I. Ebru Cakir

DOI: 10.5455/IJMRCR.MOLECULAR-PATHOLOGY-IN-LUNG-CANCER

License CC BY-NC-SA 4.0

"Advancements in Targeted Molecular Changes and Treatment of Lung Cancer: Insights into EGFR Mutations and ALK/ROS Rearrangements" is a derivative of "Molecular Pathology In Lung Cancer: A Brief Review" by International Journal of Medical Reviews and Case Reports used under CC BY-NC-SA 4.0.

How to cite this article: 

Lung cancer is a heterogeneous malignancy caused by the accumulation of multiple genetic and epigenetic alterations, as well as environmental contaminants. In the past decade, targetable specific molecular alterations have been identified, and significant advancements have been made in the treatment and survival of these patients. In recent years, many laboratories have performed analyses of molecular changes related to sensitivity to Tyrosine Kinase inhibitors, such as EGFR gene mutations and ALK/ROS gene rearrangements, in cases of advanced non-small cell carcinomas in accordance with the recommendations of international guidelines. Recommendations include including BRAF, MET, RET, HER2, and KRAS genes in next-generation sequencing panels and analysing EGFR T790M mutations associated with tyrosine kinase inhibitor resistance. As knowledge and research about genes and mechanisms increase, laboratory tests for the markers that play a role in patient selection will be determined and analysed.

The review aims to summarize clinically important information about these genes and discuss recommended methods for their analysis based on guideline information.

Key Points

- Due to late-stage detection and the heterogeneity of its histological and biological characteristics, lung cancer mortality rates differ significantly from those of other common malignancies.

- Adenocarcinoma, a subtype of non-small cell lung cancer, is characterised by specific molecular alterations and oncogenic driver mutations in over 50% of cases. 

- Squamous cell carcinomas, another subtype of non-small cell lung cancer, exhibit approximately 40% targetable molecular aberrations.

- Understanding oncogenic and tumour suppressive genes in lung cancer is essential for the development of treatment strategies and the advancement of molecular pathology knowledge.

KRAS

- KRAS is a member of the RAS family of proto-oncogenes and encodes a G protein essential for cell proliferation, differentiation, survival, and signal transduction pathways. The frequency of KRAS mutations varies among ethnic groups, with Caucasian Europeans and Americans having a higher incidence than Asians and Africans.

- KRAS mutations are rare in squamous and small cell carcinomas.

- Studies on second- and third-line treatments have linked KRAS mutations with resistance to EGFR tyrosine kinase inhibitor therapy.

- At present, the absence of a KRAS mutation does not provide clinically relevant information for EGFR mutation assays and should not be used to determine EGFR tyrosine kinase inhibitor treatment.

EGFR

- EGFR (Epidermal Growth Factor Receptor) is a protein encoded by a gene on chromosome 7p11.2 with 28 exons.

- EGFR mutations predominantly occur in the tyrosine kinase domain exons 18 and 21, with frame deletions in exon 19 and the L858R mutation in exon 21 being the most common mutations.

- EGFR mutations are associated with increased susceptibility to EGFR tyrosine kinase inhibitors (TKIs), which results in enhanced response rates, progression-free survival, and quality of life in the treatment of advanced-stage non-small cell lung carcinomas. Resistance to EGFR-TKI treatment can be caused by exon 20 insertions (e.g., T790M mutation) and other gain-of-function mutations, which are detected in a subset of patients who are initially resistant or develop secondary resistance.

- EGFR mutations are more prevalent in Asians, younger individuals, females, nonsmokers, and histological subtypes of adenocarcinomas. They are uncommon in pure squamous cell carcinomas but may be present in those with EGFR variant III mutations, gene amplification, or protein overexpression. EGFR mutation is frequently the initial molecular alteration identified in nonsmokers with lung cancer.

ALK

- ALK (Anaplastic Lymphoma Kinase) encodes a tyrosine kinase receptor that is routinely expressed in specific neuronal cell types and is associated with a series of fusion proteins. EML4 (echinoderm microtubule associated protein-like 4) fusion with the intracellular domain of ALK is the most common observed rearrangement. Typically, breakpoints in the ALK gene occur in intron 19.

- ALK rearrangements are more prevalent in youthful, nonsmoking patients between the ages of 40 and 50, notably among Asians and males with advanced disease at the time of diagnosis.

- Patients with ALK-positive non-small cell lung cancer typically exhibit non-squamous cell and non-neuroendocrine histological subtypes. Cancer characteristics can differ between Asians and Westerners.

- ALK rearrangements are infrequently associated with driver mutations such as EGFR and KRAS mutations, although studies have demonstrated their coexistence with EGFR mutations.

- Compared to patients with EGFR mutations or wild-type tumours, patients with ALK rearrangements exhibit more lymph node metastases, an advanced T stage, and reduced survival periods.

ROS:

- The ROS1 gene is located on chromosome 6q22 and encodes a tyrosine kinase receptor with homology to ALK.

- ROS1 rearrangements are found in 1-2% of cases of non-small cell lung cancer. Similar to ALK, ROS1 rearrangements are more common in youthful, non-smoking patients, especially Asians.

- Kinase inhibitors, such as crizotinib, are effective in the treatment of patients with ROS1 rearrangements.

BRAF:

- The BRAF gene codes for a serine/threonine protein kinase that controls cell proliferation and survival and activates the MAPK pathway.

- Mutations that activate BRAF are frequently observed in melanomas and 1-3% of non-small cell lung carcinomas.

- The V600E mutation in exon 15 is the most common BRAF mutation, followed by the G469A and D594G mutations.

- V600E mutations are associated with a poorer prognosis and are more common in female nonsmokers.

MET:

- The MET oncogene is located on chromosome 7q21-q31 and encodes hepatocyte growth factor receptor, a membrane tyrosine kinase receptor.

- 1-7% of non-small cell lung carcinomas exhibit MET amplification, which is associated with acquired resistance to EGFR tyrosine kinase inhibitors.

RET:

- On chromosome 10q11.2, the RET gene encodes a receptor kinase involved in neural crest development.

- Nonsmokers, youthful patients, and those with inadequately differentiated tumours are more likely to exhibit RET rearrangements.