Trends in Personalized Medicine for Cancer Treatment

Essay

Diana Paola Crdenas Vsquez dianapaolac@gmail.com

15.03.2010

CONTENTS 1 2 Introduction ................................................................................................ 4 The new science, Personalized Medicine ................................................ 6 2.1 3 Concepts and facts about Cancer ......................................................... 7

The personalized medicine landscape5 ................................................... 9 3.1 3.2 3.3 The Big Pharma model ..................................................................... 11 First winners: molecular diagnostics.................................................... 13 Trends in Diagnostics .......................................................................... 15 Biospecimens ............................................................................... 21

3.3.1 4

The individual Players ............................................................................. 22 4.1 Technology based companies ............................................................. 22 Electronic Health Records (EHRs)................................................ 23 Web resources.............................................................................. 24

4.1.1 4.1.2 4.2 4.3 4.4 5

Healthcare providers ........................................................................... 24 Payers ................................................................................................. 26 Government5 ....................................................................................... 28

Conclusions ............................................................................................. 29 5.1 Progress and challenges ..................................................................... 30

References ............................................................................................... 33

Appendix ......................................................................................................... 35

List of figures

Figure

1.

Personalized

Medicine

Market

Size,

2009

and

2015.

Source: adapted from PricewaterhouseCoopers analysis5............................... 12 Figure 2. A winning curve. To gain acceptance for its Oncotype DX Test, Genomic Health set out to show that the resulting recurrence score provides information that is valuable, actionable and accurate through a suit of studies. 19 Figure 3. The power of subtypes. The impact of improved diagnosis and treatment on blood related cancers demonstrates the potential of personalized medicine and helps explain why proponents have been so determined. Source Genzyme Genetics 26 ....................................................................................... 21 Figure 4. From Discovery to payer: The contribution of knowledge to the

personalized health landscape. Adapted from Health Industry Insights 32......... 26

List of tables

Table 1. Selected companies offering, developing or partnering to develop companion diagnostics26 .................................................................................. 18 Table 2. Selected tests for determining recurrences risk in early-stage breast cancer .............................................................................................................. 20

Glossary

ADRs CA125 CAGR CISH CLIA C-Path CTSA DNA EHRs EMEA FDA FISH Genome Genomics HER-2 Herceptin ISPs Nanoparticles NIH Nutraceutical Oncogen

Adverse Drug reactions Biomarker that may be elevated in the blood of some patients with specific types of cancers Compound Annual Growth Rate Chromogenic in situ hybridization Clinical laboratory improvement amendments Critical Path Institute established by University of Arizona and FDA Clinical and Translational Science awards Deoxyribonucleic acid Electronic Health Records European Medicines Agency Food and Drug Administration Immunochemistry fluorescent in situ hybridization The entirety of an organism's hereditary information the study of organisms genes "Human Epidermal growth factor Receptor 2" and is a protein giving higher aggressiveness in breast cancers The first humanized antibody approved for the treatment of HER2-positive metastatic breast cancer Internet Service Providers In nanotechnology, a particle is defined as a small object that behaves as a whole unit in terms of its transport and properties with a size between 1 and 100 nanometers National institute of Health Food or food product that provides health and medical benefits, including the prevention and treatment of disease Gene that, when mutated or expressed at high levels, helps turn a normal cell into a tumor cell created by Genomic Health, is a diagnostic test that quantifies the likelihood of disease recurrence in women with early-stage breast cancer and assesses the likely benefit from certain types of chemotherapy. Concept of personalized medicine based on the four attributes: personalized, predicitive, preventive and participatory Polymerase Chain Reaction. Technique to amplify a single or few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence

Oncotype DX P4

PCR

Branch of pharmacology which deals with the influence of genetic variation on Pharmacogenomics drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. PMC Proteomics Therasnostic Personalized Medicine Coalition The study of the proteins that genes create or express Combination of targeted therapeutics and companion diagnostics

1 Introduction
This essay seeks to show some trends in cancer treatment up to date. As well as it is part of an initiative by BioCity Leipzig, an exemplary biotechnologybiomedical center where business, science and research live and work together. A place where young companies set new standards in biotechnology, biomedicine and health care together with professors from the University of Leipzig. This initiative attempts to foster development for the Saxony region, increasingly strengthen the links between researchers institutes, biotech companies, government agencies and academicals institutes such as University of Leipzig, especially international programs to promote technical-based startups by its nature the program SMEs (Small and Medium-sized Enterprises) promotion and training. Hence, the main purpose of this paper is presenting a general overview of the main trends in therapeutic and diagnostic techniques for cancer procedures, within the concept of a tailored therapy for each individual, bringing forward to the new concept of science, personalized medicine. Over the past decade, many advances in proteomics and genomics have led to the development of targeted diagnostics and therapeutics that leverage knowledge of an individuals genetic makeup to create a more personalized approach to healthcare. This new personalized medicine has the potential to eliminate unnecessary treatments, reduce the incidence of adverse effects to drugs, increase the efficacy of treatments and finally, improve health outcomes. Oncology drugs and new diagnostics methods for cancer have been at the forefront of advancing personalized medicine, because the origin of the disease and the different technologies used in pathology and treatment. Most of the researchers have found many Biomarkers related to specific types of cancer. The purpose is to give patients, the right treatment for the right person at the right time. 4

Personalized cancer prevention is a strategy that will enable each person to reduce his or her risk for lethal cancer by matching the dose, duration and timing of an intervention with their own cancer risk profile. One of the extended discussions is about diagnostics. The traditional techniques involve biopsy and many average procedures, which in most of the cases cause annoyance to the patients. In this new era of personalized

medicine, it intended tailored therapeutic to each patient, providing an accurate early-diagnostic, reducing unnecessary costs by chemotherapy and in general improving the quality of life. Many efforts are leading the market by Biotech and diagnostic companies. The pharmaceutical industry is also conscious of focusing on the new science of personalized medicine and not only in blockbuster drugs. They possess know-how as well as the experience for doing with the biotech companies the big effort to develop the specific treatments for patients, at the end the main inheritors of this new science. Within this business model other non scientific actors came to the healthcare market such as IT companies, wellness companies, payers and government agencies taking an important part of it. Otherwise, the market for diagnostics tests that leverage this new science is growing; the biggest opportunities exist outside of the traditional healthcare sector. For instance, the U.S personalized medicine market is estimated at about $232 billion and is projected to grow 11% annually, nearly doubling in size by 2015 to over $450 billion. The core diagnostics and therapeutic segment of the market comprised primarily of pharmaceutical , medical device and diagnostics companies is estimated at $24 billion, and is expected to grow by 10% annually, reaching $42 billion by 2015.

2 The new science, Personalized Medicine

A leading-edge approach to the treatment of breast cancer: The radical Mastectomy was developed in 1898 by William Steward Halsted considered the father of the American surgery.3 A century later the Food and Drug

Administration (FDA) approved a medicament called Herceptin, a meaningful change in medicine, because Herceptin was one of the first drugs to leverage the power of genetics to treat a disease. Herceptin is only prescribed for

patients whose genetic diagnostics reveal an over expression of a protein HER2 due to gene mutation, this is an indicator of an aggressive form of cancer that is responsive to the treatment by the drug. Chemotherapy drugs present several Adverse Drug Reactions (ADRs) such as hair loss and digestive problems, because they attack any cell that is replicating rapidly, including healthy cells. Herceptin is customized to target only those cells associated with disease. Many advanced research into genomics (the study of organisms genes) and proteomics (the study of the proteins that genes create or express) were carried over the last decade. With those accelerated understanding the door is opening to a more personalized approach to healthcare, discovering individual differences in genetic makeup. The science of genomics has the potential to personalize healthcare, enabling providers to match drugs to patients based on their genetic profiles, identifying who is susceptible to which health conditions, and determine how a given patient will respond to a particular therapy, it is known as pharmacogenomics. That could eliminate unnecessary treatments, minimize the potential of ADRs and ultimately, improve patient outcomes. Personalized medicine is often defined by the right treatment for the right person at the right time, others point out that personalized medicine will never be able to have a different specific treatment for every individual, but that there are characteristics of each individual that can be better defined and incorporated into disease management once a diagnosis is made.5 Additionally, the ISB institute and Dr. Hood present a definition of personalized medicine framed by the concept of P4 because of its four attributes: It is personalized; 6

it is based on an understanding of how genetic variation drives individual treatment. It is predictive; anticipating health problems and drug reactions. It is preventive; focusing on wellness no disease and participatory; empowering patients to take more responsibility for healthcare decisions.5 There are many definitions of personalized medicine, while the P4 approach focuses mainly on genomics and proteomics, the definition given by PricewaterhouseCoopers5 is broadly and for the purpose of this essay it will be taken 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 . This definition takes into account since High tech diagnostics to low tech foods and technology companies, analyzing and linking patients with scientific data.

2.1 Concepts and facts about Cancer

Oncology drugs and new diagnostics methods for cancer have been at the forefront of advancing personalized medicine, for several reasons and cancer treatment in personalized medicine is the aim of this paper. The diagnosis of cancer is based on a biopsy, subsequent an examination of cells or tumor tissue is considered. The different slide-based technologies used in the pathology, such as immunochemistry fluorescent in situ hybridization (FISH), and chromogenic in situ hybridization (CISH) have approached the way for pharmacodiagnostic testing.4 Cancer affects people at all ages with the risk for most types increasing with age. Cancer caused about 13% of all human deaths in 2007 (7.6 million). 4 But what is cancer? - the medical term: malignant neoplasm is a class of diseases in which a group of cells display uncontrolled growth, it means division beyond the normal limits; invasion intrusion on and destruction of adjacent tissues; and sometimes metastasis, spread to other locations in the body via lymph or blood. These three malignant properties of cancers differentiate them from benign tumors, which are self-limited, and do not invade or metastasize. Most cancers 7

form a tumor but some, like leukemia, do not. The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology.1 Cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancerpromoting genetic abnormalities may randomly occur through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers is usually affected by complex interactions between carcinogens and the host's genome. Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are then inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system. Definitive diagnosis requires the histological examination of a biopsy specimen, although the initial indication of malignancy can be symptomatic or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular

abnormalities in certain tumors, and which minimize damage to normal cells.

The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histological grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments. One of the main purposes of this essay is to point out new trends in diagnostics and treatments for cancer from the point of biosciences and their development in this new era of personalized medicine. But what is personalized cancer prevention? A strategy that will enable each person to reduce her/his risk for lethal cancer by matching the dose, duration, and timing of an intervention with their own cancer risk profile. Most research studies provide us with data on the average person, but who is the average person? The central tenet of personalized cancer prevention is that the average is overrated.34

3 The personalized medicine landscape5

Consider of personalized medicine as a set of concentric rings, the middle represents medical applications of genomics and proteomics research, such as targeted diagnostics and pharmaceuticals and, the outer rings represent health and wellness products and services far removed from the traditional healthcare field. These new non health companies will play an important role in the personalized medicine due to the therapy core involves other several products and services such as functional food nutraceuticals since individuals gain greater appreciation for their unique disease risk profiles demanding that address their specific health concerns. Already, an important number of non traditional

healthcare companies are marketing personalized medicine services to consumers and supposed to be new entrants in the traditional healthcare space; consumer products companies, wellness services as well technology companies are new players on it.

All the participants in the health industry from biotechnology/pharma companies to hospitals must change their of relating to the consumer if they are to compete in a new era of personalized medicine, the biggest opportunity in personalized medicine may lie in identifying new products, services and information targeted directly to consumer for all the players through different key challenges: For Pharmaceutical, biotech and medical device companies, moving from general to specific treatments and from disease treatment to prevention. For Diagnostic companies, developing and validating new diagnostics to enable personalized medicine. For Technology companies, developing new business models to capitalize on the value of data as well developing/embracing new technologies for measurement and visualization. For other non health companies (consumer products, food, and beauty/cosmetics) there are three key challenges: Adapt to a new focus on wellness and the rise of consumerism, develop effective strategies to broaden the definition of what is considered health and finally address consumer demands for higher quality foods and products that contribute to the healthfulness. For Health systems and other providers the challenges will be providing cutting edge care while controlling health care delivery costs, getting reimbursed for providing wellness and prevention services and operationalizing a consumer-oriented business model. The big challenges for government and private payers are embracing innovation and controlling health care reimbursement costs while improving health care outcomes to increase value per dollar spent. All participants listed above play an important role within the market, personalized medicine market is growing rapidly according to the PricewaterhouseCoopers estimates. In the U.S., the total market for 10

personalized medicine is estimated at $232 billion and is projected to grow 11% annually to a total of $ 452 billion in 2015. The core of the segment, it means diagnostic test and targeted therapies- is estimated at $24 billion, and is expected to grow by 10% annually to $42 billion by 2015.5 With data showed in figure 1, the core of the personalized medicine diagnostics and therapeutics the potential is considered enormous, but the biggest opportunities exist beyond this core, particularly in less traditional sector, more consumers oriented. The landscape of personalized medicine shows a clear opportunity beyond the core of targeted diagnostics and therapeutics, our main objective in this paper. Nonetheless, is meaningful to present this information to evaluate the market size.

3.1 The Big Pharma model

For years the pharmaceutical industry has focused on blockbuster drugs that target broad populations, in this new era of personalized medicine the big Pharma model must discover and develop tailored therapies for smaller markets. This new approach is not new for the industry, pharma companies have tried to offer different treatments according type of disease or using biomarkers such as cholesterol level to guide the right treatment. Although those improvements in personalized medicine had done by the Industry, the development of new therapeutics based on genomics/proteomics will require greater efforts to achieve a level of tailoring5.

11

Figure 1. Personalized Medicine Market Size, 2009 and 2015. Source: adapted from PricewaterhouseCoopers analysis5

12

Some companies are going to great steps toward personalized medicine, including Eli Lilly and company, our business model will accommodate personalized medicine- in fact, and it may depend on it said the chairman John Leichleiter.6He sees a viable new revenue model emerging: Instead of getting a relative small share of a really large pie- the traditional blockbuster model a tailored therapy could expect to claim a relatively large share of a more segmented pie, and repeat prescribing and patient compliance almost certainly would occur at a higher rate- further supporting the economic case, with this landscape the net results, in terms of sales, actually look quite favourable.7 Rather than developed targeted therapeutics in their labs, most of the pharma companies have started to turn on small biotech companies in order to fill the pipeline with new personalized medicines that could replace the low revenues. The trend is the venture capital community is trying to capitalize on Big Pharmas interest in Biotech. On the other hand, the development of targeted therapeutics will bring new opportunities for medical devices companies whose products can deliver personalized medications to specific parts of the body. For instance, Philips has developed a technology to encapsulate drugs in biodegradable bubbles that are delivered via ultrasound to tumours while Selecta BioSciences is working on Biodegradable nanoparticles targeting lymph nodes.8

3.2 First winners: molecular diagnostics

One of the most innovative areas with the highest impact will be the whole field of early and correct diagnoses. Molecular diagnostics include lab tests and imaging, they are used to guide the treatment decision and predict which patients are likely to have an adverse reaction to a drug and, help physicians to decide what are the right therapy and dosage, patient by patient. The importance of the accurate this diagnostic phase is to produce better health outcomes and prevent black block warnings and recalls for medicines that may

13

be can be effective for the larger population but can have severe effects or adverse reaction in a small subset of patients.5 Other important aspect to take into account is the economical impact on the whole price of the therapy, because it can help to avoid even higher treatment costs by identifying patients who likely will or will not respond to a prescribed drug. For instance, Genomic Health developed the Oncotype DX breast (roughly $4,000 many times the average cost of a lab test) can help to avoid even higher costs of chemotherapy if the test demonstrates treatment is or isnt warranted. The company estimates that by identifying those who would not benefit from treatment, the test can reduce chemotherapy use by 25% - 35% and yield a savings of approximately $1900 per patient tested, aside from the cost savings, the test prevents needless pain and suffering.9 Molecular diagnostics is growing rapidly market, it represents $37 billion market for the in vitro diagnostics (see figure 1). This sector is more concentrated than the pharmaceutical sector, the 10 largest diagnostics companies accounted for approximately 75% of the market in 2007, compared with the 45% for the top 10 pharmaceutical companies. There are companies which develop diagnostics products but others one are mainly service providers that perform diagnostic testing. Moreover, Big Pharma is gradually entering to the market, as is the case of Novartis that has launched a molecular diagnostics division.10 Otherwise, this sector is facing many challenges. While growth prospects for molecular diagnostic are promising, there are other concerns as the ability of physicians and specialists to interpret the analysis. Dr Troy Brennan, executive vice president of CVS Caremaker, a major integrated pharmacy services providers says there is a need to develop reasonable guidelines for the use of genetic test results, which requires understanding a staggering amount of information, but the biggest concern is that diagnostic test will bleed into the system without clear guidelines, without enough counsellors to help patients understand the results, and without payers willing to reimburse for them.10

14

This sector also faces challenges related to a potential change in the regulatory process for validating new tests. The new diagnostics products will be approved by FDA or CLIA (Laboratory Improvements amendments) in U.S taking large period of time and stalling the growth in the market, increasing the cost, time and complexity of developing new products. About this, the office of In Vitro Diagnostic Device Evaluation and Safety of FDA is prepared to tighten regulations over diagnostics manufacturers which can diminish needless regulations to speed up the natural develop. Within the diagnostic sector appears a new concept; theranostics commonly defined as a combination of targeted therapeutics and companion diagnostics. Tailoring treatments for patients, the diagnostic must be accurate and accompanied of a targeted and selective therapy. The FDA, which has identified 28 valid biomarkers, has designed four that require a diagnostic test prior to prescribing the companion drug. The European counterpart of the FDA, the European medicines Agency (EMEA) requires companion diagnostics 11 targeted therapies. Under this scenario, the push to develop this theranostics is being driven in part by payers and also government agencies. That said, if government agencies increase the use of biomarker and diagnostics in prescribing decisions, its likely that pharma and diagnostics companies will increase their collaboration in this area.10

3.3 Trends in Diagnostics

The long anticipated field of personalized medicine finally appears to be gaining momentum. For years proponents have been pointing out to the targeted cancer drugs Gleevec (Novartis) and Herceptin (Genentech/Roche) and promising a time when most drugs, like these two gleaming examples, would be prescribed based on test that determine individual biological differences. 26 But Herceptin and Gleevec have stood alone for a very long time. It is only recently that at least a dozen or personalized medicine companies have gained noticeable momentum by developing biomarker discovery and screening 15

services, diagnostics that guide prescribing and drug/diagnostic combinations (see table 1).
Company Location Diagnostic (company if different from drug developer)/ Drug
Mammaprint/breast cancer chemotherapy Prostate Px for likelihood of recurrence of prostate cancer/hormone therapy

Technology platform

Agendia

Amsterdam, Netherlands NY, USA

Microarray with 70 genes

Aureon Yonkers

Image analysis, pattern recognition, quantitative biomarker multiplexing, multivariate statistical analysis RT-PCR, genome wide, high resolution expression profiles from more than 1,000 clinical cancer samples

Aviara Dx

San Diego, CA, USA

Cancer type ID for 39 tumors types: HOXB13/IL17BR/Breast cancer recurrence risk and response of ER + tumors to endocrine therapy MGI (Molecular grade index)/breast cancer recurrence Developing prostate cancer prognostic test
sm

CombiMatrix Molecular Diagnostics Irvine

CA, USA

HerScan test/for early detection of breast cancer HemeScan/chronic leukocytic leukemia (CLL) treatment.

Microarray Baotenal artificial chromosome comparative genome hybridization Inmunohistochemistry (IHC) IHC

Dakocytomation

Amsterdam

cKIT Pharma Dx/Gleevec. Chemotherapeutics EGVR Pharma Dx/Erbitux

IHC Hercep Test/Herceptin FISH HER2 Fish/Herceptin DiagnoCure Quebec, Canada Src homology collagen-like protein/breast cancer recurrence Guanylil cycle C test/colon cancer recurrence PCA3 prostate cancer Level of activated tyrosine phosphorylated Shc protein and p66 Shc protein in tissue specimens FISH

16

Company

Location

Diagnostic (company if different from drug developer)/ Drug

PLAC Test/cardiovascular risk stratifier Cancer risk test under development

Technology platform

DiaDexus

San Francisco, CA, USA Manchester, UK

Enzyme-linked immunoabsorbant assay (ELISA) Realtime (RT) PCR Amplifiication refractory mutation system

DxS

KRAS mutations/Vectibix and Erbitux EGFR-29 mutation test kit/tyrosine kinase inhibitors B-RAF mutation/MAPK ERK kinase inhibitors

Epigenomics

Berlin, Germany New USA Mexico,

Cancer molecular diagnostics

Methylation markers

Exagen

Prognostic and diagnostic tests for cancer and chronic diseases Oncotype Dx/breat cancer recurrence Test for colon cancer, prostate, and others in development

Computational approach and FISH platform RT-PCR

Genomic Health

Redwood City, CA, USA

Genzyme Genetics

Westborough, MA, USA

ABL Kinase domain mutation/Gleevec EGFR amplification in non small-cell lung carcinoma (NSCLC)/kinase inhibitor drugs EGFR Mutation analysis in NSCLC/kinase inhibitor drugs KRAS-mutation detection in NSCLC/kinase inhibitor drugs YGT1A1 molecular assay/ Camptostar

PCR amplification and sequencing FISH PCR amplification and sequencing Primer extension Invader (Third wave technologies, Madison, WI, USA) NanoBio chop technology

Iris Biotechnologies

Santa Clara, CA, USA

Breast cancer chip, organ transplant chip, NeuroChip, CardioChip, MetabolicChip (in development) TargetNow/chemotherapy. Mammostrat (Applied genomics, Huntsville, AL USA) Cardioevaluator, PCA profiler Probe, San Diego

Caris Molecular Profiling Institute

Phoenix, USA

AZ,

IHC Metabolic markers Expression profiling

17

Company

Location

Diagnostic (company if different from drug developer)/ Drug

Methylguanine methyltransferase methylation tests in development/alkylating agent based chemotherapies Bcl-abl fusion protein and level of phosporylation/Gleevec Janus Kinase-2 (JAK2) mutations/JAK2 inhibitors Mutations associated with Gleevec resistance Activation of intracellular kinases/response to chemotherapy

Technology platform

Oncomethylome

Liege, Belgium

Methylation status

Quest Diagnostics

Madison, NJ,USA

RT-PCR

Roche Diagnostics

Basel, Switzerland

Amplichip CYP450/metabolism of various drugs Amplichip Leukemia and Amplichip p53 in development

Expression arrays

Rubicon genomics

Ann Arbor, MI, USA

MethylPlex-noninvasive methylation test (blood, urine) in development cancer prognosis Undisclosed in development/colorectal cancer prognosis

Omniplex nucleic acid amplification

Signature Diagnostics

Potsdam, Germany

Tissue collection, array-based discovery, validation and subcellular localization invader

Third Wave Technology Ventana (Roche) Diagnostics

Madison, WI, USA Basel, Switzerland

UGT1A1 molecular assa/camptostar chemotherapeutics PATHWAY Anti-c-kit mAB/Gleevec

IHC

Table 1. Selected companies offering, developing or partnering to develop companion diagnostics

26

18

The Oncotype Dx test helps some breast cancer patients decide whether to undergo chemotherapy, is notable because uses gene expression analysis, but is done with RC-PCR rather than using an array or oligo-nucleotide chip. After surgery, a sample of tumor is analyzed and the patient receives a score between 0 and 100. Those with the lowest score (0-18) are least likely to experience a recurrence of their cancer. There with the highest score are at great risk of recurrence.

Figure 2. A winning curve. To gain acceptance for its Oncotype DX Test, Genomic Health set out to show that the resulting recurrence score provides information that is valuable, actionable and accurate through a suit of studies. (Source Genomic Health)
26

Oncotype DX test helps to spare women the discomfort of treatment that most likely wont benefit them and spares insurance companies unnecessary costs. Moreover, Doctors have adopted the test because it gives them reliable information they can act on. One result o Oncotype Dxs success has been a cluster of hopeful followers in Breast cancer testing.26 (See table 2). At the same time, Genomic Health aims to develop new tests predicting prognosis in kidney, colorectal and prostate cancers as well as others. Some of these tests are developed in collaboration with large pharmaceutical companies including Bristol Myers Squibb, Pfizer and Sanofi Aventis. 26

19

Company Agendia, Netherlands The

Test name/patient pool MammaPrint/ER or ER , patients <61 years old

+ -

Comments FDA approved, 70 gene signature on a microarraym from frozen tissue sample. The first in vitro multivariant index test to be FDA approved. CLIA certified, five gene IHC assay (mAb markers and diagnostics algorithm) FTPE tissue sample. Genes: TP53, NDRG1, CEACAM5, SLC7A5 AND HTF9C CLIA-certified. Two gene test evaluating ratio of HOXB13 to IL17BR. CLIA-certified, five gene signature. Genes: BUB1B, CENPA, NEK2, RACGAP1 and RRM2. FISH-based test. Propietary coperna computational technology used to select combinations of genes to use as markers. CLIA certified, 21-gene signature using RTPCR and PFPE tissue sample. Includes cancer genes: MK167, STK15 (AURKA), Survivin (BURC5), CCNB1, MYBL2, MMP11, CTSL2, GRB7, HER2 (ERBB2), GSTM1, CD68, BAG1, ESR1, PGR, BCL2, SCUBE2, and references genes: ACTB, GAPDH, RPLO, GUS and TFRC.

Applied genomics Huntsville, AL, USA

Mammostrat ER , node negative, post menopausal

Aviara Diagnostics, San Diego

H:I/ ER , node-negative. Determines endocrine + responsiveness MGI/ ER , early stage, node positive or negative eXagen BC/ER?PRdevelopment) (both in

eXagen New Mexico, USA

Genomic Health

Oncotype DX/ER , node negative patients who will receive tamoxifen. (Tests suggest utility in node-positive patients as well.)

Table 2. Selected tests for determining recurrences risk in early-stage breast cancer

Mara aspinal, CEO of Genzyme Genetics points out that the survival rate blood cancers soared from 0% to 70% because we can identify the subtypes and customize therapy (Figure 3). Shes hopeful that that paradigm can spread throughout the drug discovery field, to where most new drugs are effective in at least 80% of patients. Noting how difficult making progress has been so far, however she adds, I need to emphasize that thats a hope.27

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Figure 3. The power of subtypes. The impact of improved diagnosis and treatment on blood related cancers demonstrates the potential of personalized medicine and helps explain why proponents have been so determined. (Source Genzyme Genetics)
26

3.3.1 Biospecimens An issue that is intuitively obvious but rarely emphasized is that Biospecimens of high quality are the sine qua non of personalized medicine. Biospecimens such as cells, tissues, blood, and plasma are common requirements patient management in current, standard-of-care medical practice, the molecular data are the envisioned basis of personalized medicine, is in these biospecimens where the molecules resides. In cancer medicine they are the gold standard of diagnosis, staging, and prognostic/predictive factor analysis. However, biospecimens will take centre stage as the critical link between the clinic and the patient.34 The reality of personalized medicine is on the horizon. The first steps have been taken in the evolution of tumor classification, disease prognosis molecularly targeted treatment, and response to therapy based on molecular features. The usefulness of biospecimens for the types of transnational research needed to move medicine into the personalized era is limited by variation and in the ways biospecimens are annotated with clinical data and consented for scientific use. 34 21

The variation on Biospecimens quality is especially problematic for genomic and proteomic analysis technologies given their extraordinary sensitivity. Globally, there are a number of efforts to create large-scale resources in which biospecimens are collected, stored, and distributed under a new system of standards, quality control, data sharing and access. These efforts include: The United kingdom (UK) National Cancer Tissue Resource, acquisition and processing centres for tumor specimens; The UK Biobank recruiting half a million patients to create a large biospecimens resource of epidemiological studies; Biobank Japan which is creating a large-scale DNA repository from over 300,000 individuals; Kaiser Permanente which is recruiting blood or saliva specimens and the US Department of Veterans Affairs (VA) which has launched a pilot project to gather 100,000 biospecimens with the aim of linking genetic makeup with some diseases. While big efforts in matter of handling Biospecimens have been done, much more work remains to be done to achieve the vision of national and/or global resources that can support the scale and precision of molecular analysis needed to accelerate progress toward personalized medicine.34

The individual Players

So far, approaches in the Big Pharma model and Diagnostics companies as the main actors generating technology have been done, besides that there are other actors, who play an important role in the personalized medicine science. They can accelerate or not, the development, implementation and growth of this important economic sector.

4.1 Technology based companies

Within this sector are covered companies based on information and technology. These technology companies are capitalizing on emerging opportunities to manage colossal quantities of genetic and other health data. To illustrate their importance, it took more than 13 years and $2.7 billion to complete the human Genome Project in 2003- the first successful effort to sequence a humans 22

DNA. Only four years later, a similar project took two months and cost less than $1 million.11 Currently, California based pacific biosciences is working on a platform to sequence the human genome in less than 15 minutes at costs of $100. Sensing this potential, in 2008 Intel Capital the venture arm of the technology giant, co-led a group of investors that injected $100 million into the start up.13 Some companies are leveraging massive computing power to identify new personalized medicines. The company Gene Network sciences, a private company based in Cambridge is using super computers to delve biological data, going deeper insights and causes of disease and identify potential new diagnostics and treatments; this company is collaborating with cancer researchers at the University of Connecticut to model personalized medicines for cancer.14 Microsoft entered at the space of personalized medicine as well in 2009, acquiring a part of Rosetta Biosoftware, a genetic data management software to figure out which compounds might make the best drugs.
15

The

company plans to integrate the software into Microsoft Amalgama Life Sciences, which helps researchers to integrate data from multiple internal and external systems.16 4.1.1 Electronic Health Records (EHRs) Interoperable Health records (EHRs) could enable the sharing of genomic, proteomic and other health data related to personalized medicine data among research organizations, and pooling and analysis of the data to identify trends and accelerate research efforts. It is important to identify what works and what does not work in the treatment of patients based on their particular characteristics and medical histories. The possibility of generating data can overtake to understand and interpret them, for this the necessity of systematize data in other resources such as records. Achieving this goal, it requires an infrastructure of building and sharing health records electronically and a rigorous privacy code that prevents disclosure and discrimination.5

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However, connecting EHRs are facing many challenges due to the different data types and formats; it is a need for agreement on common data standards to reduce complexity, a lack of consistent terminology adds to the complexity. 4.1.2 Web resources Here new companies will emerge such as Internet service providers (ISPs), social networking sites due to ability to stay in touch with the patient. Because of the real need push closer healthcare decisions and treatments to the patients. For instance, the potential of the web is illustrated by PatientsLikeMe 17 a social networking site where the patients who have a life-disease- changing condition can share information and treatments with specialist and others patients. The site also enables researchers and industry to accelerate progress in understanding the developing new targeted treatment discovering etiology of diseases. Social media also can connect healthcare professionals in diagnostic and treatments, the company Serma enables physicians to connect with their peers, sharing information of treatments, identify trends and conglomerate their knowledge to improve outcomes for their patients. 18 These kinds of networks allow the physicians to join to the challenges posed by personalized medicine.

4.2 Healthcare providers

For all the Healthcare providers, personalized medicine presents the opportunity to learn more about therapies, to improve the quality of care through more precise diagnostics, and access to more sophisticated and accurate information with new developed tools. Under this scenario, allied health professionals such as nurse practitioners and physicians assistants may play a greater role. Physicians also could face competition from pharmacists. More specialized training is required additional by pharmacists to help patients navigate the personalized medicine environment and understand the application of targeted treatments. 5

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For Primary care providers will be able to create new lines in around prevention and wellness to replace continue revenues lost from traditional medical procedures. For professionals in primary care, in order to remain relevant in an era of personalized medicine, they must become educated in the science and clinical application of genomics and proteomics. Without the right tools and specialized training, the personalized medicine market will not advance in the provider space or elsewhere.5 Physicians will need now more than ever communication skills to provide genetic counseling and address the specific issues surrounding targeted tests and treatments. A regular physician will be able to explain to a cancer patient why the drug that saved her brother will not work for someone with her genetic makeup. To illustrate this point in ovarian cancer, a test to detect a protein biomarker called CA125 is used routinely to identify whose cancer is likely to recur, so that early treatment with chemotherapy can begin.19 Necessities in education will be required for this new market, Universities and training institutions will be offer programs in genomics and proteomics science for physicians, nurses and pharmacists. To address this gap in knowledge the Baylor college of Medicine is leading the way in developing new curricula.20 Moreover, hospitals should become more consumer-oriented service providers to barge in the business. Hospitals that have links with the Universities can develop better strategies for personalized medicine. Academic medical centers have massive amounts of patient data, which accelerate the discovery process. This rich pool of samples could be mined for data to identify trends and correlations between outcomes and genetic profiles across subpopulations, accelerating research progress.21 The National institute of Health (NIH) is creating an integrated network of leading Academic medical centers through its clinical and Translational Science awards (CTSA) program, which will link roughly 60 of the top institutions in U.S to focus on clinical and translational science. CTSA gives grants in the academic research space, to incentive more academic medical centers to involve in this new era.22

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4.3 Payers
Payers actions will drive the business models of other participants. Their reimbursement schemes will influence the business models of pharma and diagnostics companies as well as providers who depend on third-party payment. The most important barriers for growing personalized medicine are reimbursement, payment and revenues for small biotech companies and patients, the role that play payers must be considered as an essential part of the chain. Identification of several key indicators that can be used to gauge where, when, and how effectively personalized health innovations are being adopted by specific market segments. Pharmaceutical companies, biotechnology

companies, clinical trial and other supporting organizations, healthcare providers, and healthcare payers will all be affected, and segments of the value chains can benefit from specific
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knowledge-based

opportunities

for

personalized health (See figure 4).

PATIENTS
Internet information access Patient advocacy group

Drug discovery

Clinical development

Therapeutic solutions

Healthcare providers

Healthcare payers

KNOWLEDGE RESOURCES
Figure 4. From Discovery to payer: The contribution of knowledge to the personalized health landscape. Adapted from Health Industry Insights
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Until today Insurance companies 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 model.23 Personalized medicine has the potential to reduce payers costs in the long term by providing the accurate diagnostics required avoiding needless or ineffective treatments, preventing adverse reactions and events, promote prevention and wellness, and deliver more effective targeted therapeutics. Nevertheless, payers concern about two main factors: (1) they worry that the cost of personalized medicine could be unsustainable, because the costs could be additive, given the history of healthcare innovations, which typically supplement rather than replace existing treatments. (2) Payers also worry that the investments they make could benefit investors, one payer might invest in costly diagnostics and early intervention that might reduce or eliminate the need for surgery in the future, but by then member may have changed plans, and the new insurer will benefit from earlier investment.7 Under this point of view some consumers might even opt to purchase a health plan that covers personalized medicine diagnostics, and then switch to a less costly plan for their ongoing care.24 Even though major payers are leading the way, in a survey of 61 healthcare payers in the U.S found that many are beginning to move toward implementing personalized medicine solutions, and are focusing in particular on targeted and diagnostics therapeutics.25 In the search for ways to reduce costs, payers are moving away from paying for procedures (the traditional reimbursement paradigm) and toward outcomes based reimbursement or pay for performance (P4P). The trend toward P4P could accelerate the adoption of personalized medicine, if and only if clinical data shows that targeted diagnostics and therapies reduce payers costs, by contrast until there is a evidence to show that a targeted diagnostic, therapeutic or therasnostic solution will save money, payers are not likely to provide reimbursement. For Instance, consumers had to 27

pay out of pocket for the Oncotype DX test developed by Genomic Health. Only when sufficient clinical data was gathered to quantify potentials costs saving did payers begin to reimburse the test.

4.4 Government
Government worldwide play a key role in advancing or impeding the progress of personalized medicine. Government can be enabler of the new science by funding research, implementing appropriate reimbursement and regulatory policies, and addressing key issues such as data privacy and IP rights to genomic discoveries. FDA launched the critical path initiative in 2004, to improve the process by which new medical products are developed and approved. For implementing this initiative the University of Arizona and FDA formed the Critical Path Institute (C-Path), an independent non profit organization. The main goals of C-Path was the decrease of regulation which avoids offering new diagnostics and therapeutics to the marketplace and, are available and tested since long time in labs. By working with EMEA, C-Path explores the potential of global standards, which means a drug approved in Europe would be automatically approved in U.S., and vice versa. Those new global standards can reduce or eliminate duplication of efforts and accelerate the approval process, which is becoming more critical due to the number of new diagnostics and therapeutics is growing rapidly. Government has a high impact in shaping the future of personalized medicine by taking actions in the different areas: Regulatory: Create clear and reasonable pathways for approval of personalized medicine diagnostics and therapeutics, and for codevelopment of drugs and diagnostics (i.e., theranostics).

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Reimbursement: Change reimbursement models from volume to valuebased, from rewarding for treatment/disease to paying for

outcomes/wellness. Privacy: Implement policies that enable sharing of patient data and biospecimens needed for research while ensuring the privacy and security of patient data. Intellectual property (IP): Create IP policies and legislation that provide financial incentives to develop new drugs and diagnostics while balancing the need of sharing of scientific information to advance research.

5 Conclusions
The activities of various players who are moving into the personalized medicine market have been described, some aggressively others cautiously. It has been also highlighted aspects such as key scientific business, and regulatory hurdles they face, progress that has been made. This essay has showed a tremendous progress in genomics and proteomics research, especially in the early diagnostic phase. Nevertheless, still have much to learn about the precise biological mechanism that predict or provoke cancer in a given individual, the interaction of multiple genes and proteins with the environment, and how to translate this knowledge into prevention and treatment strategies. Sustainability will require a long-term strategy, cross industry collaboration and technical expertise. Personalized medicine field is a highly complex field and no one companies or organizations has all the resources; financial, knowledge, tools needed to implement solutions in this space. Unless regulatory and reimbursement models are aligned to with the requirements of personalized medicine, the new science is not likely to advance significantly. All the participants; pharmaceutical and diagnostic companies, payers and regulators

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can work together to create an economically viable, sustainable process for commercializing targeted therapeutics and diagnostics. The implementation of personalized medicine on a large scale even in well developed countries will require a major restructuring of the healthcare infrastructure to become more consumer focused, and a radical shift in the thinking and culture of the medical establishment. Such a shift is bound to require years, if not decades, to occur.

5.1 Progress and challenges

Personalized medicine seeks to reduce the burden of trial an error in healthcare through high tech approaches in proteomics and genomics, as appears above many players in the value chain of personalized medicine, who act as accelerator or in the case of government agencies can also delay the process. Given that the other participants have a big impact over the development in 2003 was based and launched in Washington the Personalized Medicine Coalition (PMC) to foster and better understanding of personalized medicine across industries. The PMC will provide a resource of knowledge and expertise to legislators, physicians, hospitals and others seeking to restructure or realign their goals and incentives for the next generation in medicine. 28 More than 50 partners are in the PMC like larger companies, Abbott, AstraZeneca, Roche, Siemens, as well Biotech companies Genentech, Genomic Health, among others. Within the main goals for the coalition are: Provide opinion leadership with respect to the evolving discussion of public policy issues that affect personalized medicine. Help educate the public, policy makers, government officials and private sector healthcare leaders about the public and personal health benefits of personalized medicine. Serve as a forum for identifying and informing others of those public policies that may impede the ability to deliver the promise of personalized medicine. 30

Create a structure for achieving consensus positions on crucial public policy issues and supporting changes needed to further the public interest in personalized medicine.28

Challenges regarding legal, ethical, and the ability of this genomic research to translate into clinical utility are also addressed in a selection of news and opinion and opinion articles. The once fantastical notion that any given human can walk into physicians office with his or her genome on a hard drive looks more and more like reality. It is not possible to anticipate everything that will happen next, but it can be better prepared for the necessities in the future.34

The main challenge for cancer personalized prevention is to find populations in which the impact of early life interventions on the incidence of cancers affecting older adults can be studied; and the interindividual differences in gene expression that may influence a persons response to a particular nutrient or treatment.

Business models will require a long-run strategy and great flexibility to succeed in a fast moving market that could evolve in unpredictable ways.5 Until now, the efforts accomplished for all the participants analyzed in this essay should be pushed by a macro level institution in each country to foster the initiative and to speed up the process already started for main core in this Business Model, Biotech companies and Pharmaceutical companies as leaders of the market. One of the most uncertain aspects to be taken into account within this science is to identify and test so it benefits more than a personalized therapy at a reasonable cost; this is one of the issues that most can slow the development of personalized medicine. As it has mentioned above, the returns on investment depend on the particular outline and are different for different stakeholders.

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Although some governments especially in U.S. and European Union have reached different levels of regulation and created policies which encourage research and development of new products in this area, the pharmaceutical and diagnostic industries still face uncertainty over the evidentiary requirements therapeutics. Consumer behaviour is another obstacle to personalized medicine, one that is often overlooked and underestimated. The concept of personalized medicine involves a big portion of wellness and self-care by patients. The main goal of personalized medicine is to design a therapy for each individual, in which he is in charge of nutritional care, health aspects, and risk factors exposure. They are the key to therapys success. And it had been shown during decades, to change or modify lifestyle still remains as one of the main barriers to break down. for approvals of new diagnostics, theranostics and

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6 References
1. Danai et al (2005), Cancer, World Health Organization (WHO), http://www.who.int/mediacentre/factsheets/fs297/en/, (Jan 19, 2010) 2. ^ Cancer Research UK (January 2007). "UK cancer incidence statistics by age".

http://info.cancerresearchuk.org/cancerstats/incidence/age/. Retrieved 2007-06-25. 3. Library of the national medical Society available at http://www.medical-

library.org/journals3a/breast_cancer_surg.htm 4. Jorgensen JT, Nielsen KV, Ejliertesen B,: Pharmacodiagnostics and targeted therapies- a rational approach for individualizing medical anti-cancer therapy in breast cancer. Oncologist 12, 397-405 (2007). 5. PricewaterhouseCoopers analysis 2009. The new science of personalized medicine translating the promise into practice. Contributors: David Allen, Laura Alves, Genevieve Caruncho, David Chin, Daniel Cohn, Deepti Damale, Bill Dracos, Simon Friend, Julie Ha, Andrea Kadar, Kim Krieghbaum, Loic Kubitza, Sandy Lutz, Mike Mentesana, Silvia Ondategui Parra, Mathew Rosamond and Barbara Walsch. 6. Lechleiter, J, PhD., Markets of one: The pharmaceutical industry and the Pursuit of Personalized medicine(presentation at the conference of personalized medicine: a call to action, Boston, Massachusetts, November 29, 2007). 7. 8. Ibid Fantastic voyage a special report on healthcare and technology. The economist, april 16, 2009. Available at http://www.economist.com/specialreports/displaystory.cfm?story_id=13437950. Accessed date January 30, 2010 9. Per Oncotype Dx website, at http://www.oncotypedx.com/ManagedCareOrgs/EconomicValidity.aspx. Accessed date January 31, 2010 10. Diagnostics 2009: moving towards personalized medicine, PricewaterhouseCoopers LLP. Available at http//www.pwc.com/us/en/healthcare/publications/diagnostics-2009-moving-towardspersonalized-medicine.jhtml. Accessed date January 31/2010 11. Louies, Alan S, PhD., jumpstarting the transformation to true Personalized Medicine: Potential catalyst and Keystones, Health industry insights #HI208059, August 2007. 12. Pacific Biosciences raised $100 to fund commercial 13. Product development, Fierce Biotech, posted July 14, 2008. Available at http://www.fiercebiotech.com/press-releases/pacific-biosciences-raises-100-million-fundcommercial-product-development-0. Accessed January 28, 2010 14. Per Gene Networks Sciences website, http://www.gnsbiotech.com/static_content/ Accessed January 19, 2010 15. Microsoft buys Genetic Data Software from Merck, Wall street Journal Helath Blog, June 2, 2009. Available at http://blogs.wsj.com/health/2009/06/02/microsoft-buys-genetic-data-softwarefrom-merck/ accessed Jan 31.01.10 16. http://www.microsoft.com/amalga/news/default.mspx accessed Jan 31.01.10 17. http://www.patientslikeme.com/ accessed Jan 15.01.10 18. http://www.sermo.com/ accessed Jan 15.01.10

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19. Andrew Pollacks, Doubts on Ovarian Cancer Relapse Test New York Times, May 31, 2009. Available at http://nytimes.com/2009/06/01/health/research/01cancer.html?r=5&refhealth. Accessed Jan 31.01.10 20. http://www.bcm.edu/medschool/ accessed jan31.01.10 21. Judd Staples, MBA et al., center for genomic Medicine, Duke institute for Genome Sciences & Policy, Duke University, The role of the academic Medical center in advancing personalized health care. Available at http://www.hhs.gov/myhealthcare/news/commissioned.html#cmish3. Accesed Jan20, 2010 22. http://www.ctsaweb.org/index.cfm?fuseaction=home.showNIH_CTSAInfo accessed 31.01.2010 23. Alan S. Louie, PhD. Et al., the personalized health paradigm: transforming the pharmaceutical and Healthcare industries for the 21 century, Health Industry insights #HI203469, October 2006 24. Judd Staples, MBA, et al., Director, Center for Genomic Medicine, Duke Institute for Genome Sciences & Policy, Duke University, The role of the academic Medical Center in Advancing Personalized Health Care. Available at http://www.hhs.gov/myhealthcare/news/commissioned.html.htm#cmish3 25. Alan S. Louie, PhD. And Janice W Young. Payers on the future of personalized medicine, Part 1: Getting Ready for Change Health Industry Insights #HI211577, April 2008 26. Allison, Maloyre; Is personalized medicine finally arriving, Nature Biotechnology, Vol 26 Number 5 May 2008 pag 509-517 27. Amado, R.G, et al. J. Clin. Oncol. 26, 1626-1634 (2008) 28. Munroe J Brain, A coalition to drive personalized medicine forward, Personalized Med (2004) 1(1), 9-13 29. Compton Carolyn, MD,PhD, Getting to personalized cancer Medicine, Am Cancer Society, DOI10.1002/cncr.22966 (2007), 1641-1643 30. Roukos Dimitrios, MD, Personal genomics and practical personalized medicine Overcomimg challenges. Gastric and Breast cancer 2008; 7(3):80-82 31. Waters David, Chiang Emily, Bostwick David, The art of casting nets: fishing for the prize of personalized cancer prevention, Nutrition and Cancer, (2008) 60 (1), 1-6 32. Alan S.Louie, PhD et al, the personalized health paradigm:transforming the pharmaceuticals and Helathcare industries for the 21 Century., helath industry insights #HI203469, October 2006.
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Appendix