Gene-Tailored Drug Concept Extends from Cetuximab to Platelet Inhibitors
What's Hot in Medicine, July/August 2010
By David W. Sharp
When Science Watch® looked at the use of drugs such as cetuximab in patients with advanced colorectal cancer, a clear-cut message seemed to be emerging—namely, that only patients whose tumors had the wild-type, non-mutated form of the gene KRAS stood to benefit from this treatment (Science Watch, November/December 2009).
The subject remains topical in citation terms (paper #6 in the current Top Ten and, just below, #11 on panitumumab [C.S. Karapetis, et al., New Engl. J. Med.,359(17): 1757-65, 2008; latest citation count 39, total cites 175]). A newcomer (E. Van Cutsem, et al., New Engl. J. Med.,360[14]:1408-17, 2009; latest citation count 36, total cites 75, currently ranking #17) adds to the story. Here, cetuximab was used as part of a first-line therapeutic regimen in metastatic colorectal cancer, and the trial looked at a drug combination known as FOLFIRI (irinotecan, fluorouracil and leucovorin) with or without the addition of cetuximab.
Structure of the CYP2C19 protein. Based on PyMOL
rendering of PDB 1r9o. From the
Wikimedia Commons.
Progression-free survival but not overall survival was significantly improved by the addition of cetuximab. Data on KRAS status, which was studied in less than half the trial patients,supported earlier findings in more advanced disease. A recently published meta-analysis (E.M. Ibrahim, et al., Int. J. Colorectal Dis.,25[6]: 713-21, 2010) made use of data on over 2,000 patients from four randomized and six non-randomized studies comparing cetuximab with no cetuximab where KRAS status was known. The findings confirmed the importance of non-mutated KRAS but noted the need for better ways of identifying likely non-responders, and work on this is in progress (e.g., A. Lièvre, et al. Oncogene, 29[21]: 3033-43, 2010).
A couple of papers lower in the citation rankings (#21, #18) record attempts to do something similar for the anti-platelet agent clopidogrel—i.e., to explain via pharmacogenetic study why it is that cardiac patients given this drug to prevent further ischemic events respond so differently. An excellent diagram in the paper from France (T. Simon, et al., New Engl. J. Med.,360[4]: 363-75, 2009; latest count 33, total cites 114; #21) points to three areas where things might go wrong. Eighty-five percent of a dose of the prodrug clopidogrel is excreted as inactive metabolites, so intestinal absorption and hepatic metabolism to active drug as well as interaction with the platelet receptor itself are all important.
The gene polymorphisms relevant to the above three areas are the focus of Simon and colleagues’ paper.They found that possession of two variant alleles of the gene CYP2C19 (metabolism) and one or two variants of ABCB1 (intestinal absorption) significantly increased the risk of an adverse clinical outcome, manifesting as death, nonfatal myocardial infarction, or stroke. For variants at the third point, the platelet receptor, no such association was found.
"Progression-free survival but not overall survival was significantly improved by the addition of cetuximab."
The companion paper has an almost identical citation record (at #18: J.L. Mega, et al., New Engl. J. Med.,360[4]:354-62, 2009; latest count 35, total cites 151) but differs in that these workers only looked at the two cytochrome P-450 dependent oxidative steps in clopidogrel’s metabolism to active drug, but they included healthy people given the drug as well as patients from a clinical trial. If the former had a reduced-function CYP2C19 allele (and that was 34% of them) there was a one-third reduction in the active metabolite. As in Simon and colleagues’ study, Mega et al. recorded adverse clinical outcomes more often in patients on clopidogrel who carried a reduced-function CYP2C19 allele.
One way to tackle clopidogrel resistance due to genetically impaired metabolism to active drug might be simply to increase the dose, but should clinicians routinely seek the help of a molecular geneticist before prescribing clopidogrel? Not yet, argues one recent analysis, for both logistic and financial reasons (K.M. Momary, et al., Pharmacotherapy,30[3]: 265-74, 2010). However, the cost of gene analyses is falling; the first human genome sequencing cost billions, while today it is less than $10,000 and could become as low as $1,000 (see N.J. Samani, et al., Lancet, 375[9725]:1497-98, 2010 and also Science Watch biology correspondent Jeremy Cherfas in these pages, March/April, 2010).
The research discussed above was done on hundreds of patients. The May 1, 2010 issue of The Lancet includes an 11-page article on just one person, a healthy 40-year-old man with a family history of vascular disease and early sudden death (E.A. Ashley, et al., Lancet,375[9725]: 1525-35, 2010). His complete genome was investigated to find areas that might explain the family history. As Ashley and colleagues note, “63 clinically relevant previously described pharmacogenomic variants” were found, and one of them was the CYP2C19 mutation associated with clopidogrel resistance.
A former deputy editor of The Lancet, David W. Sharp is a freelance writer living in Minchinhampton, U.K.
Rank | Paper |
Cites This Period Jan-Feb 10 |
Rank Last Period Nov-Dec 09 |
1 | Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team (F.S. Dawood, et al.), "Emergence of a novel swine-origin influenza A ( H1N1 ) virus in humans," New Engl. J. Med., 360(25): 2605-15, 18 June 2009. [Writing group: Ctrs. for Disease Control & Prevent., Atlanta, GA] *458WR | 85 | 2 |
2 | The ACCORD Study Group (H.C. Gerstein, et al.), "Effects of intensive glucose lowering in type 2 diabetes ," New Engl. J. Med., 358(24): 2545-59, 12 June 2008. [Writing Group: 10 U.S. and Canadian institutions] *311IJ | 63 | 4 |
3 | The ADVANCE Collaborative Group (A. Patel, et al.), "Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes," New Engl. J. Med., 358(24): 2560-72, 12 June 2008. [Writing Group: 18 institutions worldwide] *311IJ | 57 | 3 |
4 | F.H. Schröder, et al., "Screening and prostate-cancer mortality in a randomized European study," New Engl. J. Med., 360(13): 1320-8, 26 March 2009. [15 institutions worldwide] *423VP | 52 | † |
5 | J.M. Llovet, et al., "Sorafenib in advanced hepatocellular carcinoma," New Engl. J. Med., 359(4): 378-90, 24 July 2008. [22 institutions worldwide] *329FK | 51 | 7 |
6 | R.G. Amado, et al., "Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer," J. Clin. Oncol., 26(10): 1626-34, 1 April 2008. [Amgen, Thousand Oaks, CA; Ghent Univ. Hosp., Belgium; Univ. Hosp. Gasthuisberg, Leuven, Belgium; Ospedale Niguarda Ca’ Granda, Milan, Italy] *281WY | 49 | † |
7 | R.R. Holman, et al., "10-year follow-up of intensive glucose control in type 2 diabetes," New Engl. J. Med., 359(15): 1577-89, 9 October 2008. [6 U.K. institutions] *358FS | 48 | 5 |
8 | C.L. Ogden, M.D. Carroll, K.M. Flegal, "High body mass index for age among US children and adolescents, 2003-2006," JAMA, 299(30): 2401-5, 28 May 2008. [Ctrs. for Disease Control & Prevent., Atlanta, GA] *305BD | 48 | † |
9 | NICE-SUGAR Study Investigators (S. Finfer, et al.), "Intensive versus conventional glucose control in critically ill patients," New Engl. J. Med., 360(14): 1283-97, 26 March 2009. [Writing Committee: 4 Australian, New Zealand, and Canadian institutions] *423VP | 46 | † |
10 | Cancer Genome Atlas Research Network (L. Chin, et al.), "Comprehensive genomic characterization defines human glioblastoma genes and core pathways," Nature, 455(7216): 1061-8, 23 October 2008. [60 institutions worldwide] *363FG | 42 | † |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |
KEYWORDS: CLOPIDOGREL, CETUXIMAB, PLATELET INHIBITORS, KRAS, DRUG RESISTANCE, E. VAN CUTSEM, J.L. MEGA, CYP2C19.
Citing URL: http://sciencewatch.com/ana/hot/med/10julaug-med/