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CYP2D6 Testing in ER+ Breast Cancer

Will results lead to improved patient outcomes?

Many consider tamoxifen to be the first successful targeted therapy for breast cancer.  Approximately 70% of primary breast cancers are estrogen receptor (ER)-positive, meaning that they have extra receptors that bind with the hormone estrogen and may need estrogen to grow and multiply.  Tamoxifen is described as a selective estrogen receptor modulator (SERM),  because tamoxifen and its active metabolites (i.e., intermediate products of metabolism) bind to estrogen receptors, preventing estrogen activity in breast tissue.

CYP2D6

Cytochrome P450s, or CYPs, are enzymes present in the liver which metabolize the majority of drugs we take.  Every person has a unique combination of CYP enzymes, based on their genetic make-up. 

CYP2D6 is the enzyme necessary for metabolizing tamoxifen.  The enzyme converts tamoxifen into its active form, endoxifen.  There are more than 100 variations (polymorphisms) of CYP2D6, based on differences in the genes that code for it. Depending on which versions you inherit, your CYP2D6 enzyme activity could be normal, extensive or nonexistent.  Estimates are that 7-10% of the population has inherited genes that give them low or nonexistent activity of the enzyme (Hartman, 2007).  There are also interactions that can occur with other medications that can impact CYP2D6 activity (see sidebar). 

To Test or Not to Test?

Commercial tests for CYP2D6 genotyping are available, allowing patients to know what versions of the enzyme they have inherited, and whether they are considered low, intermediate, or extensive metabolizers.  However, based on currently available data it remains unclear whether testing for CYP2D6 should be part of routine clinical care for women considering initiation of tamoxifen for breast cancer.  Some investigators and clinicians are recommending routine CYP2D6 testing before prescribing tamoxifen in postmenopausal women (Goetz, 2009). However, others are stressing the need for caution, recognizing that the current evidence is limited, conflicting, and preliminary and that additional data is necessary before any conclusion can be made regarding a recommendation for routine CYP2D6 testing (Kuderer, 2009). 

What does the Research Show?

Several studies have investigated the association between different CYP2D6 genetic variants and outcomes in ER+ breast cancer patients treated with tamoxifen, with the majority suggesting an association between poor CYP2D6 metabolizer status and increased disease recurrence (Schroth, 2009; Lim, 2007; Newman, 2008).  This includes the results of a study presented during the 2008 San Antonio Breast Cancer Symposium (SABCS).  Presented by investigators from the Mayo Clinic and the Austrian Breast and Colorectal Cancer Study Group (ABCSG), the study evaluated whether recurrence risk was different in patients with poor, intermediate, or extensive CYP2D6 metabolism who received treatment with tamoxifen monotherapy or tamoxifen followed by a switch to anastrozole (Goetz, 2008).  The investigators reported that patients who received tamoxifen monotherapy and were identified as poor CYP2D6 metabolizers had a 3.8-fold higher recurrence risk than extensive metabolizers after 5 years. 

Despite these results, some investigators and clinicians are not ready to call for routine CYP2D6 testing.  Their reasons include:

• Contradictory findings: In the studies performed to date, there has not been a consistent association between CYP2D6 polymorphisms and clinical outcomes in women with ER+ breast cancer.  As noted above, although most studies have suggested an association between deficient CYP2D6 metabolizer status and worse disease-free survival, some studies have not demonstrated such an association or have shown improved clinical outcomes in those with reduced CYP2D6 activity (Wegman, 2005; Nowell, 2005).
• The published studies to date have important limitations, including the following:

• Most have a small or moderate sample size and therefore may be underpowered, with too few participants to make a reliable judgment on the study's findings.
• Many of the trials have been retrospective analyses, which are more subject to errors due to bias and confounders than prospective trials.
• Most studies have focused on genetic variations in just CYP2D6, rather than additional drug-metabolizing enzymes, although it is known that many genes play a role in tamoxifen metabolism.  The conflicting results described above could be due in part to such variants regardless of an individual's CYP2D6 genetic polymorphism.
• It is also important to note that the dose as well as the duration of tamoxifen therapy differed across trials (Kuderer, 2009).
• Many of the studies conducted to evaluate an association between CYP2D6 polymorphisms and clinical outcomes have not controlled for adherence to tamoxifen therapy (Kuderer, 2009; Henry, 2009; Rae, 2007). However, data from multiple clinical trials of adjuvant tamoxifen have reported significant non-adherence, with discontinuation rates varying widely, from approximately 23% to 40% (Kelly, 2006).  It is crucial to adjust for compliance, since a poor metabolizer of CYP2D6 who is compliant with tamoxifen treatment could gain greater benefit than an extensive CYP2D6 metabolizer who stops taking tamoxifen.
• Most studies also did not control for other confounding factors, including simultaneous (i.e., concomitant) treatment with other medications that can also inhibit CYP2D6 and lead to lowered concentrations of endoxifen (Kuderer, 2009; Henry, 2009; Rae, 2007).