Genetic testing guides the treatment of ALK positive lung cancer

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Cancer genetic testing

Cancer gene testing guides targeted therapy as the core technology for precise cancer treatment. Every cancer patient should perform cancer gene testing for himself, looking for effective targeted drugs and clinical trials for treatment. The Global Oncologist Network, in conjunction with the US genetic testing agency and the domestic top-notch genetic testing agency, provides patients with accurate cancer genetic testing and expert consultation services to help patients formulate the most accurate treatment plan. 

If your doctor tells you that you have a mutation in the ALK gene, or ALK-positive lung cancer, you may be at a loss as if you live in a foreign-speaking country without an interpreter. What exactly is ALK, how common is ALK mutation, and how should patients with ALK-positive lung cancer be treated?

Definition of ALK mutation

ALK mutations are genetic mutations that cause abnormalities in the genome. It can produce cancer cells such as lung cancer cells. As a review, genes are part of the genome in our DNA that encodes substances, such as the color of eyes and the color of hair. They are also gene models that encode proteins that keep our bodies functioning properly—and cause cells to divide and grow.
Cancer cells are cells that have some genetic mutations in the process of becoming cancer cells. For example, every cancer in humans is different and carries different genetic mutations. These mutated genes in turn encode proteins, which make these proteins abnormal, which in turn triggers abnormal functions-such as driving the growth of cancer.
The ALK gene mutation was discovered in 2007. This gene mutation is called ALK (anaplastic lymphokine). More precisely, this mutation is actually a gene rearrangement-a fusion of two genes called ALK and EML4 (Echinoderma microtubule-associated protein type 4.). This is an abnormal gene (fusion gene) that turns to encode an abnormal protein called tyrosine kinase (there are many types of tyrosine kinases.) Tyrosine kinase is an enzyme (protein) that acts as a chemical messenger Role, send a signal to the cell growth center, to transmit information that allows cells to divide and proliferate.
In short, tyrosine kinase “drives” or controls the growth of cancer (mutations such as EML4-ALK mutant fusion genes are called “drive mutations.”)
What ’s interesting about this study is that some cancer patients can now be treated with tyrosine kinase inhibitors. This drug blocks tyrosine kinase (in this case, the protein EML4-ALK is fused) and by blocking Cell division signalling pathways inhibit the growth of cancer. By controlling the critical “on-off” switch of love, these drugs have been shown to treat cancer patients with ALK gene mutations.
Some people are familiar with another genetic mutation found in patients with non-small cell lung cancer, called the EGFR mutation. Such mutations can also lead to the formation of abnormal tyrosine kinase proteins, and the EGFR tyrosine kinase inhibitor Trokai (Crotinib) has successfully extended the lives of many patients with such mutation-positive lung cancer.

What is ALK positive lung cancer?

ALK-positive lung cancer patients refer to those lung cancer patients who have been detected positive for ALK mutation (EML4-ALK fusion gene). This mutation occurs in 3-5% of people with non-small cell lung cancer. At first glance, this seems to be a very small number, but considering that there are a large number of patients diagnosed with lung cancer, this number is actually very large. This fusion gene has also been found in patients with neuroblastoma and anaplastic large cell lymphoma.
An important event that is confusing and requires attention. This is not an inherited mutation, such as the BRCA1 and BRCA2 mutations in some breast cancer patients we have heard of. Patients with lung cancer who have a positive EML4-ALK fusion gene are not born with such mutations, nor do they have a tendency to inherit from their parents. Instead, this acquired mutation occurs in some cancer cells as part of the cause of cancer.

Diagnosis of ALK positive lung cancer

ALK gene mutations can be diagnosed by molecular analysis of tumor cell samples. This test is very important, it requires enough lung biopsy tissue or lung cancer surgery to obtain tissue. Researchers are also trying to find ways to determine if the ALK gene mutation has been identified before genetic testing, or it can replace genetic testing. Some of the ALK gene mutations include
Blood test – This test, called CEA (carcinoembryonic antigen), is mostly negative in patients with ALK mutations.
However, molecular level analysis (genetic testing) is still the best test and the standard treatment option.

What kind of people are prone to ALK mutation?

The difference in the types of mutations in lung cancer is based on the type of lung cancer itself. The EML4-ALK fusion gene is by far the most common genetic mutation in patients with non-small cell lung cancer. This type of lung cancer is also called lung adenocarcinoma. Even so, ALK gene mutations are rarely found in patients with lung squamous cell carcinoma (another type of non-small cell lung cancer) and small cell lung cancer.
Some specific populations are more likely to have ALK fusion genes. This includes young parents who never smoke (or rarely smoke), women, and ethnic characteristics of East Asia. In a recent study in a foreign country, it was found that nearly 50% of young parents younger than 40 were positive for the EML4-ALK fusion gene (compared to 3 to 5% of lung cancer patients of all ages).

Who should perform the ALK mutation test?

Some institutions collaborate to develop guidelines for what kind of people should be tested for ALK mutations. The consensus is that all patients with advanced adenocarcinoma should be tested for ALK mutations and EGFR mutations regardless of gender, smoking history, other risk factors, and race.
One limiting factor is that some tumors may present different types of lung cancer locally. For example, one part of the tissue looks like adenocarcinoma, but another part of the tissue of the biopsy sample shows small cell lung cancer.
There are some exceptions for doctors to master this guiding principle. For example, some people who have never smoked may be recommended for testing, even if their lung cancer type does not show adenocarcinoma. These guidelines may change. Once we know more about mutations, other mutations are discovered and subsequent treatments are developed.

How to treat ALK mutation positive lung cancer?

Although the ALK mutation in lung cancer was just discovered in 2007, treatment with this mutation (and metastatic lung cancer) has been approved by the FDA. Just four years after the approval of the US Food and Drug Administration, a rearrangement was discovered. This exciting finding in the treatment of lung cancer has not significantly increased survival rates in the past few years.

What is its mechanism of action? 

Medication-Xalkori (crizotinib) is a tyrosine kinase inhibitor. Xalkori adheres to the surface of lung cancer cell tyrosine kinase receptors, blocking the abnormal ALK protein. There is a simple way to understand this process. Think of the tyrosine kinase receptor as a lock, and the tyrosine kinase protein (produced by abnormal genes) as a key. Patients with mutations in the ALK gene have an abnormal key. When the key is “inserted”, the signal is transmitted to the growth center, causing the cell to divide continuously. Medications such as Xalkori act to block the keyhole-just as you plug your front door with concrete to add a keyhole. If this key (abnormal protein) is unable to enter the keyhole (combined with the receptor), the signal for cell division and growth will not reach the control station, and cell division (tumor growth) will be stalled.

Drug resistance solution

Unfortunately, even if more than half of the patients begin to be effective for treatment, drug resistance will almost always occur over time, and the drug will lose its effectiveness. For those who develop drug resistance, there are still other treatment options. The Roche anticancer drug ALectinib was approved in 2013 to treat ALK-positive lung cancer as a drug after the resistance to Crizotinib. In March 2014, another drug treatment, Zykadia (seritinib)-was also approved by the US Food and Drug Administration as a breakthrough treatment plan. The initial response rate to Zykadia is similar to Xalkori. In addition-many people still respond to Zykada after Xalkori resistance. New drug treatment methods for patients with drug resistance are being studied in clinical trials. Some researchers hope that patients will be able to use these drugs for continuous treatment after drug resistance develops in the future.
“In addition, tumors often change after a period of time (new mutations occur). Sometimes, one drug therapy can target another treatable mutation (such as an EGFR mutation), even if the tumor starts not as an EGFR mutation. Positive. Hope that in the near future, we will be able to treat lung cancer at least a certain subspecies-like other chronic diseases.
Finding mutant genes through genetic testing and ultimately achieving individualized treatment of lung cancer has always been the goal of doctors.

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