Personalized medicine

Personalized medicine is a medical model emphasizing the systematic use of information about an individual patient to select or optimize that patient's preventative and therapeutic care. Personalized medicine can broadly be defined as products and services that leverage the science of genomics and proteomics (directly or indirectly) and capitalize on the trends toward wellness and consumerism to enable tailored approaches to prevention and care.

Over the past century, medical care has centered on standards of care based on epidemiological studies of large cohorts. However, large cohort studies do not take into account the genetic variability of individuals within a population. Personalized medicine seeks to provide an objective basis for consideration of such individual differences. Traditionally, personalized medicine has been limited to the consideration of a patient's family history, social circumstances, environment and behaviors in tailoring individual care.

Advances in a number of molecular profiling technologies, including proteomic profiling, metabolomic analysis, and genetic testing, may allow for a greater degree of personalized medicine than is currently available. Information about a patient's proteinaceous, genetic and metabolic profile could be used to tailor medical care to that individual's needs. A key attribute of this medical model is the development of companion diagnostics, whereby molecular assays that measure levels of proteins, genes or specific mutations are used to provide a specific therapy for an individual's condition by stratifying disease status, selecting the proper medication and tailoring dosages to that patient's specific needs. Additionally, such methods can be used to assess a patient's risk factor for a number of conditions and tailor individual preventative treatments.

Examples of successful personalized treatments exist in the field of oncology. Measurements of erbB2 and EGFR proteins in breast, lung and colorectal cancer patients are taken before selecting proper treatments. As the personalized medicine field advances, tissue-derived molecular information will be combined with an individual's personal medical history, family history, and data from imaging, and other laboratory tests to develop more effective treatments for a wider variety of conditions.

Traditional approaches of clinical medicine

Traditional clinical diagnosis and management focuses on the individual patient's clinical signs and symptoms, medical and family history, and data from laboratory and imaging evaluation to diagnose and treat illnesses. This is a reactive approach to treatment, i.e., treatment/medication starts after the signs and symptoms appear. Recent advances in medical genetics and human genetics have enabled a more detailed understanding of the impact of genetics in disease. Large collaborative research projects (for example, the Human genome project) have laid the groundwork for the understanding of the roles of genes in normal human development and physiology, revealed single nucleotide polymorphisms (SNPs) that account for some of the genetic variability between individuals, and made possible the use of genome-wide association studies to examine genetic variation and risk for many common diseases.

Now in the post-genome era, other "-omic" technologies are beginning to advance to the bedside. Indeed, the field of proteomics, or the comprehensive analysis and characterization of all of the proteins and protein isoforms encoded by the human genome, may have the greatest impact on personalized medicine over the next decade. This is because while the DNA genome is the information archive, it is the proteins that do the work of the cell: the functional aspects of the cell are controlled by and through proteins, not genes. Moreover, most of the FDA approved targeted therapeutics are directed at proteins, not genes. Consequently, protein-based assays were the first "companion diagnostic" assays to be approved by the FDA, mostly through a technique called immunohistochemistry or IHC. Important biological functions: growth, death, cellular movement and localization, differentiation, etc. are controlled by a process called signal transduction. This process is nearly entirely epi-genetic and governed by protein enzyme activity. Diseases such as cancer, while based on genomic mutations, are functionally manifest as dysfunctional protein signal transduction. Pharmaceutical interventions aim to modulate the aberrant protein activity, not genetic defect. Comparative analysis of gene expression and protein expression have largely found little concordance between the two information archives, thus many scientists now feel a direct analysis of the proteome is required and cannot be inferred from genomic or genetic analysis.

Historically, the pharmaceutical industry has developed medications based on empiric observations and more recently, known disease mechanisms. For example, antibiotics were based on the observation that microbes produce substances that inhibit other species. Agents that lower blood pressure have typically been designed to act on certain pathways involved in hypertension (such as renal salt and water absorption, vascular contractility, and cardiac output). Medications for high cholesterol target the absorption, metabolism, and generation of cholesterol. Treatments for diabetes are aimed at improving insulin release from the pancreas and sensitivity of the muscle and fat tissues to insulin action. Thus, medications are developed based on mechanisms of disease that have been extensively studied over the past century. Recent advancements in the genetic etiologies of common diseases will likely improve pharmaceutical development. Thus, "personalized medicine" is in many ways simply an extension of traditional clinical medicine taking advantage of the cutting edge of genetics research.

Despite the great advancements in medicine, there remain a number of concerns:

• Adverse effects attributed to medications.
• Costs of developing new therapeutic agents (an average of $1 billion and 12 to 15 years to develop a new therapeutic and further $1 billion to successfully market a new product). The failure rate of product development is very high and in many cases failure is not evident until a great proportion of this investment has been committed to large scale clinical trials.
• Recent slow-down in the generation of novel therapeutic agents.

Potential applications

Fields of Translational Research termed "-omics" (genomics, proteomics, and metabolomics) study the contribution of genes, proteins, and metabolic pathways to human physiology and variations of these pathways that can lead to disease susceptibility. It is hoped that these fields will enable new approaches to diagnosis, drug development, and individualized therapy.

Pharmacogenetics

Pharmacogenetics (also termed pharmacogenomics) is the field of study that examines the impact of genetic variation on the response to medications. This approach is aimed at tailoring drug therapy at a dosage that is most appropriate for an individual patient, with the potential benefits of increasing the efficacy and safety of medications. Gene-centered research may also speed the development of novel therapeutics.

Examples of pharmacogenetics include:

• Genotyping for SNPs in genes involved in the action and metabolism of warfarin (coumadin). This medication is used clinically as an anticoagulant but requires periodic monitoring and is associated with adverse outcomes. Recently, genetic variants in the gene encoding Cytochrome P450 enzyme CYP2C9, which metabolizes warfarin, and the Vitamin K epoxide reductase gene (VKORC1), a target of coumarins, have led to commercially-available testing that enables more accurate dosing based on algorithms that take into account the age, gender, weight, and genotype of an individual.
• Genotyping variants in genes encoding Cytochrome P450 enzymes (CYP2D6, CYP2C19, and CYP2C9), which metabolize neuroleptic medications, to improve drug response and reduce side-effects.

Cancer management

Oncology is a field of medicine with a long history of classifying tumor stages and subtypes based on anatomic and pathologic findings. This approach includes histological examination of tumor specimens from individual patients (such as HER2/NEU in breast cancer) to look for markers associated with prognosis and likely treatment responses. Thus, "personalized medicine" was in practice long before the term was coined. New molecular testing methods have enabled an extension of this approach to include testing for global gene, protein, and protein pathway activation expression profiles and/or somatic mutations in cancer cells from patients in order to better define the prognosis in these patients and to suggest treatment options that are most likely to succeed.

Cancer genetics is a specialized field of medical genetics that is concerned with hereditary cancer risk. Currently, there are a small number of cancer predisposition syndromes in which an allele segregates in an autosomal dominant fashion, leading to significantly elevated risk for certain cancers. It is estimated that familial cancer accounts for about 5-10% of all cancers. However, other genetic variants with more subtle effects on individual cancer risk may enable more precise cancer risk assessment in individuals without a strong family history.

Examples of personalized cancer management include:

• Testing for disease-causing mutations in the BRCA1 and BRCA2 genes, which are implicated in familial breast and ovarian cancer syndromes. Discovery of a disease-causing mutation in a family can inform "at-risk" individuals as to whether they are at higher risk for cancer and may prompt individualized prophylactic therapy including mastectomy and removal of the ovaries. This testing involves complicated personal decisions and is undertaken in the context of detailed genetic counseling.

• Minimal residual disease (MRD) tests are used to quantify residual cancer, enabling detection of tumor markers before physical signs and symptoms return. This assists physicians in making clinical decisions sooner than previously possible.

• Targeted therapy is the use of medications designed to target aberrant molecular pathways in a subset of patients with a given cancer type. For example, Herceptin is used in the treatment of women with breast cancer in which HER2 protein is overexpressed. Tyrosine kinase inhibitors such as Gleevec have been developed to treat chronic myeloid leukemia (CML), in which the BCR-ABL fusion gene (the product of a reciprocal translocation between chromosome 9 and chromosome 22) is present in >95% of cases and produces hyperactivated abl-driven protein signaling. These medications specifically inhibit the Ableson tyrosine kinase (ABL) protein and are thus a prime example of "rational drug design" based on knowledge of disease pathophysiology.

Pharmacometabonomics

Researchers at Imperial College London have recently demonstrated that pre-dose metabolic profiles from urine of rats and humans can be used to predict how they will metabolise drugs such as acetaminophen (paracetamol). The authors observed that individuals having high predose urinary levels of p-cresol sulfate, a gut bacteria cometabolite, had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide.

Concerns

Correlation with epidemiology and evidence-based medicine

The laboratory discoveries will be translated into clinical applications for diagnosis and therapy known as bench to bedside research. In this precess epidemiology will be used to test the newly discovered intervention from pre-clinical trials in first clinical trials. In this process population studies and clinical studies will involve assessment of prevalence, associations,interactions, sensitivity, specificity, and predictive value of testing for genetic risk factors.

Genetics discrimination

One of the significant barriers to genetic testing is thought to be the fear of discrimination. Discrimination from an insurer or even worse an employer. This fear has been indicated in several polls, including the Harris Poll in 2002. For the last decade there has been some form of legislation which had been mired in the United States House of Representatives. The current bill is called the Genetic Information Nondiscrimination Act. The bill has now been signed by President Bush. This legislation will break down a significant barrier to this technology.

Response

There are several stakeholders: the industry, the regulators, the patients and the general public.

Pharmaceutical industry

The technologies underpinning personalized medicine could enable the pharmaceutical industry to develop a more efficient drug development process, based on the latest research on disease pathophysiology and genetic risk factors. Furthermore, a therapeutic agent could be marketed on the basis of a companion theranostic test result.

Diagnostics industry

The traditional diagnostics industry is mature and only achieving a growth rate of the order of 4% per annum. Its products are very cost sensitive and have a relatively short life cycle. The diagnostics industry has not been as successful as the pharmaceutical industry in attracting investment funding. However, the advent of molecular diagnostic tests, or theranostics, opens new opportunities in a small but believed to be rapidly growing niche market. Molecular diagnostics—tests used to identify proteins and other biomarkers of disease, or disease susceptibility is expected to grow 14% annually between 2007 and 2012, from $2.6 billion to $5.0 billion.

The forecast for theranostics is mixed. One factor that could spur growth in the diagnostics sector is the trend toward “theranostics”—combinations of targeted therapeutics and companion diagnostics. Thus far, there is little evidence that diagnostics companies are embracing partnerships with pharma companies to develop theranostics. The development risk and time to market associated with drug candidates make the development of a companion diagnostic significantly less attractive to major diagnostics manufacturers than the revenues they generate from their traditional target market of clinical laboratories. If government agencies increase the use of biomarkers and diagnostics in prescribing decisions, it’s likely that pharma and diagnostics companies will increase their collaboration in this area. New relationships are likely to develop between industry partners committed to personalized medicine embracing the approach of successful, specialised pharmaceutical firms.

Insurers

The emergence of personalized medicine raises issues for those who pay for treatment. The cost of new diagnostic tests and individualized medications may be more expensive, but it is hoped that the predictive potential of personalized medicine could avert more costly treatments required after the onset of a disease. Currently, less than 5% of all US private companies reimburse for genetic tests, indicating that the current health care delivery system may not be able to deliver effective "personalized medicine".

Insurance premiums today are based on actuarial statistics that apply to large, predictable populations. By contrast, personalized medicine targets small populations, which are far less stable and predictable from an actuarial standpoint. Payers will need to develop new actuarial assumptions on which to base their reimbursement models. Personalized medicine has the potential to reduce payers’ costs in the long term by providing the precise diagnostics required to avoid unnecessary or ineffective treatments, prevent adverse events, develop prevention strategies, and deliver more effective, targeted therapeutics. The trend toward pay for performance could accelerate the adoption of personalized medicine, if clinical data shows that targeted diagnostics and therapies reduce payers’ costs.

Physicians

For healthcare providers, personalized medicine offers the potential to improve the quality of care, through more precise diagnostics, better therapies, and access to more accurate and up-to-date patient data and sophisticated decision support tools. Primary care providers may have to build new service lines around prevention and wellness in order to replace revenues lost from traditional medical procedures. Decision support tools will be essential to guide treatment decisions based on test results, but physicians will also require a solid background in genomics and proteomics to make the best use of these sophisticated tools.

Government agencies

The Food and Drug Administration (FDA) in the United States and their counterparts appear convinced that personalized medicine is going to make a profound impact on society and they are guiding this process. Dr. Andrew von Eschenbach, Commissioner of the FDA, is a strong proponent of personalized medicine, as evident from a briefing he gave to the Personalized Medicine Coalition. He and the FDA appear to be committed to bring new testing and treatments to market that are molecularly based. Dr. Eschenbach envisions a "molecular metamorphosis in medicine" that will improve our understanding of disease processes and lead to more effective tests and treatments based on this molecular-level knowledge. He likens the potential impact of these enhanced molecular approaches to the revolution in medicine made possible by the bacterial theory.

The Genomics and Personalized Medicine Act was introduced in the U.S. Congress to address scientific barriers, adverse market pressures, and regulatory obstacles. In addition, U.S. Secretary of Health and Human Services Mike Leavitt created a committee known as the Secretary's Advisory Committee on Genetics Health and Society (SACGHS) to study issues related to personalized medicine.

Patients

Since the aim of personalized medicine is to improve healthcare, patients will continue to benefit from advances in biomedical research and individualized treatments. Public education about the potential benefits of personalized medicine will be an important facet of its widespread acceptance.

Collaboration, infrastructure and technology : key enablers

The march toward personalized medicine is not driven, in some instances, on the basis of scientific hypothesis but through hypothesis generation sometimes starting with natural history. The key task is to find proteins, activated proteins, genes and gene variations that play a role in a disease. The first step is to associate the occurrence of a particular protein or gene variant with the incidence of a particular disease or disease predisposition - an association that can vary from one individual to another depending on many factors, including environmental circumstances. The outcome is the development of biomarkers which are stable and predictive. Today's biomarker is tomorrow's theranostic.

The infrastructure necessary includes molecular information -biological specimens derived from tissue, cells, or blood provided on the basis of informed donor consent and suitably annotated. Clinical information is also necessary based on patient medical records or clinical trial data.

A very high level of collaboration involving scientists and specialists from varying disciplines is required to integrate and make sense of all this information.

The Harvard Partners Center for Genetics and Genomics was founded in 2001 with the specific goal of accelerating the realization of personalized medicine. Likewise, Duke University's Institute for Genome Sciences & Policy is an interdisciplinary effort aimed at personalizing medicine through the translation of advances in the genome sciences into clinical practice. The Personal Genome Project was announced by George Church in 2006; it will publish full genome sequences and medical records of volunteers in order to enable research into personalized medicine.

The Coriell Personalized Medicine Collaborative- The goal of the Coriell Personalized Medicine Collaborative (CPMC) is to research whether personalized genetic information can be used to improve people’s health. To do this, participants are asked to give a saliva sample that is used to look for genetic variants associated with common diseases and medication response. Participants are also asked to provide information about their health, medication use, family history and lifestyle. This information is then used to create customized risk reports. Collaborating Institutions include: Helix Health of CT/NY, Fox Chase Cancer Center, Virtua Health, Cooper Hospitals.

Although genes contribute to our risk for every condition, the CPMC will only test for diseases that are potentially actionable.

The Laboratory for Personalized Molecular Medicine was founded in 2007 to identify specific mutations in genes linked to clinical outcome in patients with leukemia and lymphoma, and actively collaborates and assists academic centers and hospitals in the development of patient-specific molecular tests from patient tumor DNA samples. Identifying the presence or absence of mutations (e.g., FLT3 and NPM1) is becoming a standard of care for patients with acute myeloid leukemia. LabPMM also developments patient-specific molecular tests from patient tumor DNA samples. The ultra-sensitive tests are used by leading cancer treatment centers worldwide to monitor residual disease and treatment.

Not only is personalized medicine tailoring the right drug, for the right person, at the right time but it also includes evaluating predisposition to disease sometimes decades in advance of its threatened onset.

New Market Participants

While the market for personalized medicine diagnostics and therapeutics shows great potential, a big opportunity exists beyond these core products and services— particularly in less traditional, more consumer-oriented areas. The nutrition and wellness market— including retail health, complementary and alternative medicine, nutraceuticals and organic care, and health clubs and spas—is estimated at $196 billion and projected to grow by 7% annually to $292 billion by 2015. The personalized medical care portion of the market—including telemedicine, electronic medical records, and disease management services—is estimated at $4 billion to $12 billion and could grow tenfold to over $100 billion by 2015. This segment is largely composed of a range of healthcare players, as well as information technology companies that are starting to enter the space. Such robust market size and growth potential will continue to attract many new players and require the development of new business models. A wide variety of organizations are entering this space, including consumer products, food and beverage, leisure and retail companies, as well as more traditional health companies that are successful in marketing directly to consumers.

US market size

While still in the early stages, personalized medicine is steadily emerging as the new healthcare paradigm. In the U.S., the total market for personalized medicine currently is estimated at $232 billion and is projected to grow 11% annually, nearly doubling in size by 2015, to a total of $452 billion, according to PricewaterhouseCoopers’ estimates. The core segment of the market — consisting primarily of diagnostic tests and targeted therapies — is estimated at $24 billion, and is expected to grow by 10% annually to $42 billion by 2015... There are other companies that also provide informational services to specific diseases to doctors within the US. One such company that provides informational service to community oncologist under the product name OncInsights is Intervention Insights interventioninsights

Education

There are several universities involved in translating the burgeoning science into use. The difficulty is that medical education in all countries does not provide adequate genetic instruction.

A small number of universities are currently developing a subspecialty in medicine that is known by several names including, molecular medicine, personalized medicine, or even prospective medicine. These include, Duke University in North Carolina USA, Harvard in Cambridge USA, The Mount Sinai Hospital in New York City. A medical school is currently being constructed in Arizona USA to teach the field of personalized medicine; this is a project of Arizona State University and the not-for-profit Translational Genomics Research Institute (TGen). Lastly, the first private medical practice focusing solely on Personalized Medicine, Helix Health of Connecticut is currently teaching medical residents about the utility of pharmacogenomics and family history in personalized medicine.

See also

• Predictive medicine
• Full Genome Sequencing
• Theranostics
• Drug development
• Targeted therapy
• Stratified medicine
• Translational Research
• International Journal of Functional Informatics and Personalized Medicine (IJFIPM)
• International Journal of Computational Biology and Drug Design (IJCBDD)
• International Society of Intelligent Biological Medicine (ISIBM)
• Dynamic treatment regimes

External links

• Cedar Associates LLC Clinical Effectiveness Decision Analytical Research
• WIN Symposium in Personalized Cancer Medicine A major annual event presenting breakthrough scientific technologies and achievements in personalized cancer medicine, with a special focus on individualized treatment and early diagnosis of cancer, 7–9 July 2010, Paris, France.
• The Era of Personalized Medicine - Edward Abrahams
• Duke University's Institute for Genome Sciences & Policy, a comprehensive, campus-wide approach to advancing the Genome Revolution and addressing its implications for science, health and society.
• The Coriell Personalized Medicine Collaborative A pioneering research study that seeks to explore the utility of using genome information in clinical decision-making.
• genomestohealth.org, a Duke Institute for Genome Sciences & Policy initiative aimed at translating genomic advances into medical practice through clinical trials.
• The Personalized Medicine Coalition, a group of companies and research institutions devoted to the promotion of personalized medicine
• The Gene Sherpas: Personalized Medicine Blog, A HON Code certified blog about personalized medicine written by the Clinical Genetics Fellow at the Yale School of Medicine
• CTS: The Clinical and Translational Science journal, a journal represented by over 300 leaders in translational medicine and dedicated to personalized medicine
• TGen, Translational Genomics Research Institute
• Personalized Medicine. A peer-reviewed journal published by Future Science Group
• Personalized Medicine investors coverage on Yahoo
• PGxNews.Org - Daily updates about advances in Pharmacogenomics and Personalized Medicine
• ISCSPM. A forum announcement for scientific membership to the International Society for Collaborating Scientists in Personalized Medicine or the ISCSPM.

Further reading

• Acharya et al. (2008), Gene Expression Signatures, clinicopathological features, and individualized therapy in breast cancer, JAMA 299: 1574.
• Potti et al. (2006), Genomic Signatures to Guide the Use of Chemotherapeutics, Nature Medicine 12: 1294.
• Potti et al. (2006), A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer, New England Journal of Medicine 355: 570
• Sadee W, Dai Z. (2005), Pharmacogenetics/genomics and personalized medicine, Hum Mol Genet. 2005 October 15;14 Spec No. 2:R207-14.
• Steven H. Y. Wong (2006), Pharmacogenomics and Proteomics: Enabling the Practice of Personalized Medicine, American Association for Clinical Chemistry, ISBN 1-59425-046-4
• Qing Yan (2008), Pharmacogenomics in Drug Discovery and Development, Humana Press, 2008, ISBN 1588298876.
• Willard, H.W., and Ginsburg, G.S., (eds), (2009), Genomic and Personalized Medicine, Academic Press, 2009, ISBN 0123694205.
• Haile, Lisa A. (2008), Making Personalized Medicine a Reality, Genetic Engineering & Biotechnology News Vol. 28, No. 1.
• “Pharmacogenomics and Ethical Implications of Drug Development” at the meeting of the Association of Clinical Research Professionals. Chiron Park, Emeryville, CA, 2001.
• “Pharmacogenomics in Drug Development” in the Symposium "Pharmacoeconomics and Pharamcogenomics: The End of Blockbuster Drugs?" at the Sixth Annual Meeting of the International Society of Pharmacogenomic and Outcomes Research (ISPOR). Washington, 2001.
• “Economic Challenges in Developing Pharmacogenomic Products” at the University of Arizona College of Pharmacy’s 9th Annual Invitational Conference entitled: “Pharmacogenomics: Implications for Patients, Providers, Policy, and Payers.” Tucson, Arizona, 2001.
• Hornberger J, Habraken H, Bloch DA. Minimum data needed on patient preferences for accurate, efficient medical decision making. Medical Care 1995; 33:297-310.
• Lyman GH, Cosler LE, Kuderer NM, Hornberger J. Impact of a 21-gene RT-PCR assay on treatment decisions in early-stage breast cancer: an economic analysis based on prognostic and predictive validation studies. Cancer 2007; 109(6):1011-8.
• Hornberger J, Cosler L and Lyman G. Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node–negative, estrogen-receptor–positive, early-stage breast cancer. Am J Managed Care 2005; 11:313-24.de:Pharmakogenomik

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