Genetic Tests for Precision Tumor Drug Use in One Article

An article to read and understand the tumor precise medication genetic testing

According to the World Health Organization (WHO) statistics, about 60% of the world's population died of cancer, diabetes, cardiovascular diseases, chronic respiratory diseases, which are the four major categories of diseases, and cancer is one of the most important causes of death. 2008 global cancer deaths of patients amounted to 7.6 million people, accounting for 13% of the world's total number of deaths. The results of the third national cause of death survey by the Ministry of Health of China also showed 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 has become the first cause of death in China's cities.

At present, the incidence of malignant tumors is increasing year by year, and its huge medical costs and other factors, making everyone "talk about cancer". The good thing is that the rapid development of treatment means, including surgery and radiotherapy of local treatment and anti-tumor drugs of systemic therapy category. Among them, drug therapy has become one of the most important means of clinical treatment for cancer. And when it comes to tumor drug therapy, it is inevitable to mention genetic testing technology. For doctors and patients, genetic testing is a "familiar and unfamiliar" high technology! How to make doctors or patients understand oncology genetic testing is really a technical work. Today, I'm going to do a dry sharing for the genetic testing related to oncology medication.

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

○? What exactly does genetic testing for oncology drugs detect? What anti-tumor drugs need genetic testing?

○? Is it true that the more genes tested, the better?

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

○? What is the best sample to choose for genetic testing of tumors?

1. Why should genetic testing for oncology be done?

The main reason for genetic testing is that tumors are a highly heterogeneous group of diseases. That is to say, even if they suffer from the same kind of 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 the clinical treatment of tumors needs to develop individualized and precise plans. Genetic testing is a very important part of evaluating the effectiveness of drugs used by patients, and can give precise guidance to doctors on the use of drugs from the molecular level.

2. What does genetic testing for oncology drugs detect? What antitumor drugs require genetic testing?

In fact, the genetic testing programs for different types of antitumor drugs are different.

In fact, there are different types of genetic testing for different types of antineoplastic drugs.

At present, the common clinical antitumor drugs can be broadly divided into the following six categories: cytotoxic drugs, hormonal drugs, targeted drugs, immune checkpoint inhibitors, biological response modifiers and adjuvant drugs.

Cytotoxic drugs

Introduction: Often called "chemotherapeutic" drugs, this kind of drugs is mainly based on the growth characteristics of cancer cells such as proliferation and other growth characteristics of the cancer cells to kill the cancer cells, and therefore have similar characteristics of healthy cells will be attacked indiscriminately, there are many kinds of drugs including:

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

(2) Drugs affecting nucleic acid synthesis, such as methotrexate, pemetrexed, etc.

(3) Drugs acting on nucleic acid transcription, such as adriamycin, epimedipine, etc.

(4) Inhibitors of topoisomerase Ⅰ, such as irinotecan, etc., acting on DNA replication;

(5) Drugs that act mainly in the mitotic M phase to interfere with microtubule protein synthesis, such as paclitaxel;

(6) Other cytotoxic drugs.

Purpose of genetic testing: To assess the effectiveness or safety (toxicity) of a drug for a patient.

Types of genetic testing: Based on the polymorphisms of the genes related to the metabolism of the drug, to assess the metabolic response of different chemotherapeutic drugs in the patient's body.

The need for genetic testing:

Because it does not involve the analysis of genetic mutations in tumor cells, chemotherapy drug genetic testing can not be considered as precision medicine in the full sense, but under other external conditions are the same, chemotherapy drug genetic testing can provide patients with a reference for choosing from the two aspects of the drug benefit or toxicity and side effects.

Hormonal drugs

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

Purpose of the genetic test: Similar to cytotoxic drugs, hormonal drug genetic testing mainly evaluates the effectiveness or safety (toxicity and side-effects) of the drug for patients. or safety (side effects).

Type of genetic testing: Same as chemotherapy.

Need for genetic testing: ?

Targeted drugs

Description: Drugs that are directed at a specific "target" on cancer cells, such as a specific gene mutation, to inhibit the growth of cancer cells until they are killed. Targeted drugs theoretically only inhibit cancer cells without causing significant damage to normal cells, and therefore have much fewer side effects. For this type of drugs, if the patient has the corresponding therapeutic target, the targeted drugs are highly effective and fast-acting, which can quickly relieve the symptoms brought by the tumor, improve the patient's quality of life, and significantly increase the survival rate within a certain period of time.

Targeted drugs are mainly divided into two categories: large molecule monoclonal antibody drugs and small molecule targeted drugs. Among them, small molecule targeted drugs are mainly concentrated in protein tyrosine kinase agents, proteases and other types, typically represented by Gleevec (Bcr-Abl gene mutation) for leukemia and ERISA (EGFR gene mutation) for lung cancer.

Purpose of genetic testing: To assess the efficacy or resistance of a targeted drug in a patient.

Types of genetic testing: Due to the large number of targeted drugs, each targeted drug is usually tested for point mutations/insertions/deletions/copy number variations/fusions (structural variations) in specific genes in the tumor signaling pathway, which are often collectively referred to as "gene mutations". The major genes and signaling pathways involved in small molecule targeted drugs include:

(1) Epidermal growth factor receptor (EGFR);

(2) VEGFR family;

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

(4) Fibroblast growth factor receptor (FGFR); and (5) Fibroblast growth factor receptor (FGFR) family. growth factor receptor (FGFR) family;

(5) four families of non-receptor tyrosine kinases closely associated with malignant tumorigenesis: the ABL family, the JAK family, the SRC family, and the FAK family;

(6) the PI3K/Akt signaling pathway associated with mTOR inhibitors.

Need for genetic testing: ?

Targeted drug genetic testing is the true sense of precision medicine through the patient's cancer cell genetic testing, so as to select a specific drug or program that is effective for the patient. As many targeted drugs have clear efficacy/resistance targets, genetic testing must be followed before use! They should not be used blindly without relevant genetic testing!

Due to the heterogeneity and evolution of tumors, targeted drugs may become resistant after a period of time and need to be changed, so it is best to have regular testing for targeted drug genetic testing along with drug efficacy.

Immune test point inhibitors

Introduction: At present, this kind of drugs is often referred to as "immune drugs", mainly through the inhibition of cancer cells to suppress the immune response, so as to activate the function of T-cells, so that the patient's own immune system to kill the mutated tumor cells, mainly including the recent big fire PD-1/PD-L1 inhibitors, which can be used to treat tumors, but also to treat tumors. /PD-L1 inhibitors and CTLA-4 inhibitors. Many of the patients responding to this type of drug will benefit in the long term, and a small number of patients have even been cured, making it one of the key research and development directions for antitumor drugs today.

Purpose of genetic testing: To assess the potential benefit to patients of this class of drugs.

Types of genetic testing: Genetic testing for this type of drug is mainly to assess the biomarkers of benefit, including:

(1) PD-L1 expression, only for PD-1/PD-L1 inhibitor drugs;

(2) MMR/MSI test, the patient's DNA mismatch function test, both belong to the same type of test, microsatellite instability (MSI) can reflect the MMR/MSI side by side. MSI) can flank whether the MMR system is working well;

(3) Tumor mutation load (TMB).

The need for genetic testing:

The biggest problem with the current class of immune-detecting point-of-care drugs is that they are not very effective, only 10% to 20%, and they are currently expensive, so genetic testing is necessary to assess the possible benefit of the drug.

The genetic testing of the above three types of biomarkers for immune drugs, only one of which can be selected in the current practical application. Generally speaking, in case of lung cancer patients, it is recommended to choose the PD-L1 expression test as the currently listed drugs for lung cancer are basically PD-1/PD-L1 inhibitors; in case of colorectal cancer patients, it is recommended to choose the MSI test, and of course, it is possible to choose the simultaneous test for comprehensive assessment or blinded use of the drug according to the actual situation.

Biological response modifiers

Introduction : Mainly through the body's immune function to inhibit tumors, such as interferon, interleukin-2, thymic peptides.

Genetic testing purpose: At present, such drugs basically do not need to do genetic testing.

Type of genetic testing: None.

Need for genetic testing: None.

Adjuvant drugs

Introduction: In tumor treatment, drugs that assist the efficacy of other drugs or reduce the side effects of other drugs, such as

(1) blood-boosting drugs (eg, G-CSF, GM-CSF, interleukin-11, EPO, etc.);

(2) antinausea drugs (eg, endocetone, granisetron hydrochloride, etc.);

(3) analgesics (e.g. aspirin, paracetamol, codeine, tramadol, morphine, fentanyl, etc.);

(4) osteoclast inhibitors (e.g. clodronate disodium, pamphiphosphate disodium, etc.).

Purpose of genetic testing: At present, such drugs basically do not need to do genetic testing.

Type of genetic testing: None.

Need for genetic testing: None.

3. Is it better to test for more genes?

The answer is no. Depending on the actual drug to be evaluated, the corresponding genetic testing program should be selected, especially for targeted drugs, where the efficacy/resistance target genes of each drug are relatively fixed.

With the rise of high-throughput sequencing (NGS) technology, the commercial market will see hundreds of genes packaged for testing, i.e., sequencing panels or "gene packages", but because the marketed targeted drugs are relatively fixed, when the number of sequenced genes covers enough target genes, then increasing the number of genes may not further provide more target genes. However, since the number of sequenced genes covers enough target genes, increasing the number of genes may not provide further guidance on target drugs, and these panels often provide some additional analysis, such as genetic evaluation; in addition, large panel gene sequencing can also be used to fit the TMB calculation, but there is no unified standard or conclusion on the calculation method of TMB based on large panel.

In addition, the sequencing result of Panel is also related to its sequencing coverage (the current gene region that can be covered), sequencing depth (which can be measured by the amount of sequencing data), and so on. Based on the above points, the selection of panel size for NGS sequencing should be based on the actual needs, not only according to the amount of genes.

4. What are the methods of genetic testing?

Which is the best?

The method of genetic testing is directly related to the type of genetic testing, and each type of genetic testing has a more appropriate genetic testing method. Due to the complexity of the genetic testing system, the best approach is to select the appropriate test based on the drug to be evaluated. Here is a brief summary of the common tests associated with each type of genetic test:

(1) Gene polymorphism: PCR;

(2) Relative expression detection: fluorescence quantitative PCR;

(3) Point mutation/small insertion deletion: PCR;

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

(5) Fusion (structural variation): FISH;

(6) Fusion (structural variation): FISH;

(7) Fusion (structural variation): FISH mutations): FISH;

(5) Multi-gene, multi-type mutations (except for relative expression assays): NGS;

(6) Peptide and protein detection: immunohistochemistry (IHC).

5 .? What are the best samples for genetic oncology testing?

What are the best samples for genetic oncology testing?

Currently, tissue samples are still the gold standard for oncology genetic testing, and some genetic tests can only be performed with tissue samples. Therefore, if possible, tissue samples should be preferred. If tissue samples are not available, it is best to use peripheral blood for ctDNA gene testing for patients in middle to late clinical stages (after clinical stage III). At the same time, peripheral blood ctDNA gene test for targeted drugs should preferably be performed before any treatment, because both radiotherapy and targeted therapy will have an impact on the peripheral blood ctDNA test results. According to the detection rate, fresh tissue > paraffin sections > pleural and abdominal fluid supernatants > pleural and abdominal fluid cells > peripheral blood.

In addition, since the ratio of peripheral blood ctDNA to peripheral blood cfDNA is positively correlated with tumor size and progression, ctDNA testing (tumor liquid biopsy) currently has another more important application in the clinic in addition to the guidance of tumor medication--tumor progression monitoring , the specific The applications include:

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

Liquid biopsy (including ctDNA testing) can detect cancer early in healthy, asymptomatic people through blood and other tests, which is a very promising technology that can be used in combination with whole genome sequencing to detect the risk of cancer in real time, one for real-time detection of the occurrence of cancer, and the other for the understanding of the familial inheritance and the normal probability of cancer occurrence (e.g., primary cancer). The combination of a real-time detection of cancer occurrence and an understanding of familial inheritance and the normal probability of cancer occurrence (e.g., proto-oncogene P53 and breast cancer BRAC gene testing, etc.) will lead to better cancer prevention.

(2)? Tumor treatment efficacy tracking

Although ctDNA levels vary greatly from patient to patient, ctDNA levels in individual patients are closely correlated with changes in tumor load and treatment efficacy over time. Some studies have suggested that ctDNA levels may be transiently elevated after the start of treatment when tumor cell death results in increased ctDNA release. However, ctDNA levels in patients who respond to treatment drop sharply 1 to 2 weeks after treatment initiation. In some respects, changes in ctDNA are superior to standard tumor markers in predicting treatment efficacy. This is an important reason why ctDNA can be used clinically as a long-term tracker of cancer treatment effects.

(3)? Tumor recurrence monitoring

For the time being, the main treatment for solid tumors remains surgery, and it is not yet possible to determine which patients contain residual lesions immediately after surgery, and any residual tiny cancer cell lesion may lead to cancer recurrence. In established studies, postoperative ctDNA testing can predict residual lesions and tumor recurrence in breast, lung, colorectal and pancreatic cancers. This makes ctDNA a promising postoperative management strategy. For now, ctDNA testing can help cancer patients better manage and treat their cancer, and in the future, ctDNA will certainly become an integral part of cancer treatment.

Conclusion

Finally, I would like to say that the core goal of oncology medication genetic testing is to provide medication guidance, and due to technical reasons, it is difficult for doctors or patients to read the results of genetic testing directly, which requires genetic testing providers to provide a corresponding high standard of interpretation, and based on the results of the interpretation of the medication for patients and doctors to provide relevant medication assessment. Therefore, doctors or patients should choose the appropriate genetic testing program based on the corresponding target anti-tumor drugs.

-?END?-