Faculty peer reviewed
The country mourned over the loss of Senator Kennedy this week, 15 months after his diagnosis with malignant glioma. As plans for healthcare reform undergo increasing scrutiny and the American public becomes ever more disillusioned, Mr. Kennedy’s passing reminds us of his vision for a nation in which “every American…will have decent, quality healthcare as a fundamental right and not a privilege.”Healthcare policy, however, seems to move in the opposite direction of science. While policy often calls for less costly imaging and laboratory tests, scientists are discovering expensive, but useful, genetic tests upon which to tailor drug therapy. A review of this past week’s literature takes a look into the field of pharmacogenomics.
The Annals of Internal Medicine published an opinion article last week which evaluated the utility of warfarin dosing based on genotype. As we are now well aware, warfarin metabolism is affected by, among other things, CYP2C9 gene mutation and VKORC1 gene polymorphisms. Specific mutations of both genes may lead to increased warfarin sensitivity.
While the FDA suggests genetic testing for patients on warfarin, the authors of this recent article recommend against it. According to Dr. Rosove and Dr. Grody from UCLA, commercially available test kits vary in the number and type of polymorphisms they test and genetic testing only predicts about 1/3 of all dosing variation. Therefore, there are many other factors outside of genetics that predict warfarin metabolism. In addition, cost-benefit analyses have not shown genetic testing to be cost-effective. So, while genotyping provides us with a greater understanding of each patient’s pharmacokinetics, we are still far away from utilizing it in real practice – at least when it comes to warfarin.
Another popular drug that has undergone similar study is clopidogrel. JAMA published a large scale study looking at CYP2C19 mutations and clopidogrel activity this week. Because of their homogenous gene pool and relatively controlled lifestyle, the study used an Amish population to study the role of genotype on clopidogrel’s effect on platelet aggregation. In brief, these patients were given clopidogrel for 7 days and ex vivo platelet aggregation was measured. Genotyping was performed, specifically evaluating CYP2C19 variants. Statistical models were then used to evaluate for associations between clopidogrel response and polymorphisms.
A second part of the study, termed replication analysis, looked at ischemic events in a more heterogenous population of patients on clopidogrel post-PCI. These patients also underwent platelet aggregation studies and genotyping. Simply put, the collective results from the two studies revealed that platelet response to clopidogrel was highly heritable and strongly associated with the CYP2C19*2 genotype. What this means for the future of clopidogrel administration is to be determined by future research.
The field of oncology also had its share of publications related to genome sequencing this week. “Finding the Weakness in Cancer,” printed in the NEJM, reviews recent basic science research on K-RAS oncogene inhibition. A large portion of tumor cells have K-RAS oncogene mutations which, generally speaking, promote uncontrolled cell growth. Utilizing RNA interference, researchers found a kinase that, when inhibited, is most specific for K-RAS oncogene killing. This new research paves the way for exciting new targets for anticancer drugs.
Lastly, the inhibition of EGFR signaling in lung cancer is another example of personalized medicine that got some press this week. The NEJM online published an article that looked at screening for EGFR mutation in lung cancer patients in Spain. Those with mutations were provided erlotinib (an EGFR inhibitor). Results revealed that mutations were more prevalent in female patients, non-smokers, and non-squamous tumors. There was an improvement in progression-free survival and overall survival in those patients receiving customized erlotinib therapy.
While more investigation is needed to determine the efficacy of genetic testing, this week’s literature review is a glimpse into the near future. We only hope that healthcare reform will make such testing possible for all.
Peer reviewed by Barbara Porter, MD MPH, Clinical Assistant Professor of Medicine, NYU Medical Center
1. Transcript: Edward Kennedy’s DNC Speech. CNN online. http://www.cnn.com/2008/POLITICS/08/25/kennedy.dnc.transcript/index.html
2. Rosove M, Grody W. Should We Be Applying Warfarin Pharmacogenetics to Clinical Practice: No, Not Now. Annl Int Med. 2009 18 Aug;151(4):270-273.
3. Shuldiner A, O’Connell J, Bliden K, Gandhi A, Ryan K, Horenstein R, Damcott C, Pakyz R, Tantry U, Gibson Q, Pollin T, Post W, Parsa A, Mitchell B, Faraday N, Herzog W, Gurbel P. Association of Cytochrome P450 2C19 Genotype with the Antiplatelet Effect and Clinical Efficacy of Clopidogrel. JAMA. 2009 26 Aug;302(8):849-857.
4. Downward, J. Finding the Weakness in Cancer. NEJM. 2009 Aug 27;361(9):922-924.
5. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, Majem M, Lopez-Vivanco G, Isla D, Provencio M, Insa A, Massuti B, Gonzalez-Larriba JL, Paz-Ares L, Bover I, Garcia-Campelo R, Moreno MA, Catot S, Rolfo C, Reguart N, Palmero R, Sánchez JM, Bastus R, Mayo C, Bertran-Alamillo J, Molina MA, Sanchez JJ, Taron M; the Spanish Lung Cancer Group. Screening for Epidermal Growth Factor Mutations in Lung Cancer. NEJM [Epub ahead of print]. 2009 Aug 19. Available from: http://content.nejm.org/cgi/content/full/NEJMoa0904554
6. Gazdar, A. Personalized Medicine and Inhibition of EGFR Signaling in Lung Cancer. NEJM [Epub ahead of print]. 2009 Aug 19. Available from: http://content.nejm.org/cgi/content/full/NEJMe0905763
7. Bhatt, Deepak. “Tailoring Antiplatelet Therapy Based on Pharmacogenomics.” JAMA. 2009 Aug 26;302(8):896-897.