Personalized medicine: Right drug, right patient, right time

In his 2015 State of the Union address, President Barak Obama launched a Precision Medicine Initiative stating: “Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type-that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?”

Whereas there are a number of barriers to personalized medicine in the general pediatric practice such as cost of testing and lack of knowledge and expertise in genetics, personalized medicine is increasingly making its way into pediatric practices. The pediatrician is likely to experience parents who have undergone some sort of prenatal genetic screening, purchased a direct-to-consumer test from companies such as 23andMe, and want help in evaluating the results. Increasingly, the pediatrician may be asked to evaluate and offer patients genetic tests that may aid in both diagnosis and treatment of a number of pediatric conditions.

What is personalized medicine?

Precision or personalized medicine can be thought of simply as the right drug for the right patient at the right time. At its core, personalized medicine seeks to use a patient’s genetic information to guide decisions for the prevention, diagnosis, and treatment of certain conditions.

What are the benefits?

Today the pediatrician begins treatment mostly with therapies with demonstrated benefit to the general population.

Personalized medicine may benefit patients in a number of different ways:^1,2

·      Anticipate which patients are likely to get certain diseases based on their genetic profile.

·      Deliver therapy based on genetic testing instead of a trial-and-error approach.

·      Reduce exposure to less therapeutic medications and treatments.

·      Avoid toxicity of drugs less likely to produce a therapeutic effect.

·      Improve patient satisfaction, tolerance, and compliance by quickly identifying a treatment more likely to be effective.

Recommended: Screen routinely for central neurologic disorders

However, it is not always clear that genetic testing will be beneficial. In one evaluation of a direct-to-consumer testing program, provision of genetic results failed to change anxiety levels, dietary habits, exercise patterns, or increased use of screening tests.³ Additionally, skeptics cite the high costs of testing, gene environment interactions where behavioral interventions are highly effective, and a lack of other treatment options based on genetics as reasons not to pursue genetic testing.^4,5

NEXT: Diseases that benefit from genetic testing

Diseases benefitting from genetic testing

ASTHMA

Although not widely used in clinical practice yet, research has identified genes that eventually could significantly impact how pediatricians treat asthma. In one study, a gene present in 14% of asthmatics demonstrated a poor response to salmeterol and an improved response to montelukast. The study was small; however, the impact for the 62 treated patients was significant. Importantly, the cost of the test was less than $20, making it incredibly cost effective.⁶

More: Adverse childhood experiences are linked to ADHD

Likewise, another study identified a genomic marker indicating a poor response to inhaled steroids.⁷ Both studies demonstrate the promise of personalized medicine: to identify therapies to which patients are more likely to respond, to avoid treatments from which the patient will be unlikely to benefit, and to avoid potential adverse effects.

CROHN DISEASE

Azathioprine is one of the most common treatments for Crohn disease and inflammatory bowel disease. However, low or absent levels of the thiopurine S-methyltransferase (TMPT) enzyme can lead to toxicity and dose-dependent adverse effects. As a result, standard of care is now to check the levels of TMPT before beginning treatment. Azathioprine may still be used but will often have the dose reduced to attempt to avoid toxicity.¹

ADHD

In attention-deficit/hyperactivity disorder (ADHD), the presence of several different genes have shown a positive effect related to treatment symptomology. However, no specific gene or combination of genes has been associated with a clinically relevant treatment impact.^8,9 A slightly different take has demonstrated a neurobiologic subgroup of ADHD patients with electroencephalograph (EEG) characteristics that may identify a specific treatment. Electroencephalograph studies of ADHD with a subgroup termed “impaired vigilance” demonstrate excess frontal theta or alpha activity that will respond to stimulant medication. These patients, if depressed, may not respond to traditional antidepressant therapy and may need larger doses of stimulant medication instead. Another subgroup of patients with a slow individual alpha peak frequency on EEG demonstrates resistance to treatment for both ADHD and depression.¹⁰

Commercially available tests such as GeneSight collect a patient’s DNA through a buccal swab. The provider is then given a report on how individual and combinations of a patient’s genetic makeup may impact treatment with certain US Food and Drug Administration (FDA)-approved medications for ADHD as well as other behavioral health conditions. Assurex Health (Mason, Ohio), the maker of GeneSight, has demonstrated significant improvement in depressive scores, increased likelihood of a treatment response, and decreased costs when this testing is used in adult patients with depression.^11-13 The company includes in its panel common drugs the pediatrician will use in treating ADHD.

NEXT: Pain management and pediatric cancer

PAIN MANAGEMENT

Atypical cytochrome P450 2D6 (CYP2D6) pharmacogenetics is both indicative of a poor pain response and associated with several postoperative deaths following the use of codeine for pain management. Poor metabolizers of CYP2D6 may never achieve pain control and rapid metabolizers may experience severe toxic effects. Although some hospitals have simply removed codeine from their formularies, St. Jude Children’s Research Hospital, Memphis, Tennessee, and others have developed pharmacogenetic testing programs for its safe use through widespread testing.^14-16

PEDIATRIC CANCER

In addition to identification of the TMPT gene mentioned previously for the use of 6-mercaptopurine, associations with certain genes have been linked to risks for ototoxicity from cisplatins and cardiotoxicity from anthracyclines.¹⁷ Similarly, there is hope that genetic testing may be able to identify patients at increased risk of adverse effects from chemotherapy such as neuropathy, neurocognitive problems, and several other adverse effects in pediatric cancer treatment.^18,19

Genetic subtypes also have been associated with outcomes and likely response to treatment. Some genetic subtype advances have identified patients likely to experience poor outcomes in acute lymphoblastic leukemia (ALL) therapy and in need of a different therapeutic approach.^20,21 On the other hand, some genetic subtypes indicate that certain patients’ cancers are more likely to respond to particular drugs and are targets for therapy tailored to an individual patient.²² The development of targeted and novel therapies based on the genetics of pediatric cancer has lagged behind their identification, but a great deal of studies are ongoing.

Conclusions

Genomic analysis will continue to impact how pediatricians identify and treat disease. It will be important for pediatricians to increase their knowledge and skills in this quickly changing field to be able not only to implement competency in their own practice, but also to explain to patients and parents so they can fully understand.

Next: Reimagining chemotherapy

The pediatrician is also likely to be challenged because, as the field is advancing quickly, the literature has not often addressed areas that other aspects of medicine do not often address, such as the impact of developmental stages and how this might affect diagnosis or treatment.

REFERENCES

1. Yousif TI, Bizanti K, Elnazir B. Uses of personalized medicine in current pediatrics. Int J Clin Pediatr. 2016;5(1):1-5.

2. Elborn JS. The impact of personalised therapies on respiratory medicine. Eur Respir Rev. 2013;22(127):72-74.

3. Bloss CS, Schork NJ, Topol EJ. Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med. 2011;364(6):524-534.

4. Coote JH, Joyner MJ. Is precision medicine the route to a healthy world? Lancet. 2015;385(9978):1617.

5. Vogenberg FR, Barash CI, Pursel M. Personalized medicine: part 3: challenges facing health care plans in implementing coverage policies for pharmacogenomics and genetic testing. P T. 2010;35(12):670-675.

6. Basu K, Palmer CN, Tavendale R, Lipworth BJ, Mukhopadhyay S. Adrenergic beta(2)-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. J Allergy Clin Immunol. 2009;124(6):1188. e3-1194.e3.

7. Tantisira KG, Lasky-Su J, Harada M, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med. 2011;365(13):1173-1183.

8. Kieling C, Genro JP, Hutz MH, Rohde LA. A current update on ADHD pharmacogenomics. Pharmacogenomics. 2010;11(3):407-419.

9. Shastry BS. Pharmacogenomics and its importance in pediatric medicine. J Pediatr Genet. 2012;1(2):79-84.

10. Arns M, Olbrich S. Personalized medicine in ADHD and depression: use of pharmaco-EEG. In: Kumari V, Bob P, Boutros NN, eds. Electrophysiology and Psychophysiology in Psychiatry and Psychopharmacology. Vol 21. Cham, Switzerland: Springer International Publishing AG; 2014:345-370. Curr Top Behavioral Neurosci. 2014;21:345-370.

11. Winner JG, Carhart JM, Altar CA, et al. Combinatorial pharmacogenomic guidance for psychiatric medications reduces overall pharmacy costs in a 1 year prospective evaluation. Curr Med Res Opin. 2015;31(9):1633-1643.

12. Winner JG, Carhart JM, Altar CA, Allen JD, Dechairo BM. A prospective, randomized, double-blind study assessing the clinical impact of integrated pharmacogenomics testing for major depressive disorder. Discov Med. 2013;16(89):219-227.

13. Hall-Flavin DK, Winner JG, Allen JD, et al. Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting. Pharmacogenet Genomics. 2013;23(10):535-548.

14. Rasmussen-Torvik LJ, Stallings SC, Gordon AS, et al. Design and anticipated outcomes of the eMERGEPGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems. Clin Pharmacol Ther. 2014;96(4):482-489.

15. Hudak ML. Codeine pharmacogenetics as a proof of concept for pediatric precision medicine. Pediatrics. 2016;138(1):e20161359.

16. Gammal RS, Crews KR, Haidar CE, et al. Pharmacogenetics for safe codeine use in sickle cell disease. Pediatrics. 2016;138(1):e20153479.

17. Rieder MJ, Carleton B. Pharmacogenomics and adverse drug reactions in children. Front Genet. 2014;5:78.

18. Mlakar V, Huezo-Diaz Curtis P, Satyanarayana Uppugunduri CR, Krajinovic M, Ansari M. Pharmacogenomics in pediatric oncology: review of gene-drug associations for clinical use. Int J Mol Sci. 2016;17(9):e1502.

19. Kandula T, Park SB, Cohn RJ, Krishnan AV, Farrar MA. Pediatric chemotherapy induced peripheral neuropathy: a systematic review of current knowledge. Cancer Treat Rev. 2016;50:118-128.

20. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125-134.

21. Mullighan CG, Su X, Zhang J, et al; Children’s Oncology Group. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-480.

22. Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153-166.