September 14, 2018

Is It Time to Use Pharmacogenomics to Guide Tamoxifen Dosing?

A guide for physicians


By Jennifer Hockings, PharmD, PhD


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Pharmacogenomic testing can help providers prescribe medications and doses that are safe and effective, optimizing clinical outcomes with minimal side effects. Research in this field is ever-evolving; however, studies suggest that certain patients metabolize tamoxifen differently, which may make a difference in chemotherapy dosing.

CYP2D6 involved in metabolism of nearly a quarter of prescription medications

Tamoxifen is a selective estrogen receptor modulator and has been an integral part of therapy for patients diagnosed with estrogen receptor (ER) positive breast cancer. The use of tamoxifen for five years after surgery has been demonstrated to reduce recurrence by 50 percent. Tamoxifen is a prodrug that is metabolized to the active metabolites endoxifen and 4-hydroxytamoxifen (4HT), involving the enzyme CYP2D6. Individuals who have decreased or low CYP2D6 enzyme activity have lower serum concentrations of 4HT and endoxifen, which may be associated with recurrence. CYP2D6 is involved in the metabolism of 20 to 25 percent of the drugs that are prescribed. CYP2D6 has more than 100 allelic variants that have been defined and can be characterized as normal function, decreased function, or no function. CYP2D6 genotype results are generally reported as a diplotype, but some individuals may have gene deletions or carry more than two copies of CYP2D6. Unlike many other genes, CYP2D6 alleles are each assigned an activity value that can be used to calculate an activity score for phenotype classification.

* There is discussion as to the predicted phenotype of those with an activity score of 1. Whether an activity score of 1 equates to a CYP2D6 NM or IM may depend on the substrate.

In terms of tamoxifen, those with an activity score of 1 may have less active metabolite concentrations than those with an activity score of 1.5 or 2. The majority of the general population carry two normal function alleles and are classified as CYP2D6 NM. However, it has been estimated that up to 10 percent of the general population are CYP2D6 PM.


How do we use CYP2D6 genotype results in regards to tamoxifen?

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recently published guidelines to provide therapeutic recommendations for patients with a CYP2D6 genotype and prescribed tamoxifen. As a brief summary, the CPIC guidelines recommend use of aromatase inhibitors in post-menopausal women who are CYP2D6 IM or PM. For premenopausal women who are CYP2D6 IM or PM, ovarian function suppression in addition to an aromatase inhibitor could be considered. Should aromatase inhibitors be contraindicated in either case, the tamoxifen dose could be increased to 40 mg/day. Individuals who are CYP2D6 NM or UM should have tamoxifen initiated at 20 mg/day. As with other guidelines published by CPIC, the focus is to provide therapeutic recommendations for patients who have a CYP2D6 genotype and does not address whether patients should be tested prior to tamoxifen initiation.

Drug-drug interactions

It is important to note that many drugs inhibit CYP2D6 enzymatic activity. When a CYP2D6 inhibitor is prescribed with a drug that is a CYP2D6 substrate, this can lead to a phenomenon called phenoconversion. In such a situation, patients who are predicted to be CYP2D6 NM or UM may actually have enzymatic activity similar to a CYP2D6 IM or PM. Given this phenomenon, it is important to avoid CYP2D6 inhibitors when prescribing tamoxifen.

The DNA source is also important

In addition to considering drug-drug interactions, the DNA source for genotyping is important. Given that DNA from tumor cells may harbor chromosomal instabilities (loss of heterozygosity in particular), it is strongly recommended for CYP2D6 that the DNA is obtained from peripheral blood or buccal swab to reflect the germline genotype of the liver.

Controversies with pharmacogenomic testing and tamoxifen

Studies have demonstrated a statistically significant difference in endoxifen and 4HT serum concentrations based on CYP2D6 activity score. However, tamoxifen bioactivation also involves CYP3A4, CYP3A5, CYP2C19 and CYP2C9, and these each have identified genetic polymorphisms with altered functions. Recent studies seem to indicate that CYP2D6 genetic variations are critical to bioactivation and that genetic variants in other genes may have a minor contribution towards endoxifen serum concentrations and, subsequently, outcomes. In addition to further studies on the involvement of other genes, there still remains questions to the extent of the dose increase that should be considered for patients who are CYP2D6 PMs. In a study of 353 adult females diagnosed with ER positive breast cancer, serum concentrations of endoxifen were obtained at baseline after initiation of tamoxifen at 20 mg/day, and individuals who were CYP2D6 IMs and PMs then had their tamoxifen dose increased to 40 mg/day. After 4 months, serum concentrations were evaluated in all study participants. At baseline there was a statistically significant difference in endoxifen serum concentrations between CYP2D6 NM and IM as well as CYP2D6 NM and PM groups. After 4 months, the statistically significant difference in endoxifen serum concentrations was negated between the CYP2D6 NM and IM groups. However, a statistically significant difference in serum concentrations was still observed between the CYP2D6 NM and PM groups, suggesting that individuals who are CYP2D6 PM may need a further dose escalation to reach serum concentrations similar to CYP2D6 NM. Given that there remains controversy as to an association with CYP2D6 phenotype and outcomes, it would be reasonable to question whether patients should be preemptively genotyped to initiate tamoxifen at a higher dose or if therapeutic drug monitoring of endoxifen would have greater clinical utility.

Current testing options

In patients for whom a CYP2D6 genotype is clinically indicated, a single gene test can be ordered or pharmacogenomics panels including CYP2D6 is available. Both options require a sample to be sent to a reference laboratory. Out-of-pocket costs vary depending on the reference laboratory. It should be noted that in certain circumstances patients may have less out-of-pocket costs with panel genotyping.


There is also variability in regards to time until results return. Prior to sending a sample, the CYP2D6 variants detected by the reference laboratory need to be evaluated. Variants that are not tested for will be reported as *1, indicating a normal function allele when the patient may harbor a variant not reported by that reference laboratory.

The potential to personalize therapy with pharmacogenomic testing to optimize efficacy is great — particularly in regards to cancer. As with other genetic tests, the risk, limitations and benefits must be discussed with the patient.

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