حول ALK + سرطان الرئة

ALK-positive lung cancer is a type of non-small cell lung cancer (NSCLC) in which there is an abnormal fusion of the anaplastic lymphoma kinase (ALK) gene and another gene, echinoderm microtubule-associated protein-like 4 (EML4).

 

This fusion causes cell enzymes (specialized proteins) to send signals to cells instructing them to divide and multiply more quickly than usual. The result: the spread of lung cancer.

ALK-positive lung cancer is an acquired condition but it is not known exactly what triggers this. 

The ALK rearrangement is present in about 5% percent of people with NSCLC and this equates to about 1,600 new cases each year in the UK. ALK-positive lung cancer has been found in squamous cell carcinoma of the lungs (another type of NSCLC) and small cell lung cancer. 

The EML4-ALK fusion gene is not exclusively related to lung cancer and has been found in neuroblastoma and anaplastic large cell lymphoma.

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The difference between hereditary (germline) and acquired (somatic) gene mutations in cancer can lead to much confusion. This is especially true if you're hearing about genetic testing for a genetic predisposition to cancer at the same time you hear about genetic testing for mutations that may be treatable in a cancer already present.

Somatic mutations are often referred to as driver mutations as they drive the growth of a cancer. In recent years, medications have been developed that target these mutations to control the growth of a cancer. When a somatic mutation is detected for which a targeted therapy has been developed, it is referred to as an actionable mutation. The field of medicine known as precision medicine is a result of medications such as this that are designed for specific gene mutations in cancer cells.

Germline mutations, in contrast, are inherited from a mother or father and increase the chance a person will develop cancer.

ALK-positive lung cancer is a somatic mutation which has not been inherited and cannot be passed down to children.

Certain people are more likely to have cancer cells with the ALK fusion gene:

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An X-ray, CT scan or PET scan may identify lung cancer but an ALK rearrangement has to be diagnosed through genetic testing (also known as molecular profiling). Healthcare providers obtain a sample of a lung tumour via a tissue biopsy or may examine a blood sample obtained via a liquid biopsy. These samples are checked for biomarkers that show the ALK rearrangement is present.

A few other tests that suggest an ALK rearrangement may be present include:

- Bloodwork: Carcinoembryonic antigen (CEA), which is present in some types of cancer, tends to be negative or present at low levels in people with ALK mutations.

- Radiology: Imaging of ALK-positive lung cancer can appear different from other types of NSCLCs, which may help direct testing for the mutation early.

All patients with advanced-stage adenocarcinoma should be tested for ALK and other treatable genetic mutations, regardless of sex, race, smoking history, and other risk factors..

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Stage at Diagnosis

Patients diagnosed at Stages 1, 2 and 3 are likely to be offered surgery, radiotherapy or chemotherapy with curative intent.

About 85% of ALK-positive patients are diagnosed at Stage 4 and are likely to be treated with oral drugs that work to shrink the tumours.  These drugs are called Tyrosine Kinase Inhibitors (TKIs).

Five TKIs have been approved by the National Institute for Health Care Excellence (NICE) in England and Wales for treating advanced ALK-positive lung cancer.

The terms of NICE approval depends on the pharmaceutical company’s submission and this can affect the order (pathway) in which these drugs can be used.  A table showing these pathways is at the foot of our NICE page.

 

1st Generation

Crizotinib

2nd Generation

Alectinib

Brigatinib

Ceritinib

3rd Generation

Lorlatinib

Currently, most patients diagnosed at Stage 4 will start their treatment with Alectinib or Brigatinib.

Tyrosine kinases are cell proteins that allow signals to be sent from one cell to another. Tyrosine kinase receptors are located on the cells that receive these signals.

To understand how ALK targeted therapy medications work, think of the cell's tyrosine kinase protein as a messenger that sends a message understood only by the tyrosine kinase receptor. If you have an ALK mutation, you have the wrong message. When the wrong message is “inserted”, signals are sent to the cell's growth centre telling cancer cells to divide without stopping.

Tyrosine kinase inhibitor (TKI) medications work by blocking the receptor.  As a result, the signal telling the cancer cells to divide and grow never gets communicated.

It’s important to keep in mind that TKIs are not a cure for lung cancer, but rather a treatment that allows a tumour to be kept in check. Tumours can often be managed for years with these drugs, reducing the likelihood that the cancer cells will spread.  Hopefully, one day, lung cancer may be treated like other chronic diseases.

TKIs can have immediate beneficial effects for some patients by significantly reducing the size and number of lesions but it is essential that patients are regularly monitored.  Leading experts recommend that CT scans should be carried out every three months.

Lung cancer, and in particular ALK-positive lung cancer, often progresses to the brain. Patients should receive a brain MRI at diagnosis and, if no brain lesions are found, at six-monthly intervals thereafter.  If brain lesions are found, MRI scans should be carried out every three months.

We have produced a 'Good Practice from the Patient’s Perspective' guide and, in this, we suggest some questions you may wish to ask your oncologist about the frequency of scans and other matters:

Lung cancers may initially respond very well to targeted therapy medications. However, patients almost always become resistant to the medication over time and their cancer progresses.

If patients develop resistance to an ALK inhibitor, their healthcare provider may try a new medication. If the progression is localised, radiotherapy may be offered.  Chemotherapy may also be offered. 

Like other cancer medications, it can be expected that TKIs will produce side effects although these are likely to be much less than the side effects of chemotherapy.  Each of the TKIs will produce its own side effects – some effects may be mild but others may be uncomfortable and disrupt everyday life. 

Blood tests should be taken at regular intervals to ascertain whether the treatment is affecting vital organs.  It may be necessary to reduce dosage, to pause treatment or, in severe cases, to stop the treatment.

Recent research in the UK suggests that the median survival for people with stage 4 ALK-positive lung cancer is 6.2 years, i.e over half of patients will survive longer than this.

Of course, whatever the mean survival rate is, half will live longer, some much longer, and half will live shorter, some much shorter.  At present, it is not possible to predict how long individual patients will survive.

TKIs bring the possibility of having a good quality of life and of living progression-free without serious side effects for many years.

 

If you would like more comprehensive information about ALK-positive lung cancer, please click here.

ALK Positive Lung Cancer (UK)

The vision of the Charity is that everyone in the UK who is diagnosed with ALK-positive lung cancer:

  • Receives the best possible care

  • Lives their best life possible

  • Lives as long as possible.

To achieve this, we:

  • Support patients

  • Empower patients to enable them to demand a high level of care,

  • Advocate on behalf of patients nationally to ensure that patients receive a high level of care wherever they live in the UK.