30 January 2008

Commendation of Personalized Medicine (1)

An abridged (mainly due to the list of references) translation of the article The Case For Personalized Medicine (pdf, 0.5 M), published on the Personalized Medicine Coalition website.

When looking for an answer to the question of the viability of personalized medicine in the future, a look into the past indicates that this approach to medicine has always existed in one form or another. However, in its modern incarnation, which is based on the use of molecular analysis and preventive measures, personalized medicine needs a powerful support system. This system should include new regulatory approaches, updated medical education curricula, an integrated medical information system, legislation to ensure protection against genetic discrimination, insurance coverage for complex molecular diagnostic tests and a compensation system that encourages preventive measures. Due to the large number of obstacles to the development of personalized medicine, some experts doubt whether it will become the dominant direction of the health care system or only a transitional stage. In this brochure, we present the arguments in favor of personalized medicine, shedding light on its advantages and limitations and sketching a realistic scenario for its evolution.

By using molecular genetic analysis to achieve optimal medical results in the fight against a disease or a patient's predisposition to a particular disease, personalized medicine can lead to the introduction of new health standards.

Molecular methods that enable the existence of personalized medicine include testing for variations in gene expression, protein structure and metabolites, as well as new treatment methods that selectively act on certain molecular mechanisms. The test results correlate with clinical factors, such as the course of the disease and its prognosis, the response to treatment and the prognosis of treatment, which allows doctors to individualize the approach to the treatment of each patient.

In a certain sense, doctors have always used and continue to use personalized medicine. They constantly use diagnostic tests to determine the patient's condition. They also change medications or select dosages to optimize treatment and prevent the development of dangerous side effects. However, the traditional form of personalized medicine is based on visible manifestations of the disease or treatment, such as the presence of a tumor on a mammogram, the characteristics of cells under a microscope, or the patient's complaints of dizziness when taking the drug. Only recently, doctors have been able to use molecular information about the patient when choosing treatment methods, such as the presence of biomarkers in the blood indicating an increased risk of developing cardiovascular diseases, the presence of a tumor or inflammation.

Some diseases, such as many forms of cancer, can now be characterized by their molecular profile. In the past, the diagnostic characterization of cancer was carried out depending on the organ or location of the tissue in which the tumor was originally formed, for example, breast or liver cancer. Today, a patient's tumor can be classified depending on the genes expressed by its cells, surface markers and other molecular parameters. Such molecular characteristics provide new information about the rate of cancer spread and its possible response to various treatments.

The widespread use of genetic and other molecular diagnostic tests in clinical practice can completely change approaches to medical care. Such tests can provide significantly more information about the patient's condition, including susceptibility to the disease and its progression, as well as the most likely reactions to medications. Based on the results of such tests, due to their prognostic capabilities, it is possible to plan the most effective preventive interventions. Moreover, since many tests are designed to identify inherited genetic parameters, their results may be important not only for the patient himself, but also for his blood relatives.

Molecular diagnostic tests challenge the healthcare financing system, which for a long time has been based on the registration of visible symptoms of the disease and general clinical classification. At the same time, the ability to classify diseases into various molecular subcategories undermines the foundations of traditional economic models of pharmaceutical business, implying the creation of universal drugs for the treatment of all patients with a certain diagnosis. As a result, the economic rationality of decisions dictated by personalized medicine in the field of healthcare will be based to a greater extent on reducing the cost of treatment through preventive and preventive measures. This approach requires cultural and political changes in the current approaches to the implementation and payment of medical services.

The use of genetic and other molecular tests also raises ethical, legal and social issues. For example, should a doctor, in case of detection of a genetically determined predisposition of a patient to the development of breast cancer, recommend other family members to be tested for the presence of the same altered gene in the genome? How is it necessary to ensure the protection of test results in order to prevent misuse of information when applying for a job and denial of insurance payments?

The benefits provided by personalized medicine far outweigh any disadvantages and doubts. Proponents of personalized medicine emphasize that it provides an opportunity:

– to detect diseases at early stages of development, easier to treat;
– to select the optimal therapy and resort to trial and error less often;
– reduce the frequency of side effects of drugs;
– to increase the level of compliance with the requirements of therapy by patients;
– facilitate the selection of targets when searching for drugs;
– reduce time and financial costs, as well as the frequency of clinical trial failures;
– to give a second life to drugs that have not passed clinical trials and have been withdrawn from the market;
– to avoid the recall of sold drugs from the market;
– shift medical priorities from responding to disease prevention;
– reduce overall health care costs.

To date, most of the prospects and many problems of personalized medicine have not been tested and forecasts of its future, based on limited data, range from quite pessimistic (The Royal Society 2005; Williams-Jones et al. 2003) to emphatically optimistic (Ginsburg et al. 2006). In this message, we present evidence that personalized medicine has already proven its value and its importance will continue to grow, while at the same time recognizing that uncertainty remains throughout the path to achieving its ultimate goals.

COLLECTING EVIDENCESelection of optimal treatment

Doctors have long noticed that patients' reactions to the same drug can vary significantly.

For example, statin drugs used to lower cholesterol in the blood are effective only in 30-70% of cases (Spear et al. 2001). The results of the studies indicate the existence of a relationship between differences in drug response and variations in genes encoding drug-metabolizing liver enzymes, drug carrier molecules or their targets (Mangravite et al. 2006; Rieder et al. 2005; Terra et al. 2005). The identification of such hereditary features makes it possible to use genetic or other forms of molecular screening for the initial selection of optimal treatment, without using the traditional trial and error method.

The proportion of the patient population in relation to which some drugs are ineffective is:Antihypertensive drugs – angiotensin converting enzyme inhibitors (ACE, angiotensin converting enzyme) – 10-30%

Drugs for the treatment of heart failure – beta blockers - 15-25%
Antidepressants – 20-50%
Cholesterol lowering drugs – statins – 30-70%
Anti–asthmatic drugs - beta-2-agonists – 40-70%

Women diagnosed with breast cancer were the first to feel the benefits of a personalized medical approach. About 30% of malignant breast tumors are characterized by overexpression of the cell surface protein – human epidermal growth factor receptor-2 (human epidermal growth factor receptor 2, HER2). In physiological amounts, HER2 stimulates the growth of normal cells. However, in cases where the mutation leads to overexpression of HER2 on the cell surface, certain breast epithelial cells begin to divide uncontrollably and penetrate into surrounding tissues (Menard et al. 2003).

Women with HER2-positive breast cancer respond poorly to standard treatments. The appearance of the drug Herceptin (Herceptin, trastuzumab), the active component of which is antibodies selectively inhibiting the HER2 receptor, significantly increased the survival rate of women with this severe form of cancer (Piccart-Gebhart et al. 2005; Romond et al. 2005). Molecular diagnostic tests developed by specialists that detect the level of the HER2 protein or the number of copies of the gene encoding it are used to identify patients who will respond to Herceptin treatment.

Gleevec (imatinib) – the second successful example of personalized medicine – is used for the treatment of chronic myeloid leukemia (CML) and malignant stromal tumors of the gastrointestinal tract. The cause of the development of CML is a chromosomal rearrangement that causes the fusion of two normal proteins to form the protein Bcr-Abl, which stimulates a rapid increase in the number of white blood cells. Glivec binds specifically to Bcr-Abl and suppresses its activity. The expediency of prescribing Glivec is determined using a diagnostic test that detects the presence of the BCR-ABL gene. According to research results, Glivec causes a much higher level of response in patients with CML and is less toxic than traditional methods of chemotherapy (Druker et al. 2001). More than 90% of patients receiving Glivec respond positively to the first course of treatment, while many of them go into complete remission.

Recently, a genetic test has appeared on the market to monitor the development of Glivec resistance, observed in 4-5% of patients with CML (Genzyme 2006). It provides additional opportunities for personalizing treatment with this drug.

Personalized medicine has also revolutionized the treatment of acute lymphoblastic leukemia (ALL), the most common form of cancer in children and adolescents (Pui et al. 2006). In 1962, only 4% of children with ALL survived for 10 years after diagnosis (the criterion of cure). Today, thanks to the use of genetic screening methods and improved treatment, the cure rate is more than 80%, while the five-year survival rate is approaching 90%. The use of genetic analysis to determine subtypes of ALL allows clinicians to select the optimal drugs and their dosage individually for each patient and thus reduce the likelihood of toxic reactions and relapses. In some cases, it is even possible to avoid chemotherapy and radiotherapy, thereby limiting the likelihood of damage to vital organs and the development of new tumors. Doctors also have the opportunity to identify patients for whom standard treatment methods are not suitable and more stringent protocols are needed. In some cases, the potential degree of effectiveness of various standard treatment methods can be determined for individual cancer patients (Burstein et al. 2006).

One of the first diseases targeted by personalized medicine is HIV/AIDS. Twenty years ago, the diagnosis of "HIV infection" was almost a death sentence. Today, the use of information on phenotypic and genotypic resistance allows doctors to refuse drugs to which this strain of the virus has acquired resistance, and to hold alternative methods of treatment for the future. Thanks to this, HIV, like any chronic disease, can be suppressed for a long time. Since 1996, HIV genotyping has become an integral part of working with HIV-infected patients and over time can be taken as the basis of a model for the application of personalized medicine approaches in other areas of clinical practice (Blum et al. 2005).

Reducing the severity of side effects. According to experts, more than 2 million people in the United States develop serious adverse reactions to medications every year, which takes about 137,000 lives (Lazarou et al. 1998). Some of these deaths can be prevented by preliminary detection of genetic variations in patients, indicating a predisposition to the development of toxic reactions when taking drugs, most often showing undesirable side effects.

Many adverse reactions to drugs are caused by variations in genes encoding enzymes. Enzymes are complex proteins that catalyze chemical reactions occurring in the body, including the metabolism of nutrients or chemical compounds. About half of all drugs are cleaved by cytochrome P450 enzymes contained in the liver and gastrointestinal tract (BCBS 2004). There are more than 300 different forms of these enzymes, each of which is encoded by a separate gene. Variations of these genes cause slow or fast metabolism of certain drugs. As a result, some individuals may have problems with inactivating a particular drug and removing it from the body, while in other individuals it is excreted even before the therapeutic effect is manifested. For drugs that break down too slowly, there is a high risk of overdose when taking the usual dose, which is fraught with serious side effects.

The U.S. Food and Drug Administration (FDA) has approved the use of Amplichip, a test that identifies variations of two important genes in the cytochrome P450 family (Jain 2005). The information provided by Amplichip and similar tests will help clinicians select the optimal dosages of the most safe drugs for patients. The UGT1A1 kit has also received FDA approval to predict the safety of irinotecan, used for the treatment of colon cancer. The test allows doctors to adjust the dosage of irinotecan for about 10% of patients who metabolize the active form of the drug very slowly.

The use of the drug warfarin, which prevents the formation of blood clots, is complicated by variations in genes encoding enzymes that break down the drug itself (the CYP2C9 gene) and vitamin K (the VKORC1 gene). The dosage in each case is adjusted by trial and error, which puts patients at risk of developing severe bleeding or thrombosis. The need to initially select the optimal dosage of warfarin in order to avoid side effects led to the appearance of the recommendation of the FDA advisory committee on genotyping all patients taking warfarin (Womack 2005). Currently, the process of reviewing the labeling of the drug is suspended pending the results of the final phase of clinical trials.

Thiopurine Methyltransferase (TPMT) is another enzyme studied from the standpoint of personalized medicine. TPMT inactivates purine drugs used to treat ALL and other diseases (Wang et al. 2006). Variations of the TPMT gene cause differences in enzymatic activity and, accordingly, the metabolism of drugs. In one of about 300 patients, both copies of this gene encode an inactive form of TPMT, which leads to TPMT deficiency. Taking regular doses of purine drugs causes an accumulation of the active form of the compound in such patients, which can cause a deadly reaction from the bone marrow, expressed in an abnormal decrease in the number of white blood cells. After several fatal cases in children with TPMT insufficiency who were treated with purine drugs for ALL, before prescribing therapy, doctors began screening for variations of the TPMT gene. If TPMT insufficiency is detected, the patient is prescribed a dosage of the drug that is 10-15% of the standard. This correction ensures that the systemic concentration of the drug in the patient's body is maintained at a level comparable to the levels observed in patients with a normal variant of TPMT taking standard doses of the drug.

Improving patient compliance with therapy requirements. Failure by patients to comply with the requirements of therapy negatively affects the course of treatment and leads to increased costs for it. If the higher effectiveness of personalized treatments and fewer associated side effects are proven, it can be assumed that patients will be more willing to adhere to the prescriptions. This can have the most pronounced effect on the treatment of diseases such as asthma and diabetes, in which non-compliance with the treatment protocol usually aggravates the patient's condition. To date, only cases from practice have been described, but there are no reliable published results concerning the specifics of patients' compliance with the requirements of personalized treatment protocols.

Reducing the duration, cost and percentage of failures during clinical trials. The development of a new drug is an expensive and time-consuming process (DiMasi et al. 2003). Theoretically, the use of pharmacogenomics data – information about how patients' genes affect their reactions to drugs – can reduce the cost and duration of drug development. With the help of genetic tests, researchers can pre-select patients and invite those who are more likely to respond to treatment and not experience side effects to conduct clinical trials. The so-called "enrichment" of the group of participants in clinical trials will reduce their scale, time and cost. Moreover, the use of pharmacogenomics at the early stages of drug development can reduce the percentage of failures due to preferred work with candidate drugs that potentially have maximum efficacy and safety. According to a report by the Boston Consulting Group (Tollman et al. 2001), the use of such information in certain drug development programs will allow pharmaceutical companies to save up to 335 million US dollars on each drug.

Cases from practice indicate that pharmacogenomics can also shorten the duration of clinical trials. For example, the 3rd phase of clinical trials of the drug Tikerb (Tykerb, lapatinib) was stopped earlier than usual due to the pronounced effectiveness of the drug in the treatment of a genetically determined group of patients with breast cancer (Pollack 2006). In the case of Herceptin, both time and costs were reduced due to the use of a special diagnostic test during the preliminary selection of patients for the main phase of clinical trials.

Preservation of drugs that have not passed clinical trials. When working with Herceptin, the researchers adhered to the model of adaptation of clinical trials, which influenced the fate of the new drug. The results of the Phase 3 clinical trials conducted in 1997 testified to the ineffectiveness of the drug in relation to the entire tested patient population, however, subsequent re-processing of the results showed that women with positive test results for HER2 hyperexpression respond to Herceptin treatment much better. In 1998, clinical data were submitted to the FDA for review, according to which Herceptin treatment is effective against a group of HER2-positive patients determined by a diagnostic test (Cobleigh et al. 1999). The drug + diagnostic test combination quickly received FDA approval.

Preservation of drugs withdrawn from the market. To date, there are no examples when a drug withdrawn from the market due to repeated serious side effects would be returned to practice based on the results of genetic or molecular tests. However, Iressa (Iressa, gefitinib) is an example of a drug that is currently being tried to give a second life.

Approved in 2003 for the treatment of advanced non-small cell lung cancer, which is the leading cause of cancer death in the United States, Iressa significantly reduced the size of tumors, but only in a small proportion of patients (Tamura et al. 2005). Later, scientists identified a molecular marker correlating with the reaction to Iressa. However, the phase 3 clinical trials conducted after that showed that the drug does not improve the survival of the entire population of patients with lung cancer. Faced with the paradox that pronounced success in the treatment of some patients is accompanied by failure at the level of the entire population, the FDA limited the population taking Iressa to several thousand patients who respond well to the drug and started taking it before receiving the results of phase 3 clinical trials. Currently, the drug manufacturers are working on creating a genetic test that would identify patients responding to treatment.

Shifting the emphasis of clinical practice from response to prevention. Personalized medicine provides the possibility of using molecular markers indicating an increased risk of developing the disease or its presence, before the onset of clinical signs and symptoms. This information is the basis of a medical strategy primarily aimed at prevention and early intervention, rather than responding to the symptoms of the later stages of the disease. Such a strategy ensures delaying the onset of the disease or minimizing the severity of its course. Examples of currently used molecular prognostic markers are C-reactive protein, indicating the risk of developing cardiovascular diseases, and low- and high-density lipoproteins (different forms of cholesterol), the ratio of which indicates the likelihood of atherosclerosis. The detection of abnormal levels of these markers is an indication for the beginning of preventive measures.

To date, there are only two tests on the market to identify hereditary predisposition to diseases. One of them is designed to identify variants of the BRCA1 and BRCA2 genes that indicate a hereditary predisposition to breast and ovarian cancer (Nelson et al. 2005). For women with genetic risk factors BRCA1 and BRCA2, the risk of developing breast cancer during life is 36% and 85%, respectively, while for the entire population this indicator does not exceed 13%. Certain variants of the BRCA1 and BRCA2 genes also correspond to a 16 and 60 percent risk of ovarian cancer with an average risk of 1.7% for the general population. Genetic testing for variants of the BRCA1 and BRCA2 genes is used to plan preventive measures, such as frequent mammography, preventive surgical interventions and chemoprophylaxis.

The second available genetic test is the p16 melanoma marker test (Begg et al. 2005). P16 is detected in 40% of cases of hereditary melanoma development, and is also associated with pancreatic cancer. For people with positive results of this test, several preventive measures are available, including early detection, preventive removal of suspicious formations and reduction of exposure to sunlight.

Approaches to the treatment of early stages of breast cancer may change several kits being developed designed to scan a panel of genes associated with the risk of developing the disease and a different response to treatment (Paik et al. 2004; Cronin et al. 2004). One of these tests, Oncotype DX, which allows analyzing the expression of 21 genes, is already used in clinical institutions (Hornberger et al. 2005; Paik et al. 2006). The information provided by this test facilitates both treatment and disease monitoring decisions based on predicting disease progression, time to onset of symptoms, and the likelihood of treatment success (Paik et al. 2006; Habel et al. 2006).

Ending: A word of Praise for Personalized Medicine (2)Portal "Eternal youth" www.vechnayamolodost.ru


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