CYP2D6 Testing in Breast Cancer: Ready for Prime Time?

ABSTRACT: Despite recent advances in hormonal therapy for breast cancer, tamoxifen(Drug information on tamoxifen) remains a major therapeutic option, with indications ranging from primary prevention to metastatic disease. Understanding the variation in response to tamoxifen may significantly improve our ability to personalize cancer care and maximize therapeutic efficacy. One area of particular interest is the impact of cytochrome P450 CYP2D6 genetic polymorphisms on tamoxifen metabolism. Tamoxifen is considered a prodrug, whose efficacy may be dependent on active metabolites, including endoxifen. Patients with reduced CYP2D6 enzymatic activity tend to have lower endoxifen levels, but clinical relevance of reduced endoxifen levels remains to be determined. Several small to moderately sized retrospective studies have suggested an intriguing association between poor metabolizer status and increased disease recurrence. However, these data are limited by sample size and methodologic challenges, including the inability to adjust for major prognostic and confounding factors. Several subsequent studies have failed to find an association or found improved outcomes among reduced CYP2D6 metabolizers. Therefore, current findings are conflicting and should be considered preliminary. Nevertheless, the CYP2D6 test is commercially available, making clinical use possible even as evidence in this area is still evolving. More definitive clinical research is needed before routine CYP2D6 testing can be recommended and considered standard of care. Anticipated data from retrospective analysis of large adjuvant randomized trials of tamoxifen should help address the clinical utility of CYP2D6 testing.

Despite recent advances in hormonal therapy for breast cancer, tamoxifen, a selective estrogen receptor modulator first approved in the 1970s, remains one of the most effective interventions in our therapeutic armamentarium, with indications ranging from prevention of breast cancer to treatment of metastatic disease. However, for reasons that remain incompletely understood, not all patients with endocrine receptor–positive breast cancer will respond to or benefit from tamoxifen. There are now multiple alternative endocrine therapies available, with variable efficacy and toxicity profiles, making it increasingly important to understand the optimal endocrine strategy for an individual patient.

One area of particular interest is the rapidly evolving evidence in the field of pharmacogenetics, evaluating the association between genetic differences in drug metabolism and patient outcomes. Recent studies have suggested that we may soon be able to rationally select drugs for specific patients based on differing drug metabolism in addition to other clinical factors. This article will review and summarize the current data regarding the influence of the major cytochrome P450 2D6 (CYP2D6) genotypes and CYP2D6 inhibitors on tamoxifen metabolism and clinical efficacy. We will discuss the clinical relevance and limitations of this data and how to best incorporate our current understanding of CYP2D6 genotyping into our clinical practice and discussions with patients.

Tamoxifen

The majority of breast cancers are dependent on estrogen, and estrogen deprivation has been recognized as an effective treatment for breast cancer for over 100 years, following Beatson’s initial publication on the role of oophorectomy in advanced disease.[1] Our ability to provide endocrine therapy for patients advanced markedly with the approval of tamoxifen by the US Food and Drug Administration (FDA) in 1977 for the treatment of postmenopausal women with metastatic breast cancer.[2] In 1986, tamoxifen gained FDA approval for adjuvant therapy in postmenopausal node-positive women, and the drug has subsequently been proven effective in hormone receptor–positive premenopausal and node-negative breast cancer patients,[3] breast cancer prevention,[4] ductal carcinoma in situ (DCIS),[5] and male breast cancer.[6] Among estrogen receptor (ER)-positive breast cancers, adjuvant tamoxifen reduces the relative recurrence rate by over 40% and breast cancer mortality by approximately one-third.[3] Tamoxifen remains the only FDA-approved hormonal agent for the treatment of premenopausal women, and DCIS.

Recent study of genetic predictors of recurrence risk and response to therapy reminds us that tamoxifen alone is a highly effective drug for early-stage breast cancer, conveying a sufficiently low risk of recurrence that chemotherapy can be avoided for many patients.[7] While in postmenopausal women, an adjuvant strategy involving aromatase inhibitors (AIs), either alone or in sequence with tamoxifen, is now preferred for most patients, the absolute difference in disease-free survival is on the order of 3% to 4%, with no clear improvement in overall survival.[8] The AI side-effect profile is preferable for many patients, without the risks of thrombosis and uterine malignancy observed with tamoxifen. However, some patients with severe joint symptoms or refractory osteoporosis may not be able to tolerate an AI.[9-11] Further, the higher cost for AIs compared to tamoxifen may be a treatment barrier for some patients. Tamoxifen remains a standard part of treatment for many patients with breast cancer. If the factors impacting response could be identified, we might be able to obtain even greater results for some patients on tamoxifen, and use alternative endocrine therapies for other patients. Many factors, ranging from tumor biology to adherence, likely play a role in response to tamoxifen, but recently it has become apparent that understanding differences in metabolism may provide clues that can help optimize management of endocrine-responsive breast cancer.

Tamoxifen Metabolic Pathway and Active Metabolites: Endoxifen and 4-Hydroxy-Tamoxifen

TABLE 1
Frequencies of the Most Prevalent CYP2D6 Alleles Across Ethnic Groups

Once orally absorbed, tamoxifen is initially metabolized primarily by two hepatic enzymes in the cytochrome P450 family, CYP2D6 and CYP3A4/5. As demonstrated in Figure 1, the major metabolic pathway involves initial conversion of tamoxifen to N-desmethyl-tamoxifen via CYP3A4/5, followed by conversion of N-desmethyl-tamoxifen to endoxifen, via CYP2D6. In addition, some tamoxifen is initially metabolized by CYP2D6 to the active metabolite 4-hydroxy-tamoxifen, which in turn is either degraded or converted by ­CYP3A4/5 to endoxifen. Tamoxifen has weak estrogen receptor binding and is considered a prodrug. Endoxifen and 4-hydroxy-tamoxifen are much more potent blockers of the estrogen receptor than tamoxifen, with over 100 times stronger binding affinity. Furthermore, endoxifen reaches several-fold higher concentrations than 4-hydroxy-tamoxifen, suggesting that it may be the most important active tamoxifen metabolite.[12]

FIGURE 1
Tamoxifen Metabolism and Its Metabolites

Natural genetic variation in alleles for the CYP2D6 gene that lead to marked differences in CYP2D6 enzymatic activity were recognized as early as the 1970s, and variation in metabolism has been determined for a number of commonly used drugs.[13] Over 80 different CYP2D6 alleles have now been identified and can be categorized as nonfunctional alleles (also called null alleles, mainly *3, *4, *5, *6, and *8), reduced function alleles (mainly *9, *10, *17, and *41), and wild-type (wt) alleles (mainly *1, and *2), with increased enzymatic functioning (Table 1).[14-16] Allelic frequency varies among ethnic groups (Table 1), with the nonfunctional allele CYP2D6*4 being most prevalent in Caucasians, and the reduced-functioning allele CYP2D6*10 most common among Asian populations.[14,16] Based on allele combinations, (or allele duplication) patients can be classified into four major genotypes: (1) poor metabolizers (PM)—homozygous for null alleles; (2) intermediate metabolizers (IM)—heterozygous for null or partially functional alleles; (3) extensive metabolizers (EM)—homozygous for wildtype alleles; and (4) ultrarapid metabolizers (UM)—carrying more than two CYP2D6 copies in their genome. Among Caucasian populations, the prevalence of genotypes with reduced CYP2D6 function is estimated to be roughly 5% to 10% for PM.[17]