The promise of individualized therapy has resonated with scientists, healthcare providers, and patients since the inception of the Human Genome Project. The ability to use designer drugs, such as novel monoclonal antibodies and molecularly targeted tyrosine kinase inhibitors, has created a new hope in the management of the cancer patient by individualizing therapy based on the unique molecular mutations in the cancer and the patient’s germline DNA. The nuances of implementing germline and somatic genomic testing in a clinical setting are discussed and the future role of pharmacogenomics testing in personalized cancer treatment is examined.
Personalized medicine, pharmacogenomics, molecular profiling, targeted therapy, cancer management
The authors have no conflicts of interest to declare.
February 15, 2013 Accepted
March 22, 2013
Gregory J Tsongalis, PhD, HCLD, CC, Department of Pathology, Dartmouth–Hitchcock Medical Center and The Geisel School of Medicine at Dartmouth, 1 Medical Center Drive, Lebanon, NH 03756 USA. E: email@example.com
Before the inception and subsequent reporting of the Human Genome Project data, novel paradigms of more personalized therapeutics were forecast as a benchmark for the success of the project. Along with better diagnostic and prognostic applications arising from the sequencing of the human genome, the promise of novel and more specific molecularly targeted therapeutics based on genomic information is coming to fruition and changing both diagnostic and therapeutic management algorithms. These advances in molecular therapeutics are resulting in more sophisticated and focused clinical trial designs and study protocols for matching specific patients to specific therapies. These advances underscore the potential for more specialized and successful therapies for cancer patients.
The concept of an individual variation in drug handling and response is not novel and those practitioners who have emphasized the principles of therapeutics have led the way for personalized medicine. In 510 BC, Pythagoras recognized that some individuals, but not all those exposed, developed hemolytic anemia with fava bean consumption.1 Hemolytic anemia due to fava bean consumption was later determined to occur in glucose-6-phosphate dehydrogenase (G-6 PD) deficient individuals.2,3 In 1902, Garrod recognized the potential hereditary nature of a metabolic defect associated with alkaptonuria and associated this with specific enzymes that detoxify xenobiotics so that they may be excreted.4 He subsequently made the observation that some people lacking these enzymes experience significant adverse effects.5 In 1959, Fredrich Vogel was the first to coin the term pharmacogenetics, which he defined as genetic variation found in an individual that resulted in a varied response to therapeutic drugs.6 The realization that differences between individuals, both genetic and environmental, result in success or failure of a therapy holds the promise that future therapies can be tailored to an individual’s genetic make-up. For the cancer patient, additional tumor mutational analysis could be used to individualize anticancer therapies.7
Pharmacogenetics—Drug Metabolism versus
The impact of genomic testing to inform therapeutic drug selection and dosing in oncology has occurred at a record pace and includes two facets of pharmacology. The first is drug metabolism pharmacogenetics (PGXm) and corresponds to genetic variants that determine drug disposition (i.e. the processes of absorption, distribution, metabolism, and excretion) also referred to as drug pharmacokinetics.8 The second is molecularly targeted pharmacogenetics (PGXt), which relates to the selection of a therapeutic moiety based on the presence or absence of a specific drug target or pathway in the tumor.9 Unlike PGXm, where the genetic variants are typically present in the germline, for PGXt applications the variants and/or mutations are typically somatic and necessitate analysis of tumor tissue.
Examples of classic PGXm include the conversion of a parent compound to an inactive metabolite or a metabolite that is more easily excreted or the conversion of a prodrug to its active metabolite. Enzymes associated with drug metabolism have been well characterized, as have their genes and their polymorphic variants. Many of the genetic variants found in the metabolic enzyme genes are not associated with disease yet can lead to an individual being characterized as a poor, intermediate, extensive, or ultrarapid metabolizer, and this is best exemplified by the cytochrome P450 enzyme, CYP2D6. This classification of an individual patient’s drug metabolism status can be critical to both selection and dosing of a particular therapy.
An example of drug-metabolizing gene variants effecting response to a commonly used therapeutic is seen in breast cancer. Estrogen receptor (ER)-positive breast cancers are treated with hormonal therapies that are estrogen antagonists. one such moiety is tamoxifen, which itself has been shown to have altered metabolism due to CYP450 genetic polymorphisms. Tamoxifen and its metabolites compete with estradiol for occupancy of the ER, and in doing so inhibit estrogen-mediated cellular proliferation. Conversion of tamoxifen to its active metabolites occurs predominantly through the CYP450 system and its primary and secondary metabolites are important because they have a greater affinity for the ER than tamoxifen itself (specifically endoxifen has approximately 100 times greater affinity for the ER). Activation of tamoxifen to endoxifen is primarily due to the action of CYP2D6 (see Figure 1). Therefore, patients with defective CYP2D6 alleles potentially derive less benefit from tamoxifen therapy than patients with functional copies of CYP2D6. The most common null allele among Caucasians is CYP2D6*4, a splice site mutation (G1934A) resulting in loss of enzyme activity, and, therefore, lack of conversion of tamoxifen to its most active metabolite endoxifen. This could result in significantly decreased response to anti-estrogen therapy. While several retrospective studies have suggested that individuals with loss of function CYP2D6 alleles (ex. CYP2D6*4) have greater rates of tumor recurrence and shorter relapse-free survival; however, other studies have not corroborated these findings.10
The ongoing debate as to whether CYP2D6 genotype impacts outcomes with tamoxifen was addressed in a large trial from the Breast International Group (BIG) I-98 and Arimidex, Tamoxifen, Alone or in Combination (ATAC) studies where the investigators resolved that CYP2D6 genotyping has no effect.11,12 Unfortunately, these studies have come under intense scrutiny due to the departure from Hardy-Weinberg equilibrium of the results.13 This is thought to be due to errors in the genotyping performed in those studies. More specifically, those studies are said to be biased in terms of genotyping that occurred in tumor tissue DNA instead of germline DNA. The discordant genotype frequencies could most likely be due to known loss of heterozygosity of the CYP2D6 locus in breast tumor tissue and/or the detection of nearby pseudogenes. Accumulating data will need to be re-analyzed and re-assessed in terms of this potential PGXm application.
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Personalized medicine, pharmacogenomics, molecular profiling, targeted therapy, cancer management