Lung cancer and somatic variants

Non-small cell lung cancer refers to any cancer of the lung other than small cell lung carcinoma.

The most common sub types of non-small cell lung cancer are:

• Adenocarcinoma
• Squamous cell carcinoma
• Large cell lung cancer.

Adenocarcinoma lung cancer accounts for about 40% of all lung cancers.

Prevalence:

• European populations >50% lung adenocarcinomas have a ‘driver’ variant
• East Asian populations >? lung adenocarcinomas have a ‘driver’ variant
• KRAS 25% all adenocarcinomas
• EGFR 10%-20% in Europeans, 30%-50% in East Asians
• ALK fusions 4%-5%
• Variants in BRAF, MET, PIK3CA and NRAS, and fusions of ROS1, NTRK and RET, make up most of the rest.

Testing for variant is via:

• Tissue biopsy either via a bronchoscopy or need biopsy
• Liquid biopsy which requires high levels of circulating tumour DNA in the blood which in some instances is not present. The technology in this area continues to improve and in the future is likely that liquid biopsies will become a more reliable and successful mechanism for EGFR identification.

However, tissue testing with biopsy is the current gold standard.

Non-small cell lung cancer

It is recommended everyone with non-small cell lung cancer, particularly lung adenocarcinoma, has testing for EGFR.

An EGFR variant does not refer to a single gene abnormality as there are different types of EGFR variants which often form part of a diagnosis of EGFR positive lung cancer. The most common EGFR variants (around 90%) are either exon 19 deletions (which means a piece of genetic material is missing) or exon 21 L858 mutations.

EFGR statistics:

• Around 10% to 15% of lung cancers in the UK have sensitising EGFR variants.
• EFGR is more common in those of Asian descent.
• EFGR is more common in women than men and in people who have never smoked or have been light smokers (a never smoker is defined as someone who has smoked less than one hundred cigarettes in a lifetime).
• These variants are not hereditary (present at birth) but develop later in life as a part of the process of a healthy cell becoming a cancer cell.
• EFGR is more common in younger adults with lung cancer.

Non-small cell lung cancer

BRAF variants are grouped into three classes dependent on their effect on kinase activity:

1. Class one variants in autonomous kinase activity – RAS independent e.g. V600E.
2. Class two variants form kinase activating homodimers – RAS independent e.g. L597Q.
3. Class three variants from kinase inactivating heterodimers with CRAF – RAS dependent e.g.D594A.

BRAF Statistics:

• BRAF tyrosine kinase variant is present in around 1% to 3% of lung cancers with a preponderance to non-small cell adenocarcinoma.
• Around half of all BRAF mutations are V600 mutations, and most BRAF V600 mutations are V600E mutations (a class one variant).
• BRAF V600 mutations are commonly found in older people and in people with a history of smoking.
• Non V600 variants are functionally heterogenous e.g. G469A (increased kinase activity and D594G (impaired kinase activity) variants.

Non-small cell lung cancer

A variant in the PIK3CA gene can cause cells to divide and replicate uncontrollably. It contributes to the growth of many cancers, including metastatic breast cancer (MBC).

PIK3CA statistics:

• PIK3CAvariants in non-small cell lung cancer tend to be in older patients and more likely a squamous histology.
• PIK3CA is an oncogene.
• More than 80% of the mutations in PIK3CA cluster in two regions, within the helical (exon 9) and catalytic (exon 20) domains.
• PIK3CA variants are implicated as one of the mechanisms causing resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR TKI’s) in lung cancer patients.
• It is more common in heavy smokers.

Non-small cell lung cancer

A ROS1-positive lung cancer, also known as a ROS1 rearrangement in lung cancer, refers to any lung cancer that tests positive for a fusion in the ROS1 gene.

ROS1 fusions occur when part of the gene breaks off and attaches to another gene. In lung cancer cells with the ROS1 fusion, the ROS1 protein produced because of these fusions is overly active, leading to uncontrolled cell growth and tumours.

ROS1 statistics:

• ROS1 fusions are present in 1% to 2% of non-small cell lung cancers.
• ROS1 tends to be in younger than average patients.
• People with ROS1 will test negative for other known lung cancer variants such as EGFR and ALK.
• ROS1 will be present in people who have never smoked or only smoke a little.
• The median age of people with ROS1 positive lung cancer is around 50 years old. The median age for lung cancer is usually 70 years old.
• ROS1 positive lung cancer is slightly more common in women. Around 64.5% of ROS1 positive lung cancer patients are female. This differs from other statistics which show that lung cancer is slightly more common in men than in women.

Non-small cell lung cancer

There are two main types of RET genetic alterations, or errors in the gene:

1. RET point mutations which are often found in medullary thyroid cancer.
2. RET rearrangement or gene fusion. This is when a piece of DNA joins with another gene and creates a fusion. The fusion leads to uncontrolled cell growth and cancer.

RET rearrangments are the most common RET gene error in lung cancer. There are different types of RET rearrangements. The type depends on which gene is fused (or joined) with RET.

The gene KIF5b is the most common fusion partner, and CCDC6 is the second most common.

RET rearrangment statistics:

• RET rearrangements appear in about 1% to 2% of lung cancer patients and generally appear in adenocarcinoma non-small cell lung cancer.
• Patients tend to be younger than the average lung cancer patient and have little to no smoking history.

Around 50% of patients with advanced non-squamous non-small cell lung cancer have a targetable driver mutation.

Liquid biopsies help people receive earlier, more targeted, lung cancer treatments. They are currently being trialled by the NHS.

CtDNA (circulating tumour DNA) tests, also known as liquid biopsies, are minimally invasive blood tests that can detect tiny amounts of ctDNA shed by the cancer into the blood. Tumours often release pieces of DNA into the bloodstream (known as circulating tumour DNA) and these can be sampled using a ctDNA blood test to identify key genetic drivers of tumours.

The test can identify key genetic mutations in a patient's cancer which can potentially enable them to receive targeted treatments rather than standard chemotherapy.

Liquid biopsy opens a new way for the early screening, diagnosis, and treatment of lung cancer, especially when tissue samples cannot be obtained.

The ctDNA test will be offered to 10,000 patients by March 2025. 20250 to patients that receive CT scan results showing suspected lung cancer will have a small blood sample sent to a genomic laboratory for ctDNA testing, with results returned in around 14 days.

Currently, tissue biopsies are used to confirm a diagnosis of lung cancer and samples can then be sent for genomic testing. This new test could provide patients with these results faster, meaning they could start targeted treatment sooner. Find out more on the NHS England website.