According to the statistics of the World Health Organization (WHO), about 60% people in the world die of cancer, diabetes, cardiovascular diseases and chronic respiratory diseases, and cancer is one of the most important causes of death. In 2008, 7.6 million people died of cancer worldwide, accounting for 13% of the global death toll. The results of the third national cause of death survey conducted by the Ministry of Health of China also show that cancer has become the second leading cause of death in China after cardiovascular and cerebrovascular diseases, accounting for 22.32% of the total number of deaths and the first leading cause of death in China.

At present, the rising incidence of malignant tumor and its huge medical expenses make everyone "talk about cancer discoloration". Fortunately, treatment methods have developed rapidly, including local treatment of surgery and radiotherapy and systemic treatment of anti-tumor drugs. Among them, drug therapy has become one of the important means of tumor clinical treatment. When it comes to tumor drug therapy, it is inevitable to mention gene detection technology. For doctors and patients, genetic testing is a high-tech that is both familiar and unfamiliar! How to make doctors or patients easily understand tumor genetic testing is really a technical job. Today, I will share a dry goods for everyone on the genetic testing related to cancer drugs.

○? Why do you want to do tumor genetic testing?

○? What did the genetic test of tumor drugs detect? What anti-tumor drugs need genetic testing?

○? Are the more genes tested, the better?

○? What are the methods of genetic testing? Which is the best?

○? What is the best sample for tumor genetic testing?

1. Why do you want to do tumor genetic testing?

The main reason of tumor gene detection is that tumor is a highly heterogeneous disease. In other words, even for the same tumor, different patients need to adopt different treatment plans according to their actual conditions, especially the choice of anti-tumor drugs. The sensitivity of different patients to different anti-tumor drugs varies greatly, so it is necessary to formulate individualized and precise plans for clinical treatment of tumors. Genetic testing is a very important part in evaluating the effect of patients' medication, which can give doctors accurate medication guidance from the molecular level.

2. What did the genetic test of anticancer drugs detect? What anti-tumor drugs need genetic testing?

In fact, the genetic testing items of different types of anti-tumor drugs are different. So, first of all, I will give you a comprehensive introduction to the categories of anti-tumor drugs, and then introduce the genetic testing projects of various anti-tumor drugs.

At present, the common clinical anti-tumor drugs in the world can be roughly divided into the following six categories: cytotoxic drugs, hormone drugs, targeted drugs, immune checkpoint inhibitors, biological response regulators and auxiliary drugs.

cytotoxic drug

Introduction: Commonly known as "chemotherapy" drugs, these drugs mainly kill cancer cells according to their growth characteristics such as excessive proliferation, so they will indiscriminately attack healthy cells with similar characteristics. Many types include:

(1) drugs that act on the chemical structure of DNA, such as platinum compounds;

(2) Drugs that affect nucleic acid synthesis, such as methotrexate and pemetrexed;

(3) drugs that act on nucleic acid transcription, such as adriamycin and epirubicin;

(4) topoisomerase I inhibitors acting on DNA replication, such as irinotecan;

(5) Drugs that mainly interfere with the synthesis of tubulin in mitosis M phase, such as paclitaxel;

(6) Other cytotoxic drugs.

Objective: To evaluate the effectiveness or safety (toxic and side effects) of drugs for patients.

Gene detection type: based on the polymorphism of drug metabolism-related genes in patients, evaluate the metabolic response of different chemotherapy drugs in patients.

The necessity of genetic testing:

Because it doesn't involve the analysis of gene mutation of tumor cells, the gene detection of chemotherapy drugs can't be regarded as a complete precise medical treatment, but under the same external conditions, the gene detection of chemotherapy drugs can provide reference for patients to choose from two aspects: drug benefit or toxic and side effects.

Hormone drugs

Introduction: Hormone-regulating drugs for hormone-related malignant tumor types (such as female breast cancer and male prostate cancer), including tamoxifen, letrozole, anastrozole, etc.

Objective: Genetic testing of hormone drugs, like cytotoxic drugs, mainly evaluates the effectiveness or safety (toxic and side effects) of drugs for patients.

Genetic testing type: same as chemotherapy drugs.

The necessity of genetic testing:

Targeted drugs

Introduction: Drugs that inhibit the growth of cancer cells until they are killed are aimed at specific "targets" on cancer cells, such as a specific gene mutation. Theoretically, targeted drugs will only inhibit cancer cells and will not cause obvious damage to normal cells, so the side effects are much less. For this kind of drugs, if patients have corresponding therapeutic targets, targeted drugs have high efficiency and quick effect, which can quickly alleviate the symptoms caused by tumors, improve the quality of life of patients and significantly improve the survival rate in a certain period of time.

At present, targeted drugs are mainly divided into two categories: macromolecular monoclonal antibodies and small molecular targeted drugs. Among them, small molecule targeted drugs mainly focus on protein tyrosine kinase agents, proteases and other types, and the typical representatives are Gleevec (Bcr-Abl gene mutation) for leukemia and Iressa (EGFR gene mutation) for lung cancer.

Objective: To evaluate the efficacy or drug resistance of targeted drugs in patients.

Types of gene detection: Because there are many kinds of targeted drugs, we usually detect point mutation/insertion deletion/copy number variation/fusion (structural variation) of specific genes in tumor signal pathway corresponding to each targeted drug, which is often collectively referred to as "gene mutation". Specifically, the main genes and signal pathways involved in small molecule targeted drugs include:

(1)EGFR epidermal growth factor receptor;

(2) Vascular epidermal growth factor receptor (VEGFR) family;

(3) platelet-derived growth factor receptor (PDGFR) family;

(4) Fibroblast growth factor receptor (FGFR) family;

(5) There are four families of non-receptor tyrosine kinases closely related to the occurrence of malignant tumors: ABL family, JAK family, SRC family and FAK family;

(6) PI3K/Akt signaling pathway related to mTOR inhibitors.

The necessity of genetic testing:

Gene detection of targeted drugs is to select specific drugs or schemes that are effective for patients through gene detection of cancer cells of patients, which is a real precision medical treatment. Because many targeted drugs have clear efficacy/drug resistance targets, they must follow genetic testing before they can be used! No relevant genetic testing should not be used blindly!

Due to the heterogeneity and evolution of tumors, targeted drugs may develop drug resistance after a period of use and need to be replaced. Therefore, it is best to regularly test the gene detection of targeted drugs combined with drug efficacy.

Immune checkpoint inhibitor

Brief introduction: At present, these drugs are often referred to as "immune drugs" for short, which mainly activate the function of T cells by inhibiting the immune response of cancer cells, so that patients' own immune system can kill mutated tumor cells, mainly including PD- 1/PD-L 1 inhibitors and CTLA-4 inhibitors which have been on fire in recent years. Many patients who respond to this kind of drugs will benefit for a long time, and a few patients will even recover, which is one of the key research and development directions of anti-tumor drugs at present.

Objective: To evaluate the possible benefits of such drugs to patients.

Types of genetic testing: The genetic testing of such drugs is mainly to evaluate useful biomarkers, including:

(1)PD-L 1 expression, only for PD- 1/PD-L 1 inhibitor drugs;

(2)MMR/MSI test, the patient's DNA mismatch function test, both belong to the same type of test, and microsatellite instability (MSI) can reflect whether the MMR system works well;

(3) Tumor mutation load (TMB).

The necessity of genetic testing:

At present, the biggest problem of immunoscreening inhibitors is low efficiency, only 10%~20%, and its current cost is high. Therefore, it is necessary to evaluate the possible benefits of drugs through genetic testing.

At present, only one of the above three biomarkers can be selected in practical application. Generally speaking, if you are a lung cancer patient, it is recommended to choose PD-L 1 for expression detection, because most drugs on the market at present are PD- 1/PD-L 1 inhibitors. If it is a patient with colorectal cancer, it is recommended to choose MSI detection. Of course, you can also choose comprehensive evaluation or blind medication according to the actual situation.

biological response modifiers,brm

Introduction: It mainly inhibits tumors through the immune function of the body, such as interferon, interleukin -2, thymosin and so on.

Objective: At present, there is basically no need for genetic testing of these drugs.

Genetic testing type: None.

Necessity of genetic testing: none.

Auxiliary medicine

Brief introduction: drugs that assist the efficacy of other drugs or reduce the side effects caused by other drugs in tumor treatment, such as

(1) drugs for raising blood lipid (such as G-CSF, GM-CSF, interleukin-1 1, EPO, etc.). );

(2) Antiemetic drugs (such as Ondansetron and granisetron hydrochloride);

(3) Analgesics (such as aspirin, paracetamol, codeine, tramadol, morphine, fentanyl, etc. );

(4) Osteoclast inhibitors (such as disodium chlorophosphonate and disodium pamidronate).

Objective: At present, there is basically no need for genetic testing of these drugs.

Genetic testing type: None.

Necessity of genetic testing: none.

3. Is it better to test as many genes as possible?

The answer is no, we need to choose the corresponding genetic testing items, especially targeted drugs, according to the drugs that need to be evaluated actually. The efficacy/resistance target genes of each drug are relatively fixed.

With the rise of high-throughput sequencing technology (NGS), several to hundreds of genes are packaged and tested in the commercial market, that is, sequencing plates or "gene packages". However, because the targeted drugs on the market are relatively fixed at present, when the number of sequencing genes covers enough target genes, increasing the number of genes may not necessarily provide more targeted drug guidance. These groups usually provide some additional assessments, such as genetic assessments; In addition, large-panel gene sequencing can also be used to fit and calculate TMB. However, at present, there is no unified standard and conclusion for the calculation method of TMB based on large panel.

In addition, the sequencing results of Panel are also related to its sequencing coverage (the gene region that can be covered at present) and sequencing depth (which can be measured by the amount of sequencing data). Based on the above points, the size selection of NGS sequencing plate should be judged according to actual needs, not simply according to the number of genes.

4. What are the methods of genetic testing?

Which is the best?

The method of gene detection is directly related to the type of gene detection, and each type of gene detection has a more suitable gene detection method. Because the genetic testing system is complicated, the best way is to select the corresponding testing items according to the drugs to be evaluated. Let me give you a brief summary of the common detection methods corresponding to each genetic detection type:

(1) gene polymorphism: PCR；;

(2) Relative expression detection: fluorescence quantitative PCR；;

(3) point mutation/small fragment insertion deletion: PCR；;

(4) large fragment insertion deletion/copy number variation/fusion (structural variation): FISH；;

(5) Multi-gene and multi-type mutation (except relative expression detection): NGS；; ;

(6) Detection of polypeptide and protein: Immunohistochemistry (IHC).

5 .？ What to choose for tumor genetic testing?

The sample is the best?

At present, tissue samples are still the gold standard for tumor genetic testing, and some genetic testing projects can only be realized through tissue samples. Therefore, when conditions permit, priority should be given to tissue samples. If tissue samples cannot be obtained, it is best for patients in the middle and late clinical stage (after the third clinical stage) to choose peripheral blood for ctDNA gene detection. At the same time, it is best to detect the gene of peripheral blood targeted drug ctDNA before any treatment, because radiotherapy and chemotherapy and targeted therapy will affect the detection results of peripheral blood ctDNA. According to the detection rate, fresh tissue > paraffin section > clear water of chest and abdomen > hydrothorax and ascites cells > peripheral blood.

In addition, because the ratio of peripheral blood ctDNA to peripheral blood cfDNA is positively correlated with the size and progress of tumor, ctDNA detection (tumor liquid biopsy) has another more important application possibility-tumor progress monitoring, in addition to tumor medication guidance. The specific applications include:

( 1)? Early diagnosis of tumor (early screening of tumor)

Liquid biopsy (including ctDNA test) can detect cancer early in healthy and asymptomatic people through blood test, which is a potential technology. It can be combined with whole genome sequencing to detect cancer risk in real time. One is to detect the occurrence of cancer in real time, and the other is to know the family inheritance and the probability of normal cancer (such as detecting the proto-oncogene P53 and breast cancer BRAC gene, etc.). ), which will better prevent cancer.

(2)? Follow-up of tumor treatment effect

Although the level of ctDNA in different patients varies greatly, with the passage of time, the level of ctDNA in a single patient is closely related to the change of tumor load and therapeutic effect. Some studies have shown that when the death of tumor cells leads to an increase in the release of ctDNA, the level of ctDNA may increase temporarily after starting treatment. However, after the start of treatment 1~2 weeks, the level of ctDNA in patients who responded to treatment dropped sharply. In some respects, the changes of ctDNA are superior to the standard tumor markers in predicting the therapeutic effect. This is also an important reason why ctDNA can be used for long-term follow-up of cancer treatment effect in clinic.

(3)? Tumor recurrence monitoring

At present, the main treatment for solid tumors is still surgery, and it is not clear which patients contain residual lesions immediately after surgery. Any residual tiny cancer cells may lead to cancer recurrence. In previous studies, postoperative ctDNA detection can predict the residual lesions and tumor recurrence of breast cancer, lung cancer, colorectal cancer and pancreatic cancer. This makes ctDNA a potential postoperative management strategy. At present, ctDNA detection can help cancer patients to better manage and treat cancer, and in the future, ctDNA will become an indispensable part of cancer treatment.

label

Finally, I want to say that the core goal of genetic testing for cancer drugs is to give medication guidance, but due to technical reasons, it is difficult for doctors or patients to directly read the results of genetic testing, which requires genetic testing providers to provide corresponding high-standard interpretation and provide relevant drug evaluation for patients and doctors according to the interpretation results. Therefore, doctors or patients should reasonably select the corresponding genetic testing items according to the corresponding targeted anti-tumor drugs.

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