Volume 4, December 2015


Stay up to date on educational opportunities, scientific updates and new tests from Quest Diagnostics Medical Affairs.

Charles “Buck” Strom, MD, PhD, FAAP, FACMG, HCLD
Vice President, Genetics and Genomics
Quest Diagnostics

Provide the right treatment, to the right patient, at the right time. That is the objective of personalized medicine—an objective that is being realized through the use of genetic, genomic, and molecular information for accurate diagnosis, prognosis, and clinical decision-making. Dramatic increases in diagnostic capabilities for gene sequencing and the development of companion diagnostics are providing the basis for improved risk assessment and targeted therapeutics. As a result, personalized medicine is becoming part of everyday medicine.

This edition of the Horizons Newsletter reviews the development of personalized medicine following completion of the Human Genome Project and its diverse application in medicine today. Experts from Quest Diagnostics discuss how personalized medicine is achieving advances in women’s health, cardiology, cancer care, and neurology.

Quest Diagnostics is committed to advancing the field of personalized medicine. We recognize that if healthcare providers use diagnostics to personalize intervention—and we collect the right data sets and analyze them appropriately—we can provide the correct insights to help guide patient care. In essence, this approach embodies our commitment to the concept of “Action from Insight.”

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What is Personalized Medicine? – An Overview

Personalized medicine, also referred to as “precision medicine,” is an emerging approach for disease treatment that uses genetic, genomic, and molecular information to guide diagnosis, prognosis, and therapy. Enabled by the scientific and technological advances resulting from completion of the Human Genome Project fifteen years ago, it is an approach that has been applied most notably for targeted cancer treatment, but also for diagnosis and treatment in other clinical areas, such as neurology and cardiology.

Personalized medicine tailors patient care to an individual’s characteristics. Its growing application has been enabled by a growing understanding of the link between someone’s molecular and genetic profile and their susceptibility to certain diseases. This knowledge has also led to rapid progress in pharmacogenomics, increasing our ability to predict the safety and efficacy of a drug for an individual patient.1

To accelerate broader adoption of personalized medicine, President Barack Obama launched the Precision Medicine Initiative (PMI) in January 2015, describing it as “a bold new research effort to revolutionize how we improve health and treat disease… and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.”2 The proposed initiative has two main components: a near-term focus on cancers and a longer-term aim to generate knowledge applicable to the whole range of health and disease. Underlining the potential of this initiative, Department of Health and Human Services Secretary Sylvia M. Burwell noted: “We have an incredible opportunity to advance research and make new medical breakthroughs through precision medicine, which tailors disease prevention and treatment to individuals based on genetics, environment and lifestyle.”3

The broader application of personalized medicine is being enabled by several factors: the establishment of extensive biologic databases resulting from the Human Genome Project and advances in next-generation sequencing; new approaches for identifying and defining disorders, such as proteomics, metabolomics, and genomics; and increased capabilities in bioinformatics, enabling the analysis of large sets of data and providing a basis for clinical annotation.4 Research applying these capabilities will further our understanding of disease mechanisms, improving risk assessment and therapy selection, while assessing the most promising approaches. Within the Precision Medicine Initiative, the Centers for Disease Control and Prevention (CDC) and other leading institutions will collaborate with private industry to share data, and it is proposed that one million people in the United States will participate in the initative.5 These participants will be a source of a wide range of data, including medical records; profiles of a patient’s genes, metabolites, and microorganisms in and on the body; environmental and lifestyle data; patient-generated information; and personal device and sensor data.

It is expected that these research initiatives will lead to numerous advances, including the discovery of new biomarkers to enhance risk assessment, improvements in pharmacogenomics to identify the right drug at the right dose for the right patient, identification of new targets for disease, and providing a basis for targeted therapies. These initiatives will also provide insights into the use of mobile health technologies to correlate activity, physiological measures, and environmental exposures with health outcomes.5

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Becoming Part of Mainstream Medicine - The Impact of Pharmacogenomics

Personalized medicine is not just a concept with a promising future; it’s already a reality and is having an impact on healthcare, from drug development to diagnostic testing and therapy selection. Pharmacogenomics is one field that exemplifies how scientific and technological advances are enabling an individualized approach to medicine. Our growing knowledge of how genes affect a person’s response to drugs can help predict whether a medication will be effective or may cause an adverse reaction, thereby guiding drug selection and dosing. There are 137 FDA-approved drugs have pharmacogenomic information in their labeling, and 155 pharmacogenomic biomarkers are included on an FDA-approved drug label.1

Breast Cancer Treatment Selection
One of the more established approaches for targeted therapy enabled by pharmacogenomics is the selection of breast cancer patients for treatment with trastuzumab. The ERBB2 (formerly HER-2/neu, human epidermal growth factor receptor 2) proto-oncogene encodes a 185-kd tyrosine kinase. ERBB2 gene amplification can lead to overproduction of the ERBB2 (formerly HER-2) protein and to tumor development through enhanced cell proliferation, survival, motility, and adhesion. ERBB2 amplification and overexpression are observed in approximately 20% of invasive breast cancers and are associated with an aggressive disease course and decreased disease-free and overall survival.2-3

ERBB2 status is most often used to determine patient eligibility for trastuzumab immunotherapy. Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ERBB2, inhibits proliferation of human tumor cells that overexpress ERBB2. Documentation of ERBB2 overexpression, either directly with immunohistochemistry (IHC) or indirectly with fluorescence in situ hybridization (FISH), is therefore recommended before prescribing trastuzumab therapy.4 Patients whose breast tumors amplify the ERBB2 gene and/or overexpress the ERBB2 protein are suitable candidates for this treatment.5-7

In the field of HIV therapy, genetic testing can identify those likely to suffer adverse effects from a prescribed drug. Abacavir, which is used in conjunction with other antiretrovirals in the treatment of HIV infection, causes severe adverse effects in 5% to 8% of those treated. Studies have shown that a particular gene variant in the major histocompatibility complex (MHC), called HLA-B*5701, is the key risk factor for abacavir hypersensitivity.8

Screening patients for HLA-B*5701 before treatment has dramatically reduced the number of adverse effects due to abacavir use. For individuals with the HLA-B*5701 allele, abacavir is avoided and alternative HIV treatments are given.8

Rheumatoid Arthritis
Azathioprine is an immunosuppressant used to help prevent rejection after organ transplant operations and also to treat a variety of inflammatory and autoimmune diseases, such as rheumatoid arthritis.

In some individuals azathioprine is not activated in the body properly, leading to a build-up of azathioprine in the bone marrow and a depletion of white blood cells. The conversion of azathioprine into its active form is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT). Variants of the gene encoding TPMT are the reason some individuals cannot convert azathioprine. Before prescribing azathioprine for rheumatoid arthritis, physicians can now test patients to find out which variant of the TPMT gene they possess and whether azathioprine will be an effective treatment for them.8

Pharmacogenomics is helping doctors to provide patients with the right dose of warfarin. Establishing the right dose of warfarin is a challenge for doctors as they try to achieve efficacy while minimizing the risk of bleeding. Because warfarin works by interfering with the enzyme vitamin K epoxide reductase, variations in the gene coding for this enzyme (VKORC1) can affect an individual’s sensitivity to warfarin. This information, in combination with other factors affecting a response to warfarin, can help guide physicians in determining the appropriate dose when first prescribing warfarin.8

Research and Development
Pharmacogenomics is also playing an increasingly important role in drug research and development, enabling the development of drugs tailored to a wide range of disorders. Personalized medicine is now a significant component of drug research and development. Approximately 60% of treatments in preclinical development, 50% of treatments in early clinical development, and 30% of treatments in late clinical development rely on biomarker data.9

The development and approval of some drugs will be linked to a diagnostic test to help identify patients for treatment. For example, on October 2, 2015, the FDA granted approval for Keytruda® (pembrolizumab) to treat patients with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and who have tumors that express a protein called PD-L1. Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx test, the first test designed to detect PD-L1 expression in non-small cell lung tumors.10 In the same month the FDA announced its approval of the PD-L1 IHC 28-8 pharmDx test to detect PD-L1 protein expression levels and help physicians determine which patients may benefit most from treatment with Opdivo (nivolumab). Nivolumab was approved at the same time to treat patients with advanced (metastatic) non-small cell lung cancer whose disease progressed during or after platinum-based chemotherapy.11

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Keytruda is a trademark of Merck Sharp & Dohme Corp.

Personalized Medicine in Action

Interviews with experts from Quest Diagnostics explain how advances in personalized medicine are enabling individualized approaches to care in women’s health, cancer care, cardiology, and neurology.

Douglas Rabin, MD
Medical Director, Women’s Health
Quest Diagnostics
Madison, NJ
Women’s Health

“Molecular medicine is enabling women to make more informed choices in relation to cervical cancer screening, prenatal screening, and breast health,” says Dr. Rabin.

Cervical Screening
Cervical cancer screening guidelines recommend that women aged 30 to 65 have cytology alone every three years, or have a co-test—cytology plus a molecular-based HPV test with mRNA or DNA—every five years.1-2

“When we look at the cumulative incidence of either ≥CIN3 (pre-cancer) or cancer, we know that a co-test offers greater protection from the development of cancer in an interval of three and five years than a Pap smear or an HPV test alone,” continues Dr. Rabin. “Equipped with that information, a woman may well opt for the co-test. Furthermore, data show that the cumulative incidence of cervical cancer at five years with a negative co-test is about 3.2 per 100,000/year, compared to 32 per 100,000/year with a negative HPV test—a significant difference.”3

Prenatal and Neonatal Testing
Molecular testing can also provide a woman with actionable information during pregnancy and after the birth of her child, explains Dr. Rabin.

“Noninvasive prenatal screening allows us to look at three trisomies (21, 18, 13), sex chromosome aneuploidies (X, XXY, XYY, XXX), and seven microdeletions (22q, 15q, 11q, 8q, 5p, 4p, 1p). The importance of knowing this information during a pregnancy is evolving, but there are already areas where this knowledge allows us to make an intervention. With Down’s syndrome and Turner's syndrome, or X0 syndrome, there are considerations to be made in relation to the child’s long-term development. With Turner’s syndrome, this involves the replacement of estrogen and early intervention for fertility treatment. In Down's syndrome there are data evolving which demonstrate that fluoxetine started in the third trimester, as well as other medications under evaluation, might extend the time period for brain development and enhance the child’s performance, giving that child a better chance at functioning and doing well in life.”4

Breast Health
A genetic test now familiar to many people is BRCA testing. Mutations in the BRCA1 and BRCA2 genes are associated with high risk for breast and ovarian cancer, explains Dr. Rabin. Approximately 1 in 300 to 1 in 800 individuals carry the mutation, while in the Jewish Ashkenazi population the prevalence is about 1 in 40.6-7 Identifying these patients will in the long-run save lives, while providing a cost benefit to the healthcare system, as well as a utility benefit. Hereditary breast and ovarian cancer syndrome is the most common high-risk breast cancer susceptibility syndrome. These mutations can cause female breast cancer, ovarian cancer, and male prostate and breast cancer. Patients with a confirmed BRCA mutation have a significantly increased risk of developing cancer during their lifetime—in women up to an 85% risk of breast cancer and up to a 40% risk of ovarian cancer, and in men up to a 20% risk of prostate cancer.6-7

Other genes that have been described as breast cancer susceptibility genes can also be tested. TP53PTENCDH1, STK11, and PALB2 together account for an additional 3% to 4.5% of hereditary breast cancers.9-10

“Once a patient has a BRCA mutation, the issue of personalized medicine—selecting the most appropriate action for that patient—is critical,” notes Dr. Rabin. “Genetic counseling, physician counseling, patient counseling, and support group discussion may all contribute to making a decision for appropriate management. This might include increased and more intensive screening and surveillance based on a recommendation from the National Comprehensive Cancer Network. NCCN12 guidelines include a clinical breast exam every 6 to 12 months starting at age 25, annual breast MRI at age 25 to 29, and annual breast MRI and mammogram at age 30 to 75. However, it could be a choice for prophylactic breast, ovary, and tubal surgical removal and chemoprevention. With regard to salpingo-oophorectomy (removal of the tube and ovary), a paper was recently published showing that oophorectomy after primary diagnosis of breast cancer significantly reduced breast cancer− specific mortality in women with BRCA1 mutations. Oophorectomy was particularly effective for survival benefit in women with estrogen receptor-negative breast cancer.”13

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Fred Racke, MD
Medical Director, Hematology/Oncology and Coagulation
Quest Diagnostics
San Juan Capistrano, CA
Cancer Care

In no field has the impact of personalized medicine been more apparent than in cancer treatment, where the combination of molecular testing with targeted therapeutics is increasing the effectiveness of treatment in different cancer types. Dr. Racke reviews the advances that are being made in identifying and targeting the genetic mutations in different cancers.

Individualized Treatment through Targeted Therapy
“Every solid tumor has many mutations, each of which influences the functions of the cancer cell—invasion, proliferation, metastasis, and genomic,” notes Dr. Racke. “Targeted therapies are designed to counter each of those functions by targeting a tumor based on how a certain gene is mutated, acting on the defective gene or kinase, and allowing us to treat patients in an individualized way.

Cancer traditionally has been categorized based upon its organ of origin, notes Dr. Racke. However, not only are certain cancers, such as lung cancer and breast cancer, not homogeneous, many alterations are common to different cancers. This has led to a new way of defining a tumor, so that instead of referring to it as a lung cancer or melanoma, for example, we would define it as a BRAF mutation tumor and target our treatment on that basis. This nomenclature is especially helpful to define tumors of unknown primary origin.

“The NCCN guidelines now include a list of seven genetic alterations in lung cancer, which can be targeted by a therapeutic agent,”1 notes Dr.Racke. “Some mutations may indicate a sensitivity to the therapy, while others may indicate a resistance.”

Tumor Panels
Tumor panels, using molecular testing—next-generation sequencing or FISH testing for lung cancer—enables many genes to be tested at the same time. Not only is this more efficient than testing genes separately; it allows us to see the interactions of the genes and so understand what combinations of therapies might be possible. Different drugs may target those gene mutations in different tumor types—the same mutations may occur in lung cancer or melanoma, but clinical trials have shown clinical utility for different drugs in those cancer types.

“OncoVantageTM is an example of a next-generation sequencing assay that is more sensitive than Sanger sequencing and combines many clinically actionable genes into one assay,” notes Dr. Racke.  “By sequencing 34 genes at the same time, it provides a large amount of data that has to be annotated and clinically interpreted.”

Hematologic Cancers
One area of cancer that has been particularly challenging is hematologic cancers. There remain limited targeted options to treat these, except in the case of chronic myelocytic leukemia (CML). “Hematologic malignancies are different from solid tumors in that there's frequently a specific mutation, a translocation or gene fusion, that's turning on a pathway in those early cells to create a clone,” says Dr.Racke. “CML is caused by a translocation between chromosomes 9 and 22, creating a fusion gene (BRC-ABL1) that encodes an activated oncogenic tyrosine kinase. Using fluorescence in situ hybridization (FISH) or a polymerase chain reaction (PCR)-based approach, we can detect that fused gene and so can diagnose CML in a patient based on their blood sample.

“Following treatment with a targeted therapy, imatinib, the level of disease falls significantly, but in some patients it goes back up. There are diagnostic tests that can detect this, so we can sequence the gene again to determine if other mutations have occurred, making it resistant to therapy. If so, there are now second-generation or third-generation kinase inhibitors that can treat these resistant clones so that the CML will once again effectively disappear from the blood stream,”2 concludes Dr. Racke. 

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Gerard Abate, MD
Executive Director, Medical Affairs, Clinical franchises
Medical Director, Cardiovascular Diagnostics
Quest Diagnostics
Madison, NJ

Two studies sponsored by Quest Diagnostics and published in the past year have demonstrated the potential of using genetic risk scores to identify patients at risk for events due to atrial fibrillation (AF) or coronary heart disease (CHD). Dr. Gerard Abate discusses the genetic risk scores and how they could help physicians reclassify patients not identified as high risk by traditional risk factors.

Atrial Fibrillation—Genetic Risk Score
“Silent AF accounts for 25% of all cases,” notes Dr. Abate, “but we do not have a good way for assessing these patients other than taking a history, reviewing their risk factors, such as hypertension, history of chronic heart failure, diabetes, factors associated with aging, and having them wear a Holter monitor. There is, however, a hereditary component to AF, which accounts for approximately 62% of cases,1 and this has provided a basis for genetic testing to assess risk more accurately than existing approaches.”

Study Demonstrates AF-GRS Correlates with Increased Risk
A recent study examined whether multiple single-nucleotide polymorphisms (SNPs), combined to establish an AF genetic risk score (AF-GRS), can improve the prediction of one's risk for AF.2 The study tested the hypothesis that the GRS enables us to identify risk for AF beyond the established risk factors already noted and to identify risk for stroke beyond the CHADS2 score, which is the way we assess patients who are at risk of having stroke and need to be anti-coagulated. A patient with a score of 2 or higher is eligible for risk-management with an anti-coagulant. The question is what happens to patients who have a CHADS2 score of 0 or 1 who are still at risk of having AF. This study explored the potential for a GRS system to help identify at-risk patients in these classes and restratify to a class 2 CHADS2 score or above. The AF-GRS includes 12 SNPs, which have been reported to be associated with AF at a genome-wide significance level.”

The study used a cohort from the Malmo Diet and Cancer study, a prospective, community-based study of middle-aged men (46 to 73 years) and women (45 to 73 years) enrolled between 1991 and 1996. Genetic data were obtained from 27,471 participants, who were followed for a median of 14.5 years. Of this group, 2,160 had a first AF event and 1,495 had a first stroke during follow-up.

“The AF-GRS was used to classify patient risk by quintile,” explains Dr. Abate. “Those in the top quintile were at increased risk for incident AF, with a hazard ratio (HR) of 2.00, and for ischemic stroke, with a HR of 1.23, when compared with those in the bottom quintile. Based on this analysis, those in the top quintile of the AF-GRS had around a 2-fold greater risk of AF than those at the bottom quintile. So, AF-GRS is associated with incident AF after adjustment for established risk factors and seems to be a useful tool to help identify patients at risk for AF.”

Further analysis was performed to assess the AF-GRS in relation to the most common risk factor for AF, hypertension. “It was found that those in the top quintile but without hypertension had the same risk for an AF event as those in the lowest quintile who had hypertension. So, there was a strong correlation between hypertension and the GRS score as risk factors for AF,” explains Dr. Abate.

“It was also found that AF-GRS is associated with cardioembolic stroke among those with AF,” he continues. “Participants with cardioembolic stroke who were in the top AF-GRS quintile had an 80% greater risk of cardioembolic stroke compared with those in the bottom quintile. This association was largely unchanged when adjusted for CHAD2 score. So, by adding the AF-GRS to a CHAD2 score you can reclassify a significant number of patients and better identify those eligible for management to prevent events and reduce cost.”

Genetic Risk Score and Coronary Heart Disease
Another study using a genetic risk score (GRS) was published in March 2015, in The Lancet.3 “To date, clinical, biochemical and imaging parameters have been used to stratify CHD risk, but genetic variants have also been associated with the risk of CHD,” notes Dr. Abate. “This study tested whether a composite of these variants could ascertain the risk of both incident and recurrent CHD events and identify those individuals who derive great clinical benefit from statins. The objectives were to investigate the association between a 27 SNP GRS and CHD and assess whether the clinical benefit of statin therapy differs by GRS.”

High GRS Shown to be Associated with CHD Risk
It was found that high GRS was associated with CHD, independent of established risk factors. For both the primary and secondary prevention population, risk increased consistently from the low- to high-risk category. Those in the high-risk category were at a 72% increased risk of CHD. 3

To determine the statin benefit for those in each category, the score was adjusted for consistent LDL-C and HDL levels. Patients were divided between those on treatment and off treatment. It was shown that risk reduction by statin therapy was greater for those at high genetic risk compared to those with lower genetic risk, with a relative risk reduction of 48%.3 Absolute risk reduction was also greater for those at high genetic risk. The number needed to treat to prevent one CHD event in 10 years was 66 for individuals with low GRS, 42 for those with intermediate GRS, and 25 for those with high GRS.3 The 10-year period is important because that is the period included in most guidelines.

“The CHD GRS identified individuals at increased risk for both primary and recurrent CHD after adjustment for established risk factors,” summarizes Dr. Abate. “Individuals at the highest genetic risk derived the largest relative and absolute clinical benefit from statin therapy and, in the context of people who do not meet current practice guidelines, even individuals at low risk of CHD demonstrated clinical benefit from the use of statins. It appears that the GRS helps to better identify patients for high-intensity statin therapy.”

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Joseph J. Higgins, MD, FAAN
Laboratory Director, Athena Diagnostics
Medical Director, Neurology, Quest Diagnostics
Marlborough, MA

“Personalized medicine in neurology involves the use of genetic information to assess the molecular basis of neurological disorder,” says Dr. Higgins. “We can now define where a lesion is not only on an anatomical level, but also at the molecular level. We may even be able to identify the protein aberration involved in the condition.”

“As a result of the Human Genome Project, about 3 billion base pairs of DNA have been sequenced, about 30 million of which are contained in the exome,” continues Dr. Higgins. “When neurologists localize where a lesion is for a neurological disease by clinical examination, they focus on neuroanatomy. Physicians will begin to consider the molecular etiology and focus on treatments related the basic cellular mechanisms related to the pathogenesis of neurological diseases. An analysis of the whole exome, or what we refer to as the Neurome, may provide diagnostic answers for most inherited neurological diseases.”

Gene Expression Patterns in the Brain
Gene expression patterns in the brain change during different developmental stages and changes with physical state of an individual (e.g., resting or basal, active, or stressed). Basal gene expression patterns are very similar among normal populations of people.  In the future, one can imagine that it may be possible to perform a neuroimaging scan that localizes the lesion, defines its gene expression pattern, and locates the aberrant proteins.  A system biology approach can then be employed to target treatments based on the molecular profile.

The Human Connectome Project is a new initiative that analyzes 1200 individuals to characterize heritability factors in different brain pathways, or tracts.1 Cutting-edge methods for noninvasive neuroimaging will yield invaluable information about brain connectivity, its relationship to behavior, and the contributions of genetic and environmental factors to individual differences in brain circuitry and behavior.2 “The results of this project will change our neuroanatomy paradigm and increase the focus on molecular-based imaging,” notes Dr. Higgins.

Dementia, stroke, migraine, and epilepsy are the four most common neurological diseases encountered in clinical practice. “When evaluating rare causes of common neurological diseases with a well-characterized molecular component,” notes Dr. Higgins. “curing that one patient, or managing their care more effectively, has a big economic impact.”

The use of care pathways aimed at quality and patient outcomes will provide healthcare providers with information to order the right test at the right time.  For example, testing for Alzheimer’s should be ordered when there is an early onset of dementia before age 65, or when there’s a family history. “A single MRI scan can now be analyzed in 3 dimensions and the volumes of different brain structures measured precisely enough to classify different dementia subtypes,” says Dr. Higgins. “If physicians have the tools to integrate genetic information such as whole exome or genome sequencing with the Human Connectome, healthcare providers will have sets of comprehensive information that will enable diagnostic insights and effective targeted therapies.”

“The worldwide prevalence of migraine is about 14.7%. It’s the third-most common neurological disease and the seventh most common disease across all diseases that cause disability.5 There are therapeutic implications in making the correct diagnosis. Effective management as a result of genetic testing can reduce the incidence of complications due to unnecessary procedures and contraindicated medications. Genetic testing may also remove the need for repeated neuroimaging,” says Dr. Higgins.

“There are two promising research developments in relation to migraine. One tool, related to a systems biology approach, can identify how a particular pain pathway is disturbed when a particular gene or gene mutation goes awry.  When the use of whole exome or genome sequencing is more widely adopted, one would expect the identification of more genes related to migraine or pain pathways because of strong familial factors in these disorders. As a result of such testing, the molecular mechanism of pain will become clearer.  Recently, researchers reported that blocking the calcitonin gene-related peptide with monoclonal antibodies prevents attacks of migraines.  These findings suggest that many genes and their products may be involved in a common pain pathway that involves calcium signaling.”

Epilepsy is fairly common. It is the fourth most common neurological disorder in the United States, with a prevalence of about 2.2 million people, and accounts for about $9.6 billion in medical costs annually.6, 7 Identifying a molecular lesion has economic and therapeutic benefits, says Dr. Higgins., since it allows physicians to curtail the use of MRI, lumbar puncture, and multiple EEGs. Current practice is to perform an EEG every 2 years in a child who is seizure-free and attempt to discontinue anti-epilepsy medications. However, knowing the genetic etiology would serve as evidence to reconsider this practice. “Positive genetic results may remove the need for repeated neuroimaging and can help curtail unnecessary epilepsy surgery.”

“At Quest Diagnostics, we’re performing health economic analyses with epileptologists to determine how genetic testing can impact the decision to perform epilepsy surgery. In general, neurosurgeons are reticent to operate on a child with a genetic disorder because the post-surgical prognosis is fairly poor. In the future, knowing the molecular mechanism will perhaps guide neurosurgical treatments in the context of information from the Human Connectome. We’re not there yet, but we’re making great advances in that direction.”

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Shrinking Costs, Potential Economic Benefits

The compelling case for broader application of personalized medicine is strengthened by the significant decline in diagnostic testing costs achieved in recent years, combined with the economic benefit provided by some new therapies. Whole-genome sequencing costs in 2001 were between $100 and $300 million.1 The cost today is $1,000. This remarkable reduction, which has accelerated dramatically since 2008, has been made possible by the transition from Sanger-based sequencing to “next-generation” DNA sequencing technologies. This technology, also referred to as massively parallel sequencing, enables millions of samples to be sequenced at the same time. As a result, large amounts of DNA can be sequenced at rapid speed, enabling a human genome to be sequenced in just one day.

An area of significant potential for reducing healthcare costs through personalized medicine is in risk assessment and early intervention. There are now more than 32,000 tests available for more than 3,900 genes linked to 5,800 conditions.2 Molecular markers can identify disease risk or presence before the appearance of clinical signs or symptoms, allowing for action to be taken before the disease progresses to a more advanced stage.

Patients with a confirmed BRCA mutation have a significantly increased risk of developing cancer during their lifetime—in women up to an 85% risk of breast cancer and up to a 40% risk of ovarian cancer, and in men up to a 20% risk of prostate cancer.3-4 Testing for BRCA1 and BRCA2 mutations can guide preventive measures, such as increased frequency of mammography, prophylactic surgery, and chemoprevention.

Studies have also shown the significant clinical and economic impact of using genetic information to guide therapy. One recent study showed that genetic testing for women with oestrogen receptor positive (ER+), pNO or pN1mi breast cancer resulted in changes in chemotherapy decisions in 26.8% of patients and an overall 9.9% reduction in patients undergoing chemotherapy.5 Each year 17,000 strokes could be prevented if a genetic test was used to properly dose the blood thinner warfarin.6 $604,000,000 in annual healthcare cost savings would be realized if patients with metastatic colorectal cancer receive a genetic test for the KRAS gene prior to treatment.7

Being able to prescribe the right drug the first time also has a significant financial impact. A significant proportion of patients do not respond to initial drug therapy: 38% of depression patients, 50% of arthritis patients, 40% of asthma patients, and 43% of diabetic patients do not benefit from the first drug they are prescribed.1 Studies have linked these differences in response to differences in the genes that code for drug-metabolizing enzymes, drug transporters, or drug targets.1

The use of molecular testing helps physicians identify an effective treatment from the outset of therapy, minimizing the possibility of prescribing ineffective medication, or one which will cause side effects. This is well illustrated in relation to the prescribing of clopidogrel. Genetic testing can be used to guide the use of clopidogrel to prevent blood clots, particularly in stent patients. Variations in the gene that encodes the hepatic enzyme CYP2C19 can substantially affect the metabolism of clopidogrel to its active metabolite8,9 Loss-of-function (LOF) CYP2C19 variant alleles result in reduced clopidogrel metabolism,10 whereas the CYP2C19*17 allele results in enhanced metabolism.11

The CYP2C19 genotype can be used to categorize individuals as CYP2C19 ultrarapid, extensive, intermediate, or poor metabolizers.9,12 For clopidogrel-treated patients undergoing percutaneous coronary intervention (PCI), intermediate- and poor-metabolizer genotypes carry an increased risk for cardiovascular events,9,13 including stent thrombosis.14 In contrast, several studies have found ultrarapid metabolizers treated with clopidogrel to be at decreased risk of major adverse cardiovascular events15 but increased risk of bleeding (especially for *17/*17 homozygotes).11

Although genetic testing for CYP2C19 variants has not been formally recommended, in 2010 the FDA added a boxed warning to the clopidogrel label concerning the diminished effectiveness in some patients with CYP2C19 LOF variants, particularly poor metabolizers. The 2013 update to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommends considering CYP2C19 genotype testing to guide antiplatelet therapy in patients with ACS undergoing PCI.12 The American College of Cardiology Foundation/American Heart Association guidelines suggest considering CYP2C19 genotype testing for patients who experience recurrent ACS events despite ongoing therapy with clopidogrel.816 Prospective clinical trial evidence that CYP2C19 genotyping improves clinical outcomes is beginning to emerge. For example, a prospective randomized trial with 600 patients found that CYP2C19 genotype-guided antiplatelet therapy after PCI significantly decreased the incidence of major adverse cardiovascular events.17

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  1. American Cancer Society. Cancer Facts & Figures 2013. http://www.cancer.org/research/cancerfactsstatistics/ cancerfactsfigures2013/index. Accessed 2 November, 2015.
  2. Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94:317-323.