June 15, 2015 (Vol. 35, No. 12)

Evaluating the Genetic Variations Influencing Patient Response to Drugs

One of the most practical applications of precision medicine lies within the field of pharmacogenomics, a portmanteau of pharmacology and genomics. It is a discipline designed for tailoring drug treatments to an individual’s genetic make-up.

While scientists have had clinically relevant pharmacogenetic examples of drugs functioning only for patients with specific genetic backgrounds for several decades, the field has burgeoned into the encompassing specialty of pharmacogenomics, shifting away from observing a small number of candidate genes to searching for genome wide biomarkers.

Interestingly, one of the first examples of pharmacogenetics occurred around 510 BCE, when the Greek philosopher and mathematician Pythagoras observed that the ingestion of fava beans were fatal to some individuals and not to others. What Pythagoras couldn’t do at the time was formulate a scientific hypothesis to provide him with an answer as to what had caused such a disparity in symptoms. Now we know about the disease clinicians often refer to as favism, which is a genetic mutation in the glucose-6-phosphate dehydrogenase gene that predisposes those with the mutation to potentially fatal hemolytic anemia in the presence of certain foods, drugs, or chemicals.

It would however, take well over a millennium before science would understand that common DNA variations within the human genome were responsible for Pythagoras’ subjects to have such different experiences when faced with the fava bean challenge. The most common of these variations comes from single nucleotide polymorphisms (SNPs), currently estimated to number about 11 million within the human population. A patient’s response to a drug treatment is often linked to the SNP profile contained within his or her genome.

Currently, it’s not feasible to generate and test a new compound based on every individual’s polymorphism profile, but the power of pharmacogenomics lies in its ability to determine which currently available drugs are suitable for a particular patient. This tailoring of drug therapies based on genetically determined variation in effectiveness and side effects should provide not only more accurate dosing regimens, but also safer and more powerful medicines for the future.  

So, What’s the Hold Up?

It has been generally agreed upon for some time now that the clinical application of pharmacogenomic methods would be of significant value for improving overall patient care. “No two patients are the same,” explains Jennifer Strickland, PharmD, general manager of Pharmacogenetic Testing at Millennium Health. “Even with the same diagnosis and prescription, they may exhibit significantly different clinical responses. Areas of medicine where patients have highly variable responses to treatments for reasons that previously were unclear are particularly ripe for pharmacogenomics.”

While initial expenditures seem to have been fruitful, especially when they were applied to cancer therapeutics, global adoption across all clinical disciplines has been slow. In an attempt to gain a greater appreciation of nuances surrounding the clinical implications of pharmacogenomics for precision medicine, a number of key thought leaders in the field were interviewed to get their take on the current state of affairs.

When asked what obstacles are still impeding pharmacogenomics from becoming a regular part of clinical medicine, the researchers had some different perspectives, but a common theme throughout the responses is reimbursement:

“In most cases we lack rigorous large prospective randomized clinical trials that provide a convincing evidence base for clinical utility,” explained Alan Shuldiner, M.D., vp and co-head of Regeneron’s genetics center. “Without such an evidence base, reimbursement for pharmacogenetic testing is difficult. Knowledge of pharmacogenetics—when to order a test, how to interpret a test, how to use pharmacogenetic test results to guide therapy—is lacking by most healthcare providers.”

George Patrinos, Ph.D., assistant professor of pharmacogenomics and pharmaceutical biotechnology at the University of Patras, Greece, was in agreement stating that “there is reluctance from insurance companies and reimbursement bodies to cover the costs of pharmacogenomic testing since there is not enough evidence that these tests are indeed cost-effective.”

Dr. Patrinos added that “there is often lack of pharmacogenomics education from the healthcare professionals’ point of view, while the general public and the patients are often not aware of the benefits of pharmacogenomic testing and individualization of treatment modalities.”

Dr. Strickland agreed that there has been a lack of education stating that “clinicians and patients need more information about pharmacogenetics and how guided therapies can help achieve better outcomes when compared to a trial-and-error approach to prescribing.”

Adding a different perspective, Sebastian Nijman, Ph.D., associate member of the Ludwig Institute for Cancer Research, University of Oxford and director of functional genomics at the Target Discovery Institute, stated that “in many instances high-quality biomarkers are simply not available. Therefore, I think that a concerted effort bridging basic biology and clinical research is needed to identify high quality predictive biomarkers. The validation of predictive biomarkers should be an integral part of clinical trials.”

Dr. Patrinos certainly agreed with this sentiment, noting that “there is lack of replication studies for new pharmacogenomic biomarkers that are being discovered.” 

Economics as a Science Driver

The validation of pharmacogenetic biomarkers for their accuracy at pinpointing clinically significant genetic variants is only the first step toward their enactment in the clinical setting. To the outsider, a less obvious gauge of biomarker effectiveness is its economic impact; however it remains no less of a significant benchmark.

Given the importance of accurate biomarkers for effective pharmacogenomic analysis, the experts also were asked how important the cost-effectiveness of pharmacogenomic biomarkers is with regards to their implementation in clinical practice?

“The primary driver is effectiveness,” said Howard McLeod, PharmD., medical director of The DeBartolo Family Personalized Medicine Institute at the Moffitt Cancer Center. “If a biomarker clarifies the context for efficacy, then the cost part comes into importance.  There has to be a balance between the effect size identified by the biomarker and the cost of generating that data and the cost of the intervention.”

Dr. Nijman took the discussion an additional step by explaining the point that “new targeted drugs and immunotherapies are increasingly expensive, especially in oncology. Yet only a minority of patients given a treatment will typically respond favorably. Thus the availability of more biomarkers that can predict response would be of great clinical and economic benefit. As a single round of therapy can easily exceed $50,000, spending a fraction of this to avoid pointless therapy makes perfect sense.”

Dr. Shuldiner is also a fervent believer that a biomarker’s economic impact plays a critical role in its development, stating that “cost-effectiveness will be a potent driving force for implementation of pharmacogenomics. Rigorous pharmacoeconomic analyses must be a part of all pharmacogenetic studies. These studies must not only demonstrate clinical utility, but also cost-savings to our healthcare system.”

However, providing a counter position, Deepak Voora, M.D., assistant professor of medicine at the Duke Center for Genomic and Computational Biology, stated “I think the cost-effectiveness will be less of an issue as we go forward, given the plummeting costs of generating genetic data and that systems are in place to deliver that data to physicians.”

Whatever the stance on economic issues is for all those associated with the pharmacogenomics field, what seems to be clear is that in the short term at least cost-effectiveness will be given significant consideration during any pharmacogenomic validation process. 

A classic example of applying pharmacogenomics in a clinical setting. A blood sample is taken from patients with the same condition and either added to a microarray or used with next-generation sequencing to look for genetic variants that affect drug response used to treat the condition. The analysis will yield results that allow physicians to determine if their patient will have a positive response to the drug treatment. [National Human Genome Research Institute]

Upward Trending Future

Implementing all of the aspects of precision medicine is an arduous task that at times can seem to move at a rate more easily gauged in geologic terms than in real timeframes. Juggling bureaucracy with innovation can often lead down the path of pessimism. However, our pharmacogenomics panel was asked how they envisioned the field a few years from now, all were fairly optimistic that new technology and discoveries will continue to propel ideas and decisions with upward momentum.

“It is expected that there will be new discoveries and novel pharmacogenomic biomarkers in relation to drug efficacy and toxicity,” said Dr. Patrinos. “The adoption of whole genome sequencing for pharmacogenomics and the development of new electronic translation tools of pharmacogenomic information will pave the path of pharmacogenomics into genomic medicine in the coming few years.”

Dr. Voora believes various disciplines will merge to allow for “expansion beyond the ‘inherited genome’ to the ‘expressed genome’ including transcriptomics, metabolomics, proteomics, and microbiome pharmacogenomics.”

Dr. Nijman explained that in the future “[there will be a] better understanding of how tumor heterogeneity at the single cell level plays into patient response and resistance to therapy.” He concluded that “there will be a lot of studies coming out that will reveal how tumors evolve in response to therapy. These will, we hope, provide biomarkers and testable hypotheses for combination therapies.”

Pharmacogenomics still has some barriers to climb before its full potential will be realized in a daily clinical setting, but our panel has pointed out key areas that, if addressed, should provide a smoother transition. Moreover, if future endeavors are viewed by others in the pharmacogenomics field with the same optimism and enthusiasm expressed by those  interviewed then expect to see a lot more on the topic in upcoming discussions about precision medicine.

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