KRAS-Positive Lung Cancer

This article will give an overview of KRAS-positive lung cancer, including its definition, causes and diagnosis. By learning more about this specific subtype of lung cancer, patients, their loved ones and caregivers can face this challenge with better clarity.

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a gene encoding for the K-Ras protein. The protein is involved in the RAS/MAPK cell signaling pathway that controls cell growth, proliferation (division) and differentiation (mature into specialized functions). The K-Ras acts like a switch for this signaling pathway.

KRAS gene mutations are the most common genetic abnormalities seen in non-small cell lung cancer (NSCLC).

Most of the reported KRAS mutations in lung cancer are single nucleotide point mutations where a single nucleotide is swapped with a different nucleotide. The mutations generate abnormal K-Ras proteins that fail to regulate the RAS/MAPK pathway. This results in uncontrolled cell growth, leading to tumor formation.

If you have KRAS-positive lung cancer, the KRAS proteins in the cancer cells are not functioning properly due to mutations, causing cancer development.

KRAS mutations account for 20-25% of lung adenocarcinoma (a type of NSCLC) in the United States but it is rare among small cell lung cancer (SCLC) patients. It is common among smokers or ever-smokers.

KRAS mutations detected in lung cancer patients are usually found in codon 12 (a triplet of nucleotides in the DNA that codes for one amino acid in protein). This has caused a replacement of the amino acid Glycine (G) by a different amino acid. Common KRAS mutations in lung cancer:

• G12A
• G12C – most common KRAS mutation in NSCLC
• G12D
• G12S
• G12R
• G12V

Having KRAS-positive lung cancer does not affect your prognosis. The overall survival rate depends on the cancer stage at diagnosis. The lower the stage, the higher the 5-year relative survival rate.

KRAS mutations in lung cancer are not inherited (hereditary). They are acquired due to exposure to carcinogens (cancer-causing factors). The most common risk factor for KRAS mutation is tobacco smoking and secondhand smoke.

However, non-smokers can also get KRAS-positive lung cancer. The rate of KRAS-positive lung cancer among non-smokers is much lower, about 11%, compared to 30% in smokers.

Genetic/molecular/biomarker testing is the only way to identify if you are KRAS-positive. It will also determine your specific KRAS mutation and, thus, the optimal targeted therapy for you. These tests are recommended for all patients with advanced or metastatic lung adenocarcinoma. Patients with other NSCLC subtypes can consider taking the tests.

There are various techniques to determine KRAS mutations:

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

An example of the KRAS mutation assay: therascreen KRAS RGQ PCR Kit

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 next-generation sequencing and 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 is not significant enough for an accurate diagnosis. However, recent advances in NGS combining data analytics and automation have boosted the sensitivity of liquid biopsy in lung cancer molecular profiling.

The US Federal Food and Drugs Administration (FDA) has approved these liquid biopsies in recent years: Guardant360 CDx; Agilent Resolution ctDx FIRST assay

These diagnostic methods have enhanced the understanding of this disease and its progression. They allow medical professionals to adapt treatment strategies accordingly, ensuring patients receive the most effective therapies throughout their cancer journey.

The initial treatment for KRAS mutated non-small cell lung cancer depends upon the stage of the disease as well as other determinants such as the PD-L1 (a marker of susceptibility to immunotherapy). For patients with advanced disease (i.e. those in whom the disease involves multiple parts of the lung or which has spread beyond the chest to other organs), initial treatment will usually consist of immunotherapy with or without chemotherapy. If a patient’s disease does not respond to initial treatment or progresses after an initial response, and there is KRAS G12C mutation, then the second line of treatment may be LUMAKRAS®/LUMYKRAS® (sotarasib) or KRAZATI® (adagrasib), drugs that directly target this mutation. These drugs do not work for other KRAS mutations (e.g. G12V, G12D etc).