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CYP2D6 and Ockham's Razor

Paoli-Calmettes Institute, Marseille, France

To the Editor:

Heredity has been both an explicative and a predictive tool for a long time. Not surprisingly, genes—its biologic component—are used for understanding the past and reading the future. We live in societies with more and more focus on the individuals,¹ who claim for individualized care and prevention. Gene analysis, both somatic and germline, could help to achieve that goal; however, having a hammer in the hand does not mean everything is a nail.²

With regard to the contribution of Lim et al,³ I will challenge neither the validity nor the scientific value of this article but rather the meaning of the title "Clinical implication." It is crystal clear that the real end point, the gold standard, is the individual effectiveness of the treatment, tamoxifen in that case. A close surrogate, used in this contribution, is the concentration of active metabolites. Does having a surrogate (CYP2D6) for that surrogate, improve care and challenge current clinical practice?

The rule of Ockham, "Pluralitas non est ponenda sine necessitate," means that new entities are required only if necessary. Figure 3 tells us that CYP2D6 does predict outcome, but does it do it better than plasma concentration at steady-state stage? These data are available in that survey, and therefore comparative analysis should be disclosed. It is unlikely to expect an improved discrimination, because plasma concentration of active metabolite is the end-product of many steps, each of them partially under genetic determinism: absorption, biotransformation from inactive to active product, and elimination of the active product (partially discussed in the article). The dosage of the critical product (the active metabolite) should in that case be more accurate, concerning both calibration and discrimination.

Shifting to gene testing is an absolute necessity to preclude irreversible events like dreadful adverse effects of drugs.⁴ It could also be a better collective choice if cheaper, simpler, or faster. Lastly, a genetic test that will predict a wide range of effects (such as the biotransformation of many drugs) could also be used. If none of these criteria is fulfilled, the value added by the genetic testing should be low (if any), and the need for a change in clinical practice, doubtful.

The issue of the validation of genetic testing before diffusion is critical. Many rely on ACCE model.⁵ Few tests might impact public health,⁶ and currently the main reason for rejection is insufficient evidence for clinical utility.⁷

These points do not limit the scientific value of that article, particularly the interesting and brilliant hypothesis to be tested about the "demonstrated superior efficacy" of aromatase inhibitor compared with tamoxifen. Though the contribution of Lim et al,³ gives us a better understanding on why some women do not respond to a widely used therapeutic, the clinical implications are not yet well defined. It seems that we are living in an era of gene-driven medicine, hoping it will not drive us crazy or make us simply less efficient.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Roberts BW, Helson R: Changes in culture, changes in personality: The influence of individualism in a longitudinal study of women. J Pers Soc Psychol 72:641-651, 1997[CrossRef][Medline]

2. Spallone P: Once you have a hammer, everything looks like a nail, in Clarke A, Parsons E (eds): Culture, Kinship and Genes. London, UK, Macmillan Publishers Ltd, 1997, pp 197-205

3. Lim HS, Ju Lee H, Seok Lee K, et al: Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 25:3837-3845, 2007[Abstract/Free Full Text]

4. Relling MV, Hancock ML, Rivera GK, et al: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91:2001-2008, 1999[Abstract/Free Full Text]

5. Haddow J, Palomaki G: ACCE: A model process for evaluating data on emerging genetic tests, in Khoury M, Little J, Burke W (eds): Human Genome Epidemiology. New York, NY, Oxford University Press, 2004, pp 217-233

6. Yoon PW, Chen B, Faucett A, et al: Public health impact of genetic tests at the end of the 20th century. Genet Med 3:405-410, 2001[Medline]

7. Kroese M, Zimmern RL, Farndon P, et al: How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network. Eur J Hum Genet 15:917-921, 2007[CrossRef][Medline]

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