Modern medicine made an impressive leap forward. The life expectancy of people has increased significantly late stages lung cancer. The experience of specialists at the VitaMed clinic allows us to guarantee careful and accurate differentiation of mutations in lung cancer, with the selection of an appropriate course of treatment to improve the quality of life and high chances of successful treatment.
EGFR mutation
This mutation occurs predominantly in non-smokers. The discovery of such a mutation in advanced cancer is an encouraging sign because it suggests responsiveness to treatment with tyrosine kinase inhibitors (the drugs erlotinib and gefitinib).
ALK translocations
According to research, this mutation in lung cancer is more common in young and non-smoking patients. Its detection indicates sensitivity to crizotinib.
KRAS mutation
Typically, this mutation in lung varnish occurs in smokers. Does not play a special role for the forecast. When analyzing statistical data, it was indicated that there were cases of deterioration of the condition and improvement, which does not allow us to draw an unambiguous conclusion about its influence.
ROS1 translocation
This mutation, like the ALK translocation, predominantly occurs in young, nonsmoking patients. During clinical trials installed high sensitivity Such tumors can be treated with crizotinib; studies of new generation drugs are currently underway.
HER2 mutation
Usually the changes are represented by point mutations. Tumor cells do not critically depend on this mutation in their vital activity, however, new tests have revealed a partial positive effect in patients with combined treatment through trastuzumab and cytostatic agents.
BRAF mutation
Some patients with mutations in this gene (V600E variant) respond to treatment with dabrafenib, an inhibitor of the B-RAF protein encoded by the BRAF gene.
MET mutation
The MET gene encodes the tyrosine kinase receptor for hepatocyte growth factor. There is an increase in the number of copies of this gene (amplification), while the gene itself rarely undergoes mutations, and their role is not well understood.
FGFR1 amplification
This amplification occurs in 13-26% of patients with squamous cell carcinoma lungs. Usually common among patients who smoke, in practice it carries a poor prognosis. However, relevant work is underway to develop drugs aimed at this disorder.
Basic principles for diagnosing lung cancer mutations
To accurately diagnose lung cancer, bronchoscopy with biopsy sampling for cytological and histological studies is provided. After the laboratory receives a conclusion about the presence of a mutation and the identified type of mutation, a suitable tactic will be drawn up drug treatment, appropriate biological drugs are prescribed.
Biological therapy for malignant lung tumors
Each therapy program is individual. Biological therapy involves working with two types of drugs that differ in the principle of their effect on the tumor, but are aimed at the same final effect. Their goal is to block cell mutation at the molecular level, without harmful consequences for healthy cells.
Due to the stable targeted effect exclusively on tumor cells, it is possible to stop the growth of malignant cells after just a few weeks. To maintain the achieved effect, a continuation of the course of medication is required. Treatment with drugs is practically free of side effects. But gradually the cells become immune to the active components of the drugs, so treatment needs to be adjusted as necessary.
Differences in treatment for lung cancer mutations
The EFGR gene mutation accounts for about 15% of all cases. In this case, one of the EGFR inhibitors can be used for treatment: erlotinib (Tarceva) or gefitinib (Iressa); created and more active drugs new generation. These medications usually do not cause severe side effects, released in the form of capsules or tablets.
Translocation of the ALK/EML4 genes, which accounts for 4-7% of all cases, suggests the use of crizotinib (Xalkori); Its more active analogues are being developed.
In case of tumor angiogenesis, therapy with the drug bevacizumab (Avastin) is suggested to suppress it. The drug is prescribed along with chemotherapy, significantly increasing the effectiveness of this treatment.
Oncological diseases require careful diagnosis and individual approach to determine the course effective treatment - prerequisites, which specialists from the VitaMed clinic are ready to provide.
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What causes one patient's cancer disease to be more aggressive than another? Why do some people have cancer that is resistant to chemotherapy? Genetic mutation The MAD2 protein may help answer both of these questions.
Researchers engineered an inherited mutation in the MAD2 gene in human cancer cells, which is responsible for the process of cancer cell division and proliferation. As a result, the mutation made tumor cells, which were born from existing ones, very unstable in their properties, which by all indications had characteristics corresponding to more aggressive forms cancer. In addition, the newborn mutated cancer cells were resistant to toxins (chemotherapy). The results of this study, published in the January 18 issue of the journal Nature, have important to develop new medicines and could help create a new “marker gene” to diagnose the degree of aggressiveness of tumors and detect them at an early stage.
Back in 1996, Dr. Robert Benezra and Yong Lee identified the MAD2 gene as a class of proteins responsible for some of the functions of division and budding in newborns. cancer cells from the uterine cell. They guarantee uniform distribution chromosomes to two daughter cells during the process of cell division. The loss of this normal division mechanism leads to unstable forms in which entire chains of chromosomes can be lost or extra ones added. Cancers that exhibit this type of chromosome instability are usually more aggressive and have an uncertain prognosis regarding the patient's future life prospects. Correlations between chromosome instability and MAD2 loss have been identified in human colon cancer cells. However, previously there was no evidence that there is a connection between these phenomena. Now, scientists know that the loss of MAD2 on maternal cancer cells creates chromosomal instability for newborn cancer cells.
For example, mice with complete absence MAD2 gene die even during embryonic development. Even one copy of the MAD2 gene led to the development of cancer in mice. Uniquely, this mutation led to the development of lung cancer in mice, despite the fact that the disease is extremely rare in them. Why this affected lung tissue is not yet known, but it does show that MAD2 is involved in cancer development.
The opinions of a number of other specialists in this field on the results of this study indicate other fundamental possibilities that make it possible to explain the reasons for the effectiveness of cancer treatment in some and the ineffectiveness, and sometimes even negative effects of chemotherapy in others.
In particular, one patient with cancer has, for example, unstable and mutation-prone (due to the weakness of the MAD2 gene) cancer cells of a certain type, and another has the same form of cancer, but with resistant forms. Thus, chemotherapy treatment for the first patient will most likely have no effect in destroying the tumor or slowing its growth, and may even cause an accelerated response to further cancer progression. At the same time, in another patient, a course of chemotherapy can have a positive effect and even lead to recovery.
The latter circumstance is extremely rare, which may indicate that the majority of people with cancer have unstable forms of cancer cells, which can be affected in combination, various types Therapy is sometimes simply impossible. Unstable forms exist, apparently, due to the main factors that become the reasons for the development oncological diseases. As a rule, these are carcinogens and poisons, which modern civilization poisons himself. That is, cancer cells themselves undergo constant mutations, just as healthy cells develop into malignant ones due to mutations.
Probably for the same reason, no solution has yet been found to combat this fatal disease, which ranks second as the leading cause of death, after cardiovascular diseases.
To defeat cancer that is resistant to conventional chemotherapy, it is necessary to turn on an alternative self-destruction scenario in cancer cells.
Drug resistance in cancer cells is usually attributed to new mutations. For example, after a mutation, a cell becomes invisible to drug molecules - the drug stops interacting with some receptor protein on the cell, or cancer cells, after new genetic changes, find a workaround for important processes that chemotherapy turned off in them; The scenarios here may be different.
Usually in such cases they try to create a new drug that would act taking into account the new mutation; it turns out to be something like a constant arms race. However, cancer has another strategy with which it is able to escape from drug attack, and this strategy is not associated with mutations, but with the normal ability of cells to adapt to environmental conditions. This ability is called plasticity: no changes occur in the genetic text, just signals from external environment change the activity of genes - some begin to work stronger, some weaker.
Typically, anti-cancer drugs cause a cell to enter apoptosis, or a suicide program in which the cell destroys itself with minimal harm to others. Cancer cells, due to plasticity, can go into a state where it becomes very, very difficult to turn on their apoptosis program with anything.
We can explain what is happening here like this: imagine that the cell has a switch that turns on apoptosis, and there is a hand that pulls the switch. In the case of mutational drug resistance, the switch changes shape so much that you can no longer grasp it with your hand; and in the case of stability due to plasticity, you can grab hold of this switch, but it becomes so tight that there is no way to turn it.
The fact that cancer cells can, so to speak, suppress their suicidal desires has been known for a relatively long time, but the question remained how effective such a trick was. Researchers believe that it is effective, and even very effective.
They analyzed gene activity in several hundred types of cancer cells and came to the conclusion that the more clearly the “anti-suicide” genes worked in the cells, the more resistant they were to drugs. In other words, there is a direct relationship between cellular plasticity and the ability to resist medicinal substances.
Moreover, it turns out that cells use this tactic with variations, that the non-self-destruction tactic is turned on in many, if not all, types of cancer, and that it is turned on regardless of the specific therapy. That is, non-mutational drug resistance has turned out to be a universal and widespread way of dealing with difficulties among malignant cells. (Recall that metastases scatter throughout the body not so much because of new mutations that encourage cancer cells to wander, but because of.)
The question arises: does it make sense in this case to use medications at all, since there is such an absolute shield against them? But every defense has weakness, and in the article in Nature The authors of the work say that cells resistant to apoptosis can be killed using ferroptosis.
Cells can die according to different scenarios - according to the scenario of apoptosis, necroptosis, pyroptosis, etc., and ferroptosis, which was discovered relatively recently, is one of them. From the name it is clear that the main role here with iron: under certain conditions and in the presence of iron ions in the cell, the lipids that make up the membranes begin to oxidize; Toxic oxidation products appear in the cell, membranes begin to deteriorate, so that in the end the cell chooses to die itself.
Ferroptosis, like everything else, depends on different genes, and the authors of the work managed to find the gene through which it is best to act here - this is the gene GPX4, encoding the enzyme glutathione peroxidase. It protects cellular lipids from oxidation, and if it is turned off, ferroptosis will inevitably begin in the cell. Disabling GPX4, it is possible to suppress the growth of a wide variety of tumor cells, from lung cancer to prostate cancer, from pancreatic cancer to melanoma.
All this once again suggests that malignant diseases require complex treatment– Cancer cells have a lot of tricks to help them survive. On the other hand, since everything does not always come down to new mutations, one can hope that effective therapy can be selected for a patient without a thorough genetic analysis.
In order for a cell to obey commands and prohibitions, it needs a system of signals transmitting these commands and an apparatus capable of perceiving them. These signals are substances called cytokines. By their chemical nature they are usually proteins or polypeptides- shorter chains of amino acids than proteins.They bind to receptor proteins located on the outer membrane of the cell, change their state, and they trigger a chain of reactions - they activate some molecules and take others out of play. However, a certain amount of cytokines is almost always present in the intercellular environment, and the cell reacts not to a single molecule, but to the fact that their concentration exceeds a certain threshold. Sometimes the absence of a particular cytokine itself becomes a signal. So, for example, if the concentration of growth factors (cytokines that encourage the cell to divide) is high - the cell divides, low - it does not divide, and if they for a long time no at all - it commits apoptosis.
Cell mutations
Both cytokines and their receptors are encoded by genes that we know subject to mutations. For example, a mutant form of the growth factor receptor is known, which behaves like a sticky bell button - it constantly generates intracellular signals for division, regardless of whether a signaling molecule is located on it or not. It is clear that a cell equipped with such receptors will constantly try to divide without listening to external commands. Another mutation allows the cell to produce growth factors to which it will respond.
But such a mutation alone is not enough to make cancer cell. Division without a command will be stopped by other cytokines - inhibitors of proliferation. There are other mechanisms that prevent the malignant degeneration of cells. To break through all these barriers and free yourself from the limitations imposed by the body, changes are needed in several at once (according to mathematical models- from 3 to 7) not related to each other key genes.
These genes are called proto-oncogenes(completely unfair, since their normal operation prevents the development of cancer. However, no one is surprised that the device that turns on the light is called a switch.) B different types Tumors are affected by different proto-oncogenes. In total, about 200 are known. In March 2005, experts National Institute human genome, the United States announced its intention to compile full catalog genes whose mutations are associated with malignant transformation.
If these ideas are correct, then at first glance it is not clear how anyone manages to get cancer. The probability of a particular mutation occurring in a particular gene is very low, and the combination of several such mutations in one cell borders on a miracle, unless you take into account how many cell division(and therefore acts of copying the genome) occurs in our body. Physiologists estimate that each of our cells divide about two trillion times a day.
Mutation- the event is random and can happen at any time. But certain chemical substances And physical influences
can greatly increase its likelihood: all ionizing radiation and most chemical carcinogens are well known as mutagens. It is clear why a tumor most often develops where there are many constantly dividing cells: in hematopoietic tissue, in the skin, in all kinds of epithelia (esophagus, stomach, intestines, larynx, lungs, uterus).
In other tissues, tumors arise much less frequently, and, as a rule, not from specialized cells, but from relatively rare ones stem. And let's say in the brain usually only specific childhood tumors appear (developing in the first years of life, when brain cells are still dividing), or metastases that have separated from a tumor that arose in some other tissue.
After the first mutations It may take years or decades for the affected cell to become malignant. In fact, this may not happen at all if other necessary genes do not mutate. However, it is likely that a cell capable of unlimited division and impervious to outside commands will nevertheless be born.
To turn into a tumor, such a cell needs a lot more, and above all, replicative immortality. The point is that the cells multicellular organism can only be shared a limited number of times (about 50). Next, the telomere counter is triggered - small, meaningless sequences of nucleotides at the ends of chromosomes, which are shortened by a certain amount with each division. True, the genome encodes a special enzyme - telomerase, which is capable of restoring telomeres to their original length. But normally it is present only in germ cells and stem cells, and in all others its gene is blocked. If it is not unblocked, the cell will not be able to divide indefinitely.
New cancer cells divide continuously, and control over the accuracy of DNA copying is dramatically weakened. The emerging cells are becoming more diverse. And the classic Darwinian selection begins: those who reproduce the fastest, most successfully protect themselves from neighbors and lymphocytes, and most importantly, most effectively turn surrounding cells and tissues into their resources, gain an advantage. In other words, as new clones of tumor cells arise and are selected, the latter become more and more active.
Metastasis, or the tendency of cancer cells to separate from the original tumor, migrate to other tissues and give rise to secondary tumors there, is another characteristic feature malignant neoplasms, making it very difficult to fight them. Most cells in the body do not settle in foreign tissue and do not go beyond the boundaries of their organ. For cancer cells there are no restrictions: they can move both with the bloodstream and on their own, pass through any barriers (say, from the bloodstream to the brain, which even immune and stem cells, which have access almost everywhere, cannot do) and settle anywhere.
Without responding to the body's chemical commands, cancer cells at the same time, they successfully use such commands themselves. When the diameter of a young tumor exceeds 2-4 millimeters, the cells inside stop getting enough oxygen and nutrients. But malignant cells secrete special substances that encourage nearby blood vessels to grow into the thickness of the tumor. Mature tumor cells can even suppress the activity of lymphocytes with their secretions.
Living at the expense of the conquered organism, they not only do not try to reduce the damage they cause and thereby prolong their existence, but, on the contrary, they seem to strive to destroy it as quickly as possible. Sometimes developed tumors even release a powerful volley of vasomotor hormones into the blood, which can lead to cardiac arrest and instant death organism - and with it its killers.
This is, of course, a rare and extreme case, but it demonstrates general pattern: like the biblical Samson, malignant tumor strives to completely destroy the organism in which it is located. Cancer knows no carrier chronic forms, spontaneous healing. Left to himself, he has only one outcome - death, which can only be avoided with active and timely treatment.
When in 1962 an American scientist discovered in the extract salivary gland mice a complex substance, epidermal growth factor (EGF), consisting of more than five dozen amino acids, he had no idea that he had taken the first step towards big discovery, which will be destined to change the face of lung cancer. But only at the beginning of the 21st century will it become known for certain that mutations in the receptor to which EGF binds can become the starting point in the development of one of the most aggressive tumors - lung cancer.
What is epidermal growth factor?
Epidermal growth factor (English version Epidermal Growth Factor, or EGF) is a protein that stimulates the growth and differentiation of cells lining the surface of the body (epidermis), cavities and mucous membranes.
It should be noted that EGF is a protein necessary for our body. So, located in salivary glands Epidermal growth factor ensures normal growth of the epithelium of the esophagus and stomach. In addition, EGF is found in blood plasma, urine, and milk.
EGF does its job by binding to the epidermal growth factor receptor, EGFR, located on the surface of cells. This leads to the activation of tyrosine kinase enzymes, which transmit a signal about the need for active activity. As a result, several sequential processes occur, including an increase in the rate of protein production and the synthesis of a molecule that ensures the storage and implementation of the development program of living organisms, DNA. The result of this is cell division.
If you have lung cancer, you'll probably hear about both epidermal growth factor and epidermal factor receptor. Very often in the instructions for drugs and literature, when talking about the epidermal growth factor receptor, they use the English abbreviation EGFR - from the English phrase epidermal growth factor receptor.
In the 90s of the last century, the role of the epidermal growth factor receptor as an oncogene, playing a leading role in the development of a number of malignant diseases, became obvious.
Epidermal growth factor and cancer
At the end of the 20th century, several studies were conducted confirming the importance of EGF in the development of malignant diseases. In 1990, American scientists proved that blocking the binding of epidermal growth factor to receptors and, as a result, preventing the activation of the tyrosine kinase enzyme stops the growth of malignant cells.
Of course, not everyone and not always the epidermal growth factor “triggers” the processes of abnormal cell division. In order for a normal protein necessary for the functioning of our body to suddenly become its worst enemy, genetic changes or mutations must occur in the epidermal growth factor receptor molecule, which lead to a multiple increase in the number of EGF receptors - their overexpression.
Mutations may be caused by potentially aggressive factors environment, for example, toxins, as well as smoking, intake of carcinogens from food. In some cases, “damages” in the epidermal growth factor receptor accumulate over several generations, transmitted from parents to children. Then they talk about hereditary mutations.
Mutations in EGFR cause the process of cell division to become completely out of control, resulting in the development of cancer.
It should be noted that “breakdowns” in the epidermal growth factor receptor molecule are associated with several types of cancer. First of all, this is non-small cell lung cancer (NSCLC). Much less frequently, mutations and, as a consequence, overexpression of EGFR lead to the development of tumors of the neck, brain, colon, ovary, cervix, Bladder, kidneys, breast, endometrium.
Do you have an epidermal growth factor mutation?
In some categories of patients, the likelihood of “breakdown” is significantly increased. Thus, it is known that mutation of the epidermal growth factor receptor occurs much more often in people who have never smoked. This does not mean that tobacco smokers are less likely to get sick. lung cancer– on the contrary, it is known that bad habit causes the development of the disease in 90% of cases. It's just that lung cancer develops through a different mechanism in smokers.
Epidermal growth factor receptor mutations are more often found in patients with lung adenocarcinoma who have never smoked. “Failures” of EGFR are also detected in women in most cases.
Indicative results reflecting the distribution of epidermal growth factor mutations among Russians were obtained in one large domestic study, which examined data from more than 10 thousand lung cancer patients. They showed that EGFR mutations were found:
- In 20.2% of patients with adenocarcinoma, 4.2% of patients with squamous cell carcinoma and 6.7% of patients with large cell lung carcinoma
- 38.2% do not smoking women and only in 15.5% of non-smoking men
- In 22% of smoking women and 6.2% of smoking men
In addition, the study found that the likelihood of a “breakdown” in the epidermal growth factor receptor increases with age in patients with adenocarcinoma, growing from 3.7% at 18-30 years old to 18.5% at 81-100 years old.
The results of a foreign study, which involved more than 2000 patients with lung adenocarcinoma, showed that the EGFR mutation was identified:
- In 15% of patients who smoked in the past
- 6% of patients were current smokers
- 52% of patients who have never smoked
These data confirm that epidermal growth factor receptor mutations can also be found in those who cannot imagine life without a cigarette, just much less frequently than in adherents healthy image life.
Despite the very clear trend in the spread of EGFR “driver mutations,” an accurate answer to the question of whether you have this “damage” can only be obtained from the results of molecular genetic testing, which is carried out for all lung cancer patients.
If you have an EGFR mutation
Just ten years ago, half of lung cancer patients were much less likely to successfully fight the tumor. However, today drugs have become available that have radically changed this situation. We are talking about targeted therapy, which has become available in the last decade.
The presence of an epidermal growth factor mutation, confirmed by the results of a molecular genetic study, provides oncologists with the opportunity to introduce targeted drugs into the treatment regimen. The creation of targeted drugs for the treatment of lung cancer has become a breakthrough in modern oncology.
Targeted drugs act on the root cause of a malignant disease, influencing the very mechanism that triggers unlimited cell growth and division. They block the enzyme tyrosine kinase, which transmits a signal to “start hostilities” and, in fact, activates the processes of cell reproduction and growth.
Targeted drugs “work” only if the corresponding mutations are present. If there is no gene “breakdown”, they are ineffective!
Targeted cancer therapy can significantly delay its progression, including compared to standard chemotherapy. This is a significant advantage of targeted drugs.
Progression-free survival is the time from starting the drug until your disease progresses.
The ability of targeted drugs (EGFR tyrosine kinase inhibitors) to prolong the time to tumor progression was proven in a large analysis examining the results of 23 studies involving more than 14 thousand patients with non-small cell lung cancer with an epidermal growth factor receptor mutation.
It is important to note that in the presence of an EGFR mutation, cancer treatment, as a rule, is not limited to targeted drugs. You must be prepared for a complex, lengthy and complex therapy, including surgical intervention, radiation therapy and etc.
If you do not have an EGFR mutation
A negative molecular genetic test result for the EGFR mutation does not mean that targeted therapy will not help you. First of all, it is important to find out if there is any other “breakage” found in your tumor. Although the epidermal growth factor receptor mutation is the most common among patients with lung cancer, the possibility of other, more rare “errors” cannot be ruled out.
Modern protocols, which oncologists rely on when selecting an individual treatment regimen for NSCLC, strongly recommend conducting a detailed molecular genetic analysis to identify not only the most common “driver mutations,” but also rare “breakdowns.” Modern choice targeted drugs allows you to select a “target” drug for most of the known mutations in lung cancer.
If no genetic “error” was found in your tumor sample, targeted therapy is really not indicated for you. Drugs that are designed to hit the bull's eye are not taken without purpose, because they simply will not work. But oncologists have other therapeutic options that will be effective in your case: chemotherapy and, possibly, immunotherapy. And yet you must remember - your individual treatment regimen will be determined by your attending physician, based on data on the histological type of your tumor, stage of the disease, etc.
Bibliography
- Divgi C.R., et al. Phase I and Imaging Trial of Indium 111-Labeled Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 225 in Patients With Squamous Cell Lung Carcinoma. JNCI J Natl. Cancer Inst. Oxford University Press, 1991. Vol.83, No.2, P. 97-104.
- Imyanitov E.N., et al. Distribution of EGFR Mutations in 10,607 Russian Patients with Lung Cancer. Mol. Diagn. Ther. Springer International Publishing, 2016. Vol.20, No.4, P. 40-406.
- D'Angelo S.P., et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from men and cigarette smokers with lung adenocarcinomas. J. Clin. Oncol. American Society of Clinical Oncology, 2011. Vol.29, No. 15, P. 2066-2070.
- Sharma S.V., et al. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer. 2007. Vol.7, No. 3, P. 169-181.
- Lynch T.J., et al. Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. N.Engl. J. Med. Massachusetts Medical Society, 2004. Vol. 350, No. 21, P. 2129-2139.
- Lee C.K., et al. Impact of EGFR Inhibitor in Non-Small Cell Lung Cancer on Progression-Free and Overall Survival: A Meta-Analysis. JNCI J Natl. Cancer Inst. Oxford University Press, 2013. Vol. 105, No. 9, P. 595-605.
