MET exon 14 skipping, NTRK, RET, and ROS1.
As scientific research advances, we are gaining insights into mutations associated with early-stage lung adenocarcinoma. Additionally, progress is being made in comprehending mutations in squamous cell lung cancer. Though specific driver mutations exclusive to squamous cell lung cancer remain undiscovered, mutations commonly found in lung adenocarcinoma, such as EGFR mutations and MET exon 14 skipping mutations, can also manifest in squamous cell lung cancer.
Research into driver mutations in small cell lung cancer (SCLC) and other lung cancer variants is ongoing. However, as of now, there are no approved targeted therapies available for these mutations.
Immunotherapy relies on specific biomarkers to determine its effectiveness. Currently, the primary biomarker used in clinical practice for lung cancer is the programmed death-ligand 1 (PD-L1) protein.
PD-L1 interacts with PD-1 on T cells, inhibiting their attack on cancer cells. Immune checkpoint inhibitors, a type of immunotherapy, target and block the PD-L1 fail-safe mechanism, enabling the immune system to combat cancer more effectively. Patients with high PD-L1 expression are more likely to respond to immune checkpoint inhibitors, although responses can also occur in those with low or absent PD-L1 expression.
Other immunotherapy biomarkers under investigation include the tumor mutational burden (TMB) and microsatellite instability. These biomarkers offer additional insights into immune response and potential treatment efficacy.
