EGFR-Positive Lung Cancer

Have you ever heard of EGFR-positive lung cancer? It certainly has a complex name, which is why not many people are familiar with it. Besides cell-based subtyping (e.g. small cell vs. non-small cell lung cancer), the disease can also be defined by molecular profile.

This article will provide an overview of EGFR-positive lung cancer, including its definition, causes, and diagnosis.

Epidermal growth factor receptor (EGFR) is a protein that is located on the outside of cells (cell surface protein). It receives signals from other parts of the body and transmits the signal into the cells. The signal transmitted by EGFR regulates cell growth, division and survival. The protein can be found in both healthy cells and cancer cells. Mutations in EGFR usually happen when there is

• Insertion – where additional nucleotide (DNA code) appears in a normal DNA sequence
• Deletion – where one or several nucleotides disappear in the DNA sequence
• Point mutation or substitution – where a single nucleotide is swapped with a different nucleotide
• Amplification – where many copies of the same gene are present

Any of these mutations can damage EGFR and result in a signal for the cells to multiply. In cancer, these mutations put the EGFR into a permanent “on” position and result in increased numbers of cells.

If you have EGFR-positive lung cancer, your EGFR proteins are not functioning properly due to mutations, causing cancer development.

EGFR mutations account for about 15% of lung adenocarcinoma (non-small cell lung cancer; NSCLC) in the United States. It also occurs more frequently among

• Young adults
• Non-smokers
• Women
• Asian ethnics in the US or other Asian populations

The EGFR mutation is rare among small cell lung cancer patients.

Types of EGFR mutations detected in lung cancer patients:

• Exon 19 deletion - 40-50% of lung cancer cases
• Exon 21 L858R - 40-50% of lung cancer cases
• T790M – this can occur as a second mutation in EGFR after initial treatment causing drug resistance. It is present in half of lung cancer patients developing acquired resistance to drugs such as erlotinib, gefitinib.
• Exon 20 insertion – less common
• L861Q, S768I and G719X - less common

Identifying the specific EGFR mutations driving lung cancer helps to tailor treatment plans to target those mutations. Biomarker testing, performed in the diagnostic process (see below), guides personalized treatment strategies.

In healthy cells, EGFR mutation may occur due to the normal aging process. However, our immune system normally picks up and removes the mutated cells.

The latest study has shown that harmless, pre-existing EGFR mutation in healthy cells can turn oncogenic (cancerous) when the lungs are inflamed. Particulate matter 2.5µm (PM2.5) can trigger lung inflammation, transforming lung cells with pre-existing EGFR mutation into tumor cells.

EGFR mutations are more commonly associated with lung adenocarcinoma, but may occur in other types of lung cancer.

Related: Air Pollution As Lung Cancer Risk

All patients with advanced or metastatic lung adenocarcinoma are evaluated for EGFR mutation. Patients with other NSCLC subtypes can consider taking the molecular or biomarker test. Biomarker tests help patients to identify driver mutations, at the same time, match them with available targeted therapies for the specific mutations they have.

There are various techniques to determine the presence of EGFR mutations:

EGFR mutation assay. Direct sequencing of EGFR gene at the known mutation sites mentioned above.

Examples of EGFR mutation assay: cobas EGFR Mutation Test V2; therascreen EGFR RGQ PCR Kit

Broad molecular profiling. Almost 70% of patients with lung adenocarcinoma have EGFR or other driver mutations. Doctors may recommend a broad molecular profiling that assesses multiple driver mutations. PD-L1 (programmed death-ligand 1) is a predictive marker for immunotherapy. Profiling of multiple biomarkers allows doctors and patients to decide their targeted therapies and immunotherapy simultaneously.

Examples of broad molecular profiling: FoundationOne CDx; ONCOReveal Dx Lung & Colon Cancer Assay; Oncomine Dx Target Test

Liquid biopsy. There may not be sufficient tumor samples for all the diagnostic tests needed for patient diagnosis. To avoid tissue re-biopsy (normally invasive), the doctor may order a minimally invasive biopsy technique called liquid biopsy. It involves drawing a few tubes of blood.

Using techniques like next-generation sequencing (NGS) and polymerase chain reaction (PCR), liquid biopsy analyses DNA shed from lung tumors into the bloodstream. Whereas profiling using traditional biopsy analyses DNA in the tumor tissue. In the past, the tumor DNA in the bloodstream was not significant enough for an accurate diagnosis. However, recent advances in NGS combining data analytics and automation have boosted liquid biopsy sensitivity in lung cancer molecular profiling.

The US Federal Food and Drugs Administration (FDA) has approved several liquid biopsies in recent years: FoundationOne Liquid CDx; Guardant360 CDx

The treatment depends upon the type of EGFR mutation. For the two most common EGFR mutations (deletion 19 or L858R) the initial treatment is usually an oral drug. In some instances, it can be combined with chemotherapy. Certain rare mutations (insertion 20) are treated with different drugs (amivantimab +/- chemotherapy). Unfortunately, resistance usually develops to the initial treatment and other drugs need to be used. Examples of FDA-approved targeted therapies for lung cancer:

It may be filled with uncertainties in the face of a cancer diagnosis. Nevertheless, molecular profiling opens up new therapeutic avenues for cancer patients. Biomarker tests identify the driver mutations in specific lung cancer cases and guide personalized targeted therapies.