One and Only

Personalized medicine is all about the person—or the individual patient. Despite the common sense concept, this has not been medicine’s conventional approach. Traditionally, evidence-based medicine has used data collected in very large standardized trials to measure averages that often become the basis for standards of care and regulatory guidelines.

"Everything pushes the practice of medicine in that way, and it’s really the exact opposite of personalized medicine. We don’t allow individualized treatment today from a regulatory, reimbursement, or even standards practice," says Albert Lucas V, vice president of sales and marketing at AssureRx in Mason, Ohio. Physicians, therefore, lack the support to deviate from care standards and tailor a treatment to the patient— the basis of personalized medicine.

Personalized medicine means many things to many people. For the laboratory, it ranges from tests that determine a patient’s predisposition to certain diseases to prognostics and differentiation of a diagnosis to guide treatment decisions. Many organizations, particularly diagnostic and laboratory institutions, focus on the latter application.

Matching diagnostic tests to the person and the disease is a little different from broad-based genetic testing for multiple conditions, according to Jon R. Cohen, MD, senior vice president and chief medical officer for Quest Diagnostics, headquartered in Madison, NJ. "You’re asking, ‘What’s potentially wrong with this person? What drug are they taking? Or what disease do they have, and how do we test them more specifically relative to that entity?’ " Cohen says.

The answers help guide physicians in making appropriate treatment decisions, whether it be a decision to pursue treatment or not or the identification of the most effective drug. By eliminating trial-and-error methodology, the right treatment right away may shorten length of care, reduce costs, and, most importantly, produce a better patient outcome.

Subsequently, personalized medicine is likely to wield greater influence as these capabilities are developed. Currently, however, the medical community is still in the early adoptive phase. "I would say we’re really in the first 5 percent, at best, of what the ultimate benefit and impact of personalized medicine will be," says Jeremy Bridge-Cook, PhD, senior vice president of the Assay Group at Luminex Corp in Austin, Tex.

Further development of these technologies will impact not only patient outcomes, but also the economics, efficiencies, and esteem of the laboratory. "Personalized medicine, for the clinical laboratory, should enable them to provide better information to the clinician. And, from that standpoint, [it] presents an opportunity to continue to innovate the way in which they serve their stakeholders," Bridge-Cook says.

Currently, laboratories not only conduct these tests but, often, must also provide assistance with understanding the results. "These are complex tests that require tremendous experience to help with interpretation and nuanced technologies performed by highly trained technical experts," says Steve Keiles, MS, CGC, vice president, director of genetic services, and a certified genetic counselor with Ambry Genetics in Aliso Viejo, Calif.

With time and experience, these challenges are likely to abate. In the meantime, however, innovative and entrepreneurial labs are leading the forefront in the development of personalized medicine-based prognostics, diagnostics, and differentiators.

Ambry Focuses on Intellectual Disability

Ambry Genetics recently launched a series of tests to narrow a diagnosis of intellectual disability to a specific cause. The Ambry X-Linked Mental Retardation (XLMR) SuperPanel includes a suite of genetic tests, from a genome-wide scan through focused study of the X chromosome to base-pair analysis of approximately 90 specific target genes.

"Genetic testing provides a path around the diagnostic obstacles of incomplete family history, normal variation in phenotype, and changes in phenotype over time. Repeated or nonessential lab tests and evaluations can be eliminated and costs controlled. And with a positive result, the opportunity for medical intervention is maximized," Keiles says.

Components include the XLMR Array Plus, the XLMR Next Gen Sequencing Panel, and individual sequencing tests (such as Fragile X), and they employ a variety of technologies, including next-generation sequencing, microarrays, Sanger sequencing, and traditional Fragile X testing.

"This test applies the best new technologies to the biggest unresolved diagnosis in genetics, which is intellectual disability. [It] takes us farther toward a complete genetic characterization of the medical problem—and defining a solution to genetic problems starts with defining the mutations," says Lori Ross, MS, product manager and certified genetic counselor with Ambry.

According to the company, intellectual disability affects about 2% to 3% of the general population, with XLMR accounting for 10% to 15% of cases. More than 200 monogenic XLMR conditions are known; nearly half the genes have been characterized.

Before the release of Ambry’s XLMR SuperPanel, no test was able to address all the defined causes of the disease. "Next-generation sequencing technology has made it possible to do for under $4,000 what would cost around $50,000 with traditional sequencing methods," Ross says.

Turnaround for the XLMR Array Plus component is 14 to 21 days; results of the XLMR Next Gen Sequencing Panel are provided within 12 to 16 weeks. "We expect to reduce the time for the Next Gen Sequencing Panel significantly over the next few months," Ross says.

AssureRx Moves Into the Mental Health Market

AssureRx has also released a test for mental health patients, but rather than a diagnostic, GeneSight Rx aims to help psychiatrists select the appropriate medication for a patient diagnosed with a disorder, such as depression, anxiety, or schizophrenia. The pharmacogenetic test is a five-gene, 44-SNP evaluation that is compared against 26 FDA-approved drugs, which account for 90% to 95% of psychiatric medications prescribed today.

"We’ve identified the SNPs that are well described in the literature and can affect the metabolism of psychiatric medications as well as be predictive of how certain of these medications will behave at the site of action," Lucas says. The test produces the patient’s phenotypic profile, which could be one of 432, and applies it to each drug, creating 12,000 medication profiles for each patient.

These are then sorted into three color-coded categories based on the drug’s effectiveness and risk. Psychiatrists can, therefore, prescribe appropriate medications right away and be more likely to avoid potential complications resulting from side effects, adverse reactions, and/or ineffective treatment.

"The prevalence of mental health disorders is about one in four during a person’s lifetime, and we think that probably about 30 to 40 percent of patients who go on medications have a failure," says James S. Burns, AssureRx’s president and CEO, noting one study found that patients diagnosed with major depressive disorder averaged 10 prescriptions before receiving the right one.

Both the patient and the health care system benefit with the elimination of the trial-and-error approach. "Getting patients on the right medications early in their treatment will provide substantial advances in patient outcome and actually reduce the cost of treatment: If they’re on the right medications early, they won’t make multiple visits to the emergency department nor will they decompensate to the extent they are admitted or readmitted to a hospital," Burns says.

The limitation, according to Burns, is an incomplete knowledge about all the potential SNPs that relate to patient variability from a metabolic or pharmacodynamic perspective. The company expects to expand the test to include more genes; incorporate nongenetic factors, such as environment and diet; and address additional disorders, like ADHD.

"Although we’re not competition free, we are unaware of any other company today that is exclusively focused on the neuropsych space. There is a lot of interest in the field of cardiovascular disease, oncology, and infectious disease," Lucas says.

Biocare Expands Oncology Offerings

Oncology is a popular area for personalized medicine for a number of reasons, not the least of which is the ability to tailor treatment. Biocare Medical, Concord, Calif, offers multiplex IHC tests for bladder, breast, prostate, and now lung cancers that can be used in personalized medicine regimens. Lung Adeno 2 and Lung Squamous 2 are designed to differentiate between the two types of lung cancer so that the physician can select the proper treatment—or, perhaps more importantly, avoid the wrong treatment.

"Patients with squamous cell carcinoma must not be treated with VEGF inhibitors, such as Avastin, because there is a 30 percent mortality rate resulting from fatal hemoptysis or hemorrhaging," says Rhonda Henshall-Powell, PhD, senior product manager for Biocare.

The use of the antibodies themselves is not new. Lung Adeno 2 screens TTF-1 and Napsin A; Lung Squamous 2 consists of p63 and CK5. "People tend to screen certain disease types by looking at four or five different antibodies individually as a panel, but not performing these tests together. So they might do TTF-1, then they’ll do p63, then they’ll do CK5, and it’s more like a series of elimination. We have been able to combine them into one IHC test," Henshall-Powell says.

This saves time and tissue, and helps to improve accuracy. "It’s the combination of having all these antibodies in one field of view. It’s not only what shows up, but what doesn’t show up that really tells you the story," Henshall-Powell says.

The antibodies are generally already known and trusted, though newer antibodies that provide more specificity are also incorporated. For instance, TTF-1 has been the primary bio-marker to diagnose lung adenocarcinoma. "But we have some data that shows it’s not a hard and fast absolute," Henshall-Powell says.

Studies with Napsin A have indicated that it is much more sensitive and specific than TTF-1. "It’s practically negative in all squamous cell carcinomas. So if you see Napsin A there, then you can be quite certain that it’s not squamous cell carcinoma," Henshall-Powell says. Combined with results from the Lung Squamous 2 test, the physician can have a definitive answer and confidently move ahead with treatment.

Luminex Points Out Poor Metabolizers

Austin, Tex-based Luminex Corp is developing a test also designed to help physicians confidently prescribe medications. The product, which is currently being prepared for submission to the FDA, looks at the gene CYP2D6. "The gene encodes an enzyme involved in metabolizing about 25 percent of the small molecule drugs on the market," Bridge-Cook says.

Poor metabolizers have two mutated copies of the gene that impact medication efficacy and elimination. They may lack the enzyme needed to activate the drug, reducing or even eliminating any effectiveness, or poor metabolizers may lack the enzyme needed to remove the drug from their bodies, resulting in toxic-level buildup and a subsequent adverse reaction.

The test, once cleared by the FDA, is expected to have broad clinical utility. Turnaround is roughly 6 hours, with results presented in a format that indicates whether there are mutations present on the CYP2D6 gene. However, some physicians may still require help with interpretation, an obstacle shared by many genetic tests.

"[Physician education] is a significant challenge for the clinical laboratory. If they are interested in adopting personalized medicine testing, how do they serve their physician population with those challenges regarding what to do with the data and how to assist in its interpretation?" Bridge-Cook says.

Quest Broadens its Personalized Menu

Quest has answered this question with an aggressive education program for its physician clients using any of its number of personalized medicine tests. Two of its newer launches in this area include the OVA1 test and AccuType CP, and focus on early treatment decisions.

OVA1 is intended for the presurgical evaluation of a woman’s ovarian mass for cancer so that she may be directed to the appropriate surgeon. It combines the results of five well-established protein biomarkers to produce a single numerical result to help classify the likelihood that a woman’s mass is cancerous or benign—within a 5-day turnaround. If cancerous, the patient can then be assigned to a gynecological oncologist rather than to a gynecologist.

"Unfortunately, two-thirds of women in the country currently get operated on by gynecologists, who are not specifically trained to do gynecologic cancer surgery," Cohen says. A Quest analysis found roughly 300,000 pelvic operations are performed each year, and a significant number of patients are opened up, only to be closed and referred to a specialist.

Studies have shown that removal of an ovarian cancer mass by a gynecologic oncologist is associated with more favorable outcomes. OVA1 improves the identification of these patients before surgery. In a prospective clinical study, OVA1, when combined with presurgical clinical and radiological assessments and used by non-gynecologic oncologists, detected 92% of malignant ovarian masses compared to 72% without OVA1.

AccuType CP has similar value. The test detects CYP2C19 gene variants that can impact a patient’s response to clopidrogal bisulfate, known more familiarly by its brand name of Plavix. Up to one in four patients possess relevant genetic variants that result in a suboptimal response to the drug, whether its decreased clopidrogal pro-drug metabolism, lower levels of the active metabolite, and/or reduced anti-platelet response to the drug. Adverse reactions can include ischemic events, such as heart attack and stroke.

Even so, it is the second-most-prescribed drug in the world, according to Cohen, who estimates there are 90 million people on the clopidrogal. "Roughly 40 to 50 percent of people can have an intermediate response to Plavix based on their genetic makeup—that’s a huge number of patients," Cohen says. The numbers are even higher in Africans (40%)¹ and East Asians (55%).²

Identifying these patients ahead of time will, therefore, result in better outcomes, which is, again, the aim of personalized medicine, because it’s all about the patient.

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Renee Diiulio is a contributing writer for CLP.

References

1. MyrDandara C, Masimirembwa CM, Magimba A, et al. Genetic polymorphism of CYP2D6 and CYP2C19 in east- and southern African populations including psychiatric patients. Eur J Clin Pharmacol. 2001;57:11-17.
2. Myrand SP, Sekiguchi K, Man MZ, et al. Pharmacokinetics/genotype associations for major cytochrome P450 enzymes in native and first- and third-generation Japanese populations: comparison with Korean, Chinese, and Caucasian populations. Clin Pharmacol Ther. 2008;84:347-361.