Pharmacogenetics as a Consequence of Molecular Differential Diagnosis

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As alluded to earlier, there is general agreement today that any of the major clinical diagnoses in the field of common complex disease, such as diabetes, hypertension, or cancer, are comprised of a number of etiologically (i.e., at the molecular level) more or less distinct subentities. In the case of a causally acting drug this may imply that the agent will only be appropriate, or will work best, in that fraction of all the patients who carry the (all-inclusive and imprecise) clinical diagnosis in whom the dominant molecular etiology, or at least one of the contributing etiological factors, matches the biological mechanism of action that the drug in question modulates (Figure 1C). If the mechanism of action of the drug addresses a pathway that is not disease-relevant - perhaps already downregulated as an appropriate physiologic response to the disease, then the drug may logically be expected not to show efficacy (Figure 1D and E).

Thus, unrecognized and undiagnosed disease heterogeneity, disclosed indirectly by the presence or absence of response to a drug targeting a mechanism that contributes to only one of several molecular subgroups of the disease, provides an important explanation for differential drug response and likely represents a substantial fraction of what we today somewhat indiscriminately subsume under the term 'pharmacogenetics.'

Currently, the most frequently cited example for this category of 'pharmacogenetics' is trastuzamab (Herceptin), a humanized monoclonal antibody directed against the her-2 oncogene. This breast cancer treatment is prescribed based on the level of her-2 oncogene expression in the patient's tumor tissue. Differential diagnosis at the molecular level not only provides an added level of diagnostic sophistication, but also actually represents the prerequisite for choosing the appropriate therapy. Because trastuzamab specifically inhibits a 'gain-of-function' variant of the oncogene, it is ineffective in the two-thirds of patients who do not overexpress the drug's target, whereas it significantly improves survival in the one-third of patients who constitute the subentity of the broader diagnosis 'breast cancer' in whom the gene is expressed.3 Parenthetically, some have argued against this being an example of 'pharmacogenetics,' because the parameter for patient stratification (i.e., for differential diagnosis) is the somatic gene expression level rather than particular 'genotype' data.4 This is a difficult argument to follow, since in the case of a treatment effect-modifying germline mutation it would obviously not be the nuclear gene variant per se, but rather its specific impact on either structure/function or on expression of the respective gene/gene product that would represent the actual physiological corollary underlying the differential drug action. Conversely, an a priori observed expression difference is highly likely to reflect a potentially as yet undiscovered sequence variant. Indeed, as pointed out earlier, there are a number of examples in the field of pharmacogenomics where the connection between genotypic variant and altered expression has already been demonstrated.5'6

Another example, although still hypothetical, of how proper molecular diagnosis of relevant pathomechanisms will significantly influence drug efficacy, is in the evolving class of anti-acquired immunodeficiency syndrome (AIDS)/ human immunodeficiency virus (HIV) drugs that target the CCR5 cell surface receptor.7-9 These drugs would be predicted to be ineffective in those rare patients who carry the 832 variant, but who nevertheless have contracted AIDS or test HIV-positive (most likely due to infection with an SI (simian immunodeficiency) virus phenotype that utilizes CXCR4).10,11

It should be noted that the pharmacogenetically relevant molecular variant need not affect the primary drug target, but may equally well be located in another molecule belonging to the system or pathway in question, either up- or downstream in the biological cascade with respect to the primary drug target.

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