Despite the many different clinical applications in the field of pharmacogenetics (PGx), the clinical uptake of pharmacogenetic testing has, for the most part, not yet met expectations. While not all potential PGx applications have robustly proven clinical utility, there are several tests which have strong evidence to support clinical adoption. For example, warfarin-related genotyping has been shown to lead to 28% fewer hospitalizations for thromboembolism or bleeding (1); numerous studies on clopidogrel have demonstrated a relationship between CYP2C19 poor (and intermediate) metabolizers and stent thrombosis; abacavir hypersensitivity in the Caucasian population in the presence of the HLA-B*5701 allele has a odds ratio of 960 (2); and the UGT1A1 *28 allele has been robustly associated with increased hematological toxicities and hospitalization rates in patients receiving irinotecan. Additionally, there are FDA label updates and black box warnings supporting pharmacogenetic testing for many drugs (e.g. warfarin, clopidogrel, irinotecan, abacavir, and carbamazepine). So, why aren’t these tests better utilized?
One of the common arguments heard from the clinical practice groups is that genetic testing is too expensive to perform on everyone. True, genetic testing is generally not as affordable as other lab tests. But, for many PGx tests, the recommendations are not to provide genetic testing as standard of care in all comers receiving a particular drug. Rather, the evidence supports genetic testing for specific patient population groups. For example, warfarin PGx testing is of recommended clinical utility (by some groups) for orthopedic surgery patients as well as patients in community settings that may not have the same resources as large academic centers for managing and following patients on anti-coagulation therapy. It should also be pointed out that hospitalization for an event like an intracranial bleed due to excess warfarin therapy is vastly more expensive than a $400 - $500 genetic test. Another example is with clopidogrel response genotyping and limiting testing to individuals undergoing coronary stenting, a group in whom numerous studies have demonstrated stent thrombosis in CYP2C19 *2 carriers.
Genetic testing technologies have been a limiting factor for some tests as well, primarily because test results have generally not been available prior to administering the first dose of the drug. However, technological advances have been occurring that will likely pave the way for more point-of-care PGx testing, allowing for results to be incorporated into dosing and/or drug selection decisions prior to first dose. It is anticipated that these POC technologies will provide added benefit of bringing down the cost of testing. However, a current limitation of these technologies is that they generally only allow for one sample to be analyzed per run, which may not be conducive to higher volume testing scenarios.
Another common concern from the clinical practice groups is that they would like to see outcome data from large, randomized, prospective trials. This was exemplified in a recent JAMA editorial (3) (which was based on an arguably flawed meta-analysis (4)), where the editorial author states, “Physicians should use CYP2C19 or platelet-reactivity testing rarely, if ever.” The author instead advocates for a large randomized controlled study. However, in a Heartwire blog (5) in regards to the JAMA article and accompanying editorial, Dr. Topol and colleagues state: “While such trials would always be useful, it unfortunately is a fantasy: it would require tens of thousands of patients, there is no entity that would support such a trial….Moreover, the era of individualized medicine needs to transcend megatrials of populations, which are not only unsustainable but also crowd out the benefits that can be exceptionally important and validated for the individual patient.” They further advocate the utility of CYP2C19 genetic testing in patients undergoing coronary stenting.
Another concern raised by clinical practice groups is the lack of knowledge on how to apply the genetic test results. For example, in the case of clopidogrel, it is unclear whether a genetically predicted poor/intermediate responder to clopidogrel should be given an increased dose of clopidogrel or switched to an alternative anti-platelet therapy. There are further concerns about increased bleeding risks with the alternative therapies. For other applications, however, there are guidelines for how the genetic results should be used to alter clinical management. For example, for warfarin sensitivity genotyping, the drug package insert has been updated with a genotype-guided dosing table and there are online tools and algorithms for helping to make genotype-based dosing decisions.
Many of the concerns raised by these clinical practice groups are valid at least to a certain extent. While it is true that large multi-center trials may answer some of the concerns, these trials are difficult to design and implement, extremely expensive, and will likely never have enough power to take into account all of the variables responsible for altered response (pharmacogenetic or otherwise) to drugs. Thus, to use a common saying, it is doubtful that the evidence to support clinical uptake of PGx testing will ever be able to please all of the people all of the time. Right now, it appears to appeal to some of the people some of the time. Hopefully, with advances in POC technologies and the ability to meaningfully integrate multiple genetic and clinical factors, PGx will find at least a middle road and please most of the people most of the time.
1. Epstein RS, Moyer TP, Aubert RE, et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). Journal of the American College of Cardiology 2010;55:2804-12.
2. Martin AM, Nolan D, Gaudieri S, et al. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proceedings of the National Academy of Sciences of the United States of America 2004;101:4180-5.
3. Nissen SE. Pharmacogenomics and clopidogrel: irrational exuberance? JAMA 2011;306:2727-8.
4. Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA 2011;306:2704-14.
5. Topol EJ, Teirstein PS, Price M, et al. 2011.