Precision medicine for lung cancer

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Lung cancer problem

Perhaps it is because of the direct feeling of the respiratory system. As the haze continues, we feel more and more people suffering from lung cancer around us. Indeed, lung cancer is the fastest growing malignant tumor in the world. The incidence and mortality of lung cancer are the first among men, and the incidence and mortality of women are the second. Every year on November 17th is the “International Lung Cancer Day”, and 2015 is the “First Year of Precision Medicine”. We hope that on this special day, we will pass on more lung cancer knowledge to people with lung cancer patients around us: lung cancer is not Incurable disease, scientific prevention and treatment of lung cancer, starting from understanding lung cancer.

Causes of lung cancer

The main causes of lung cancer include smoking, environmental pollution, occupational exposure, chronic lung disease, and genetic susceptibility. Among them, smoking is the first high-risk factor for the incidence of lung cancer. More than 80% of lung cancers are considered to be caused by smoking, and smokers are more than 10 times more likely to develop lung cancer than non-smokers. Women who do not smoke will have a 30% increased risk of lung cancer because their husband smokes. In particular, the “three 20” population, that is, people who have smoked for more than 20 years, people who have started smoking before the age of 20, and people who smoke more than 20 cigarettes a day are all high-risk groups for lung cancer. Because of very high number of smoker’s in India, incidence of lung cancer here is very high.

Environmental factors such as smoking, occupational exposure, and environmental pollution will have different “pathogenicity” for people with different genetic backgrounds; for example, some people meet the “three 20” conditions but will not get lung cancer, while others Got lung cancer. Genetically call this difference “genetic susceptibility”.

Lung cancer susceptibility

Genetic susceptibility means that due to the influence of genetic factors, or a certain genetic defect, it has the characteristics of being prone to certain diseases. As mentioned above, when different people smoke the same amount, some people develop lung cancer and some people do not develop lung cancer. This may be determined by genetic susceptibility. The genetic susceptibility of lung cancer is another important field of lung cancer research. Although most of the lung cancers are not related to direct genetic factors except for some familial lung cancers, through the research methods of genome-wide association analysis, scientists have found some Genes and loci related to the genetic susceptibility of lung cancer.

The cytochrome P450 family is an important oxidative metabolic enzyme involved in the metabolism of many important drugs. Several members of its family, CYP1A1, CYP1B1, CYP2D6, and CYP2A13, have multiple sites on genes that are associated with the risk of lung cancer. This is related to the metabolic capacity of chemicals brought into the body such as smoking and environmental pollutants: people with poor metabolic capacity may be more likely to accumulate substances such as polycyclic aromatic hydrocarbons (PAH), which can cause damage to lung tissue.

In addition, a cohort study of 5,739 patients with sporadic lung cancer and 5,848 healthy controls controlled the genetic susceptibility site at the rs2736100 (TERT) site on chromosome 5, and the TT genotype at this site was associated with a high incidence of lung cancer. TERT is a telomerase reverse transcriptase, under physiological conditions, it inhibits tumor production, but mutants may lose or reduce the function of the enzyme, thereby prone to tumors.

Of course, there are still many studies on genetic susceptibility related to lung cancer, and here are just a few. It is believed that with the deepening of research, more lung cancer susceptibility genes will be identified, and the relationship between these sensitive sites and the eventual lung cancer will also be gradually revealed.

Precision medicine for lung cancer

“Precision medicine” is an emerging method of disease prevention and treatment, which is based on understanding the individual’s genes, environment and lifestyle. At present, precision medicine is the most mature, or the most effective, is non-small cell lung cancer (NSCLC), which accounts for more than 80% of lung cancer. Surgery is still the most effective treatment, but it is only suitable for a small number of patients with non-localized metastases in NSCLC, and many patients will still relapse after surgery. In recent years, the role of epidermal growth factor receptor (EGFR) in the tumorigenesis of lung cancer and targeted therapy for EGFR are gradually being clinically recognized. Clinically reasonable screening of EGFR targeted therapy targets and determination of test results play an extremely important role in treatment The important role becomes the key to treatment. At the same time, KRAS and BRAF mutations and ALK gene rearrangement and the role of PD-L1 gene in lung cancer targeted therapy have also been gradually recognized clinically.

EGFR

Epidermal growth factor receptor (EGFR) and its family members play an important carcinogenic role by regulating cell proliferation, apoptosis, migration and tumor angiogenesis. Changes in EGFR signaling molecules involve the occurrence and development of various malignant tumors. Although the mechanism by which EGFR mutations cause cancer is not fully understood, it is clear that EGFR mutations can enhance tyrosine protein kinase activity.

In the United States and Asia, about 10% and 35% of patients with non-small cell lung cancer have EGFR mutations. These mutations mostly occur in exons 18-21, of which about 90% of mutations are exon 19 deletions or exons. Son 21 L858R point mutation. These mutations increase EGFR kinase activity, leading to the activation of downstream signaling pathways. In most cases, EGFR mutations are often accompanied by other types of mutations or rearrangements, such as KRAS mutations and ALK rearrangements.

At present, the molecular targeted drugs developed for EGFR are mainly divided into two categories: 1. Small molecule tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, and icotinib independently developed in China , The three can inhibit the activity of tyrosine kinase in EGFR intracellular domain; 2. Monoclonal antibody drugs (mAb), such as cetuximab and panitumumab, both of which bind to the extracellular domain of EGFR, blocking depends on EGFR activation of the ligand. The above drugs block EGFR-mediated intracellular signaling pathways through intracellular and extracellular pathways, respectively, thereby inhibiting tumor cell growth and migration, promoting tumor cell apoptosis, and increasing chemotherapy sensitivity.

KRAS

RAS is a common oncogene in human tumors. The genes associated with human tumors in the RAS gene family are composed of K-ras, H-ras and N-ras. Among them, K-ras (v-Ki-ras2 murine Kirsten sarcoma virus oncogene The highest mutation rate of homologues is 17-25%; at the same time, the K-ras gene is also the oncogenic gene with the highest mutation frequency in all tumors, and about 10-20% of tumors are related to the abnormal activation of K-ras. Can control the path of cell growth; when abnormal, it causes the cell to continue to grow and prevent apoptosis, which in turn leads to cancer.

K-ras protein is also a key regulator in the downstream of the EGFR signaling pathway. After mutation of the K-ras gene, it is always in an activated state, so it is not affected by the upstream signal of EGFR. In this state, treatment with EGFR targeted drugs is invalid. The most common way of carcinogenic mutations in the K-ras gene is point mutations at codons 12, 13 and 61 at the N-terminus, and codon 12 mutations are the most common.

BRAF

BRAF (murine sarcoma filter toxin (v-raf) carcinogen homolog B1) is a gene loca
ted downstream of KRAS in the EGFR signaling pathway and encodes the serine / threonine protein kinase in the MAPK pathway. The enzyme transduces the signal from RAS to MEK1 / 2, and thus participates in regulating various biological events in the cell.

Research groups at home and abroad have reported that BRAF has different proportions of mutations in lung cancer. These mutations mainly occurred in the activation region of exon 15, and about 92% of them were located at nucleotide 1799 (T mutation to A), resulting in the substitution of glutamic acid (V600E) for the encoded valine. This mutation can cause patients to develop resistance to antibody drugs such as cetuximab.

Verofinil is a non-receptor tyrosine kinase inhibitor that selectively inhibits the BRAF protein located at the entrance of the MAPK / ERK pathway. Approved for the treatment of malignant melanoma, it is the first approved tyrosine kinase inhibitor for tumors carrying the BRAF (V600E mutation) gene. Clinical trials have shown that the drug has an effective rate of 42.9% for patients with this melanoma, but is basically ineffective for those who have not been mutated.

ALK

The ALK (anaplastic lymphoma kinase) gene encodes a receptor tyrosine kinase and belongs to the insulin receptor superfamily. ALK proteins play an important role in brain development and can affect the nervous system of specific neurons. FDA approves ZYKADIA for patients with metastatic non-small cell lung cancer who have ALK positive progression or cannot use crizotinib, and crizotinib (XALKORI) is approved by the FDA for ALK positive non-small cell lung cancer patient. Rearranged ALK accounts for 5% of the incidence of NSCLC. In 2010, the New England Journal of Medicine reported that 82 of 1001 lung cancers were ALK-positive medications, with an effective rate of 60.8%. 347 patients with ALK positive (including platinum-based chemotherapy failure) randomized to receive crizotinib and chemotherapy significantly improved the proportion of tumor control.

Clinical trials have shown that after using ceritinib in 180 patients with ALK-fused non-small cell lung cancer, 60% of the patients had effective drug reactions, of which 121 patients who had previously received crizotinib had a response rate of 55.4 %, 59 patients who have not received any treatment have a response rate of 69.5%. PD-L1 PDCD1 (Progammed cell death1, PD1) gene encodes an immunoglobulin superfamily type I transmembrane glycoprotein, which is associated with its ligands PD-L1, PD- The combination of L2 has an inhibitory effect on the activation of lymphocytes, mediates the negative regulatory signal of the immune response, and induces the apoptosis of anti-tumor T cells. PD1 can also control the antigen-specific T cells in lymph nodes by regulating the Bcl-2 gene. Accumulation. It plays a specific regulatory role in tumorigenesis, viral infections and autoimmune diseases. PD1 and its ligand PD-L1 belong to the co-stimulatory molecule of the B7 family. This molecule has a wide tissue expression profile and high expression on some tumor cell lines. Many studies have shown that it is related to the immune escape mechanism of tumors. The signaling pathway mediated by PD1 and its ligand PD-L1 is becoming one of the methods of clinical disease treatment through immunological intervention.

PD-L1

Protein molecules are hardly expressed in normal tissues, but they are ubiquitous on the surface of human lung cancer, ovarian cancer, colon cancer, renal cancer and melanoma. Studies have speculated that it can make tumor cells have the magical ability to escape immune response. . By inhibiting PD1 or PD-L1 to activate the anti-tumor activity of T cells and maintain its ability to detect and attack cancer cells, it can provide new ideas for cancer treatment. More than 200 patients with different types of tumors were enrolled in two different clinical trials. The largest cohort samples included melanoma and non-small cell lung cancer (NSCLC) patients. Both trials reported surprisingly long-lasting response rates (6–17% in the anti-PDL1 group and 18–28% in the anti-PD1 group), especially for melanoma patients (17% and 28% in both groups) , And the incidence of drug-related adverse events is also low (9% and 14% for grade 3 and 4 drug-related adverse events, respectively). More importantly, in the anti-PD1 group, the response rate of tumor patients with positive PD-L1 expression was 36%. It is worth noting that the trial purpose and sustained response rate of NSCLC patients also meet the trial requirements, and such patients are known for their resistance to immunotherapy. This is by far the most successful immunotherapy strategy of all types of tumors, with a persistent tumor response rate of 10-15%.

As the concept of precision medicine continues to advance, the clinic has begun to use mutations to distinguish tumors rather than tissue sources. For example, if a gene mutation related to breast cancer targeted medication is found in lung cancer, then this breast cancer medication may be used in the treatment of lung cancer; the National Cancer Institute (NCI) has initiated related clinical research (NCI-MATCH) . I believe that in the near future, this concept will be fully practiced in the clinic.

Prevention of lung cancer

To prevent lung cancer scientifically, in addition to refusing active and passive smoking, paying attention to and actively treating chronic lung diseases, reducing indoor and outdoor air pollution, and maintaining ventilation after ventilation, regular medical screenings should be conducted every year. The popularity of this has played an important role in the early detection of lung cancer. For ordinary people, understanding their genetic background and being self-aware will provide a guarantee for a healthy life.

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