Minimal residual disease (MRD) is the name given to small numbers of leukaemic cells that remain in the patient during treatment, or after treatment when the patient is in remission (no symptoms or signs of disease). It is the major cause of relapse in cancer and leukaemia . Up until a decade ago, [ when? ] none of the tests used to assess or detect cancer were sensitive enough to detect MRD. Now, however, very sensitive molecular biology tests are available – based on DNA , RNA or proteins – and these can measure minute levels of cancer cells in tissue samples, sometimes as low as one cancer cell in a million normal cells. In cancer treatment, particularly leukaemia, MRD testing has several important roles: determining whether treatment has eradicated the cancer or whether traces remain, comparing the efficacy of different treatments, monitoring patient remission status and recurrence of the leukaemia or cancer and choosing the treatment that will best meet those needs (personalization of treatment). The tests are not simple, are often part of research or trials, and some have been accepted for routine clinical use.
TAILOR MADE MEDICINE BY, DR. SHREERAJ SHAH ASSOCIATE PROFESSOR, DEPT. OF PHARMACEUTICAL TECHNOLOGY, L.J. INSTITUTE OF PHARMACY, AHMEDABAD.
CONTENTS Introduction Definition Brief History Difference between common drug and personalize medicine Driving the Movement to Personalized Medicine Goals for personalized medicine Benefits of Personalized Medicine Limitation of personalized medicine Potential applications Selected Personalized Medicine Drugs, Treatments, and Diagnostics Biomarker and theranostics with reference to medicine of 2050 Future of “Theranostics” “Medicine 2050”- with respect to Personalized medicines Societal Benefits and Costs Conclusion References 2
INTRODUCTION Scientific achievements have had an immeasurable influence on the uses of innovative biopharmaceuticals and methods in medicine. These breakthrough discoveries have contributed to an irreversible change in the perception and use of diagnostics in contemporary treatment of many illnesses. Today, in addition to the well-established types of physical and chemical examination and our growing understanding of biochemical processes occurring in the body, we now have at our fingertips state-of-the-art diagnostics and therapies based on the molecular pathomechanisms of illnesses. Although the discovery of specific pathogens revolutionized medicine in the 19th and 20th centuries, making it possible to create pharmaceuticals essential to treat certain illnesses, generally improve health, or extend patients’ lives. So this will require the implementation of a fully innovative, individualized approach to illness and its treatment in patients. 3
TAILOR MADE MEDICINE OR PERSONALIZEDMEDICINE Personalized medicine refers to the tailoring of medical treatments to the individual characteristics of each patient. It does not literally mean the creation of drugs or medical devices that are unique to a patient but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease or their response to a specific treatment. Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense 4 and side effects for those who will not.
“It’s far more important to know what person the disease has than what disease the person has.” Hippocrates (ca. 400 BCE) 5
BRIEF HISTORY 1898:- Sir Archibald Garrod coins the term “chemical individuality” to describe inherited predispositions to metabolizing sulphonal drugs. 1900:- Gregor Mendel’s work, conducted in 1865 and largely ignored, is rediscovered, launching the genetic era. 1902:- Lucien Cuenot advances the hypothesis that genetically determined differences in biochemical processes could be the cause of adverse reactions after the ingestion of drugs. 1941:- The relationship between genes and the production of proteins is discovered. 1956:- The “chemical individuality” hypothesis is proven when a genetic deficiency of glucose-6-phosphate dehydrogenase is found to be linked to antimalarial primaquine toxicity. 1959:- The term “pharmacogenetics” is coined by the German geneticist Friedrich Vogel. 1967:- The genetic code is cracked, revealing how DNA sequences code for protein. 1975:- Gene sequencing techniques are invented. 1977:- Metabolism of drugs by enzymes of the CYP450 system is identified as a key genetically determined cause for variation in drug response. 1983:- A polymerase chain reaction technique is invented for in vitro amplification of DNA sequences. 6 1990:- The Human Genome Project is launched.
April 2003:- The sequencing of the human genome is declared complete after 13 years and a $3 billion investment. May 2004:-The Office of the National Coordinator for Health Information Technology is established. November 2004:- The Personalized Medicine Coalition (PMC) is launched with 18 members from industry, government, and academia. December 2004:- The Oncotype DX® gene profile for optimizing breast cancer therapy is introduced. March 2005:- The FDA issues a Guidance for Industry on Pharmacogenomic Data Submissions. April 2005:- The FDA issues a white paper on co-developed diagnostic therapeutic products. October 2005:- A haplotype map of the human genome is published, providing a powerful tool for linking genetic variation to disease susceptibility and response to treatment. February 2006:- The National Institutes of Health (NIH) launches the Genes, Environment and Health Initiative. 7 August 2006:- Senator Barack Obama introduces the “Genomics and Personalized Medicine Act.”
February 2007:- MammaPrint® becomes first predictive genetic test for breast cancer to receive formal approval by the FDA. A major genome-wide association study identifies gene variants linked to type 2 diabetes. March 2007:- The Department of Health and Human Services (HHS) announces the Personalized Health Care Initiative. June 2007:- The Wellcome Trust Case Control Consortium analyzes 17,000 Britons to find genetic variants linked to bipolar disorder, high blood pressure, coronary artery disease, Crohn’s disease, type 1 and type 2 diabetes, and rheumatoid arthritis. August 2007:- The FDA re-labels the blood thinning drug warfarin to recommend adjusting the dose based on genetic variation. April 2008:- James Watson’s genome is sequenced in two months for $1,000,000. May 2008:- The Genetic Information Non-Discrimination Act (GINA) is signed into law. The first high-resolution sequence map of human genetic variation is produced. July 2008:- The FDA recommends genetic testing before taking the HIV drug abacavir to reduce allergic reactions. August 2008:- Pharmacy benefits manager Medco collaborates with FDA to study the impact of genetic testing on the prescription of drugs and their effectiveness. September 2008:- The President’s Council of Advisors on Science and Technology (PCAST) issues the report, Priorities for Personalized Medicine. October 2008:- Ten prominent individuals release their genomic data as part of the Personal Genome Project. March 2009:- Massachusetts General Hospital announces plans to genotype every cancer 8 patient to implement personalized medical care. April 2009:- Senate brings personalized medicine into national budget discussions.
Difference between common drug and personalizedmedicine Current Practice Personalized Medicine One size fits all The right treatment Trial and error for the right person at the right time 9
Personalized medicine recognizes that individual patients may react in very 10different ways to the same treatment given for the same problem. The goal is to tailor therapies based on a patients DNA profile.
WHAT IS DRIVING THE MOVEMENT TOPERSONALIZED MEDICINE? Consumer Demand for:- Safer and More Effective Drugs Faster Time to a Cure Cost-Effective Healthcare 11
GOALS FOR PERSONALIZED MEDICINE Identify genetic differences between people that affect drug response Develop genetic tests that predict an individual’s response to a drug Tailor medical treatment to the individual # Increase effectiveness # Minimize adverse side effects 12
BENEFITS OF PERSONALIZED MEDICINE Shiftemphasis in medicine from reaction to prevention Select optimal therapies Increase safety, reduce adverse drug reactions Increase patient compliance Reduce the time, cost, and failure rate of clinical trials 13 Reduce the overall cost of healthcare
LIMITATION OF PERSONALIZED MEDICINE Healthcare workforce (incl. physicians): currently no adequate training to make use of Personalized Medicine, not implemented in medical school curricula Public may be inhibited by full participation in personalized medicine research or clinical care, unless full genetic privacy is put in place Healthcare IT needed for linking patient information to genomic research (Electronic Medical Records) 14
POTENTIAL APPLICATIONS Fields of Translational Research termed "-omics" (genomics, proteomics, and metabolomics) study the contribution of genes, proteins, and 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. I. Pharmacogenetics II. Pharmacometabonomics 15 III. Cancer management
I. 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.. 16
EXAMPLES OF PHARMACOGENETICS:- Genotyping variants in genes encoding Cytochrome P450 enzymes (CYP2D6, CYP2C19, and CYP2C9), which metabolize neuroleptic medications, to improve drug response and reduce side-effects. 17
II. PHARMACOMETABONOMICS:- Researchers at Imperial College London have demonstrated that pre-dose metabolic profiles from urine of rats and humans can be used to predict how they will metabolize drugs such acetaminophen (paracetamol). The authors observed that individuals having high pre-dose urinary levels of p-cresol sulfate, a gut bacteria co metabolite, had low post-dose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. 18
III. CANCER MANAGEMENT:- Oncology is a field of medicine with a long history of classifying tumor stages based on anatomic and pathologic findings. This approach includes histological examination of tumor specimens from individual patients (such as HER2 (Human Epidermal Growth Factor Receptor 2 /Neu in breast cancer). 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 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. 19
EXAMPLES OF PERSONALIZED CANCER MANAGEMENT:-(A) Testing for disease-causing mutations in the BRCA1 (human caretaker gene that produces a protein called breast cancer type 1 susceptibility protein, responsible for repairing DNA) 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 20 undertaken in the context of detailed genetic counseling.
(B) 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.(C) Herceptin (Trastuzumab; trade name Herceptin), a monoclonal antibody that interferes with the HER2/neu receptor ) is used in the treatment of women with breast cancer in which HER2 protein is overexpressed. 21
INEFFECTIVE THERAPIES CAN CAUSE HARM Estimated 100,000 deaths per year 6th leading cause of death in the US Medication-related health problems account for an estimated 3% to 7% of hospital admissions During their hospital stay, 15% of patients experienced adverse drug reactions 22 Increased patient non-compliance
ONE SIZE DOES NOT FIT ALL ANTI-DEPRESSANTS 38% ASTHMA DRUGS 40% DIABETES DRUGS 43% ARTHRITIS DRUGS 50% ALZHEIMER’S DRUGS 70% CANCER DRUGS 75% 23 Here, study was carried out on 100 patient for each disease condition.
A report from the Personalized Medicine Coalition: The Case for Personalized Medicine puts the advent of personalized medicine in context: "Since the mapping of the human genome in 2003, the pace of discovery, product development, and clinical adoption of what we know as personalized medicine has accelerated." For the pharmaceutical industry the advances in personalized medicines are something of a revolution. With arguably the most significant investment in bringing products to market than any other industry – it’s estimated that it takes 15 years and $1 billion in development, testing and licensing to bring a drug to market – personalized medicine brings with it significant opportunities to bring much greater efficiencies to the highly costly area of 24 clinical trials.
SELECTED PERSONALIZED MEDICINE DRUGS,TREATMENTS, AND DIAGNOSTICS THERAPY BIOMARKER/TEST INDICATION Breast cancer: “…for the treatment of patients with Herceptin® metastatic breast cancer whose tumors over express the (trastuzumab) HER-2/neu receptor HER2 protein and who have received one or moreTykerb® (lapatinib) chemotherapy regimens for their metastatic disease.” Aviara Breast Cancer Breast cancer: Calculates a combined risk analysis for Tamoxifen IndexSM (HOXB13, recurrence after tamoxifen treatment for ER-positive, node- IL17BR) negative breast cancer. Breastcancer: Prognosticimmunohistochemistry (IHC) test used for postmenopausal, node Chemotherapy Mammostrat® negative, estrogen receptor expressing breast cancer patients who will receive hormonal therapy and are considering adjuvant chemotherapy. Breast cancer: Assesses risk of distant metastasis in a 70 Chemotherapy MammaPrint® gene expression profile. Cardiovascular disease: “an increased bleeding risk for 25 Coumadin® CYP2C9 patients carrying either the CYP2C9*2 or CYP2C9*3 (warfarin) alleles.”
Cardiovascular disease: Predicts risk of statin-induced neuro-myopathy, based on a Statins PhyzioType SINM patient’s combinatorial genotype for 50 genes. Cardiovascular disease: “Doses should be individualized according to the Atorvastatin LDLR recommended goal of therapy. Homozygous Familial Hypercholestremia (10- 80mg/day)and heterozygous (10-20mg/ day).” Colon cancer: “Variations in the UGT1A1 gene can influence a patient’s ability toCamptosar® (irinotecan) UGTIA1 break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects.” Erbitux® (cetuximab) KRAS Colon cancer: Certain KRAS mutations lead to unresponsiveness to the drug. Gefitinib Colon cancer: “Patients enrolled in the clinical studies were required to have… Erbitux® (cetuximab) evidence of positive EGFR expression using the DakoCytomation EGFR pharmDx™ Gefitinib EGFR expression test kit.” EGFR positive individuals are more likely to respond to the drug than those Vectibix® with reduced EGFR expression.Erbitux® (cetuximab) and Vectibix® (panitumab) Colon cancer: Provides information of the expression of key molecular targets— Target GI™ Fluorouracil KRAS, TS, and TOPO1—to guide therapy. Camptosar®(irinotecan) Epilepsy and bipolar disorder: Serious dermatologic reactions are associated with the HLAB*1502 allele in patients treated with carbamazepine. “Prior to initiatingTagretol (carbamazepine) HLA-B*1502 Tegretol therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLAB*1502 may be present.” Heart transplantation: Monitors patient’s immune response to heart transplant toImmunosuppressive drugs AlloMap® gene profile guide immunosuppressive therapy. 26 HIV: “Patients who carry the HLA-B*5701 allele are at high risk for experiencing a Ziagen® (abacavir) HLA-B*5701 hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended.”
Multiple diseases: FDA classification 21 CFR 862.3360: “This device is used as an aid in determining treatment choice and individualizingDrugs metabolized by Amplichip® treatment dose for therapeutics that are metabolized CYP P450 CYP2D6/CYP2C19 primarily by the specific enzyme about which the system provides genotypic information.” Rifampin Multiple diseases: N-acetyltransferase slow and fast acetylators and Isoniazid NAT toxicity- “slow acetylation may lead to higher blood levels of the drug, Pyrazinamide and thus, an increase in toxic reactions.” Non-Hodgkin’s lymphoma: Detects CD-20 variant (polymorphism in PGx PredictTM: Rituximab the IgG Fc receptor gene FcgRIIIa) to predict response to cancer drug Rituximab rituximab. Pain: “Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previousCelebrex® (celecoxib) CYP2C9 history should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.” Risperdal® Psychiatric disorders: Predicts risk of psychotropic-induced (resperidone) PhyzioType PIMS metabolic syndrome, based on a patient’s combinatorial genotype forZyprexa® (olanzapine) 50 genes. Stomach cancer: “Gleevec® is also indicated for the treatment of Gleevec® (imatinib c-KIT 27 patients with Kit (CD117) positive unresectable and/or metastatic mesylate) malignant gastrointestinal stromal tumors (GIST).”
BIOMARKER AND THERANOSTICS WITH REFERENCE TO MEDICINE OF 2050 In medicine, a biomarker is a term often used to refer to a protein measured in blood whose concentration reflects the severity or presence of some disease state. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. A biomarker can be a substance that is introduced into an organism as a means to examine organ function or other aspects of health. For example, rubidium chloride is used as a radioactive isotope to evaluate perfusion of heart muscle. It can also be a substance whose detection indicates a particular disease state, for example, the presence of an antibody may indicate an infection. More specifically, a biomarker indicates a change in expression or state of a protein that correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Biomarkers are characteristic biological properties that can be detected and measured in parts of the body like the blood or tissue 28
In oncology the most commonly used biomarkers are enzymes and hormones linked with tumors. They can be detected using biochemical tests, although their presence is not always indicative of the presence of a specific tumor. For example, an increase in the levels of the prostate-specific antigen (PSA) indicates a high likelihood of a prostate tumor being present, but it can also be a result of a mild hyperplasia. Similarly, raised levels of the carcino embryonic antigen (CEA) are characteristic in between 60–90% of colon cancer cases and 50–80% of pancreatic cancers. Now it is possible to monitor the course of many illnesses by studying differences in the structures of nucleic acids. DNA biomarkers include chromosome abnormality, single nucleotide polymorphisms (SNPs), a change in the number of copied DNA fragments, or differences in the degree of methylation of promoter regions. Research shows that using a biomarker that defines the degree of DNA methylation may be a factor in differentiating between prostate cancer from mild hyperplasia. RNA biomarkers include differences in the transcription levels, or RNA molecules that 29 take part in regulation.
BRINGING BIOMARKERS TO MARKET Bringing biomarkers into general use must be preceded by thorough analyses of their safety in patients, reliability, efficacy, and the financial implications of their use in diagnostics In the US, the steps involved in introducing a new biomarker include: identification of relevant information in the patient’s biological material (using DNA microarrays, gene chips, restriction fragment length polymorphisms (RFLP) and others, depending on type), establishing possible applications, and final step clinical and analytical validation The final stage must be carried out, if the biomarker is to be approved by the FDA for clinical use, although it can be bypassed if it is to be used purely for research. The final decision regarding bringing a biomarker to market lies with the Center for Medicaid & Medicare Services (CMS), responsible for carrying out an analysis of costs versus 30 benefits including social aspects.
FUTURE OF “THERANOSTICS” Researchers have even suggested introducing a new term “Theranostics,” (a portmanteau of therapeutics and diagnostics) which is a proposed process of diagnostic therapy for individual patients - to test them for possible reaction to taking a new medication and to tailor a treatment for them based on the test results. Effort to promote this new coin-age show how far advanced the introduction of personalized medicine is in various branches of medicine. Some scientists are no longer debating whether such medicines are will be used at all, but when its use will become widespread in clinical practice. Personalized medicine (with Theranostics) is closely linked with several clinical applications, and is most advanced in oncology and infectious diseases. In the latter case, defining the genotype of the virus (HIV, hepatitis B and C) and establishing the viremic concentration play a crucial role in selecting an appropriate therapy, predicting its efficacy, discovering any drug resistance and any necessary modifications of the treatment. 31
“MEDICINE 2050”- WITH RESPECT TOPERSONALIZED MEDICINES The personalization of medicine is an irreversible process whose benefits can already be observed, and whose potential benefits cannot be overstated. This is excellently illustrated by a communication from the European Commission on 10 December 2008, which includes a declaration of support for scientific research in pharmaceutical development “With the emergence of new technologies like pharmacogenomics and patient-specific modelling and disease simulators, personalised medicine is now on the horizon. In the long term, doctors may be able to use genetic information to determine the right medicines, at the right dose and time. This field is already affecting companies’ business strategies, the design of clinical trials and the way medicines are prescribed. Although it is too early to say whether ‘omics’ technologies will indeed revolutionize the sector, the Commission 32 closely monitors the area and will reflect on how it can support its development.”
SOCIETAL BENEFITS AND COSTS Alongside the high hopes and optimism brought by the prospect of “made to measure” medicine, there are also some ethical concerns. The most frequently cited examples revolve around personal data protection, potential discrimination by insurance firms or employers against people who have a tendency towards certain illnesses, or personal stigma. These may become deciding factors in whether this novel treatment strategy ultimately gains societal acceptance, therefore they should be put forward for thorough discussion, eventually leading to concrete legislative measures Doubts may also arise because of the potential costs of introducing personalized medicine. In this instance it is essential to take a close look at the problems of efficacy and safety of current therapies, and the intentions and options in investing in innovative technologies In this specific instance it is very important to stress that a significant part of the diagnostic costs should be recompensed through targeted and effective therapeutics. Contemporary biopharmaceuticals (hormones, interferons and interleukins) are very expensive, and yet ineffective, and therefore unnecessary (or badly dosed) use of expensive drugs is wasteful The application of proteomics and transcriptomics to personalized medicine will 33 make it possible to optimize the possibilities of medicine in both economic and social aspects.
CONCLUSION We cannot predict what medicine will be like in 2020 or 2050, although we can be certain that it will be quite different from what it is today. The scientific, economic, and social circumstances all indicate that “tailor-made” medicine is likely the way of the future. 34
REFERENCES(1) President’s Council of Advisors on Science and Technology (PCAST) “Priorities for Personalized Medicine” September 2008(2) Brian B. Spear, Margo Heath-Chiozzi, Jeffrey Huff, “Clinical Trends in Molecular Medicine, Volume 7, Issue 5, 1 May 2001, Pages 201-204.(3) National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer. Volume-2, 2009(4) Abrahams A, Ginsburg GS, Silver M. The Personalized Medicine Coalition: Goals and strategies. Am J Pharmacogenomics , 2005;5(6): 345-355.(5) Personalized Medicine Coalition May 2009 35(6) The future of red biotechnology, Tailor made medicine, by Aleksandra Małyska and Tomasz Twardowski page no:-12-15