Endocrine Therapy: Translational Research on CYP2D6 Genetics for Tamoxifen Response in Breast Cancer

The recent advances in tamoxifen pharmacogenetics have raised considerable interest in the clinical application of CYP2D6 genetic testing for the identification of breast cancer patients capable to benefit from tamoxifen and distinguish them from those in need for alternative endocrine treatment options. This work shows the evidence in favor of that notion and introduces our ongoing activities with respect to tackle the yet missing link of the correlation between the patient's CYP2D6 genotype, corresponding clinically active tamoxifen metabolite levels, and treatment outcome.

Tamoxifen is considered an essential part of standard adjuvant and palliative systemic therapy for patients with steroid hormone receptor positive tumors. In primary breast cancer, adjuvant tamoxifen significantly decreases relapse rates and mortality in pre- and postmenopausal patients and the therapy benefit resulting from 5 years of adjuvant tamoxifen is maintained even more than 10 years after primary diagnosis. Tamoxifen is a valid therapy option next to aromatase inhibitors in postmenopausal patients with endocrine responsive disease. It is considered the standard care for the prevention of invasive breast cancer for women at high risk including those who have had ductal carcinoma in situ, and the treatment of male breast cancer. Tamoxifen is generally well tolerated and menopausal symptoms including hot flashes are the most common side effects whereas severe side effects such as thromboembolic events or endometrial carcinoma are rather rare. Although the clinical benefit of tamoxifen has been evident for more than three decades, up to 50% of patients receiving adjuvant tamoxifen relapse or die due to tumor specific resistance or host genome associated factors.

As a prodrug, tamoxifen is subject to comprehensive primary and secondary metabolism by cytochrome P450 enzymes. Although N-desmethyl tamoxifen (NDM) is the major metabolite, it is the 4-hydroxy tamoxifen (4-OH-TAM) and 4-hydroxy-N-desmethyl tamoxifen (endoxifen) that are the clinically potent metabolites with an up to 100-fold higher affinity for the estrogen receptor (ER) and potency to suppress cancer cell proliferation. CYP2D6 is the key enzyme in this biotransformation and recent mechanistic, pharmacologic, and clinical pharmacogenetic evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and outcome of patients treated with adjuvant tamoxifen. Particularly, non functional (poor metabolizer, PM) and severely impaired (intermediate metabolizer, IM) CYP2D6 variants are associated with higher recurrence rates. Their frequency in individuals of European descent ranges between 10 and 20% leaving these individuals with little or no capacity to convert tamoxifen into clinically relevant metabolites. Several studies in postmenopausal patients with ER positive breast cancer including our own showed that patients with PM and IM genotypes had shorter relapse-free-time and event-free-survival when compared to patients with two functional CYP2D6 alleles (For review see Brauch et al. Breast Care 2008;3:43–50). In particular, our data from a group of 206 patients with adjuvant tamoxifen monotherapy showed that a decreased metabolizer status, i.e. carriers of CYP2D6 deficiency alleles (*4, *5, *10, *41) had significantly more breast cancer recurrences and shorter relapse-free time (HR=2.24; 95% CI: 1.16 to 4.33) and worse event-free-survival (HR 1.89, CI: 1.10 to 3.25) when compared with carriers of two functional CYP2D6 alleles. No such differences were observed in a control group of 280 patients without tamoxifen treatment (Schroth et al. Journal of Clinical Oncology 25:5187 to 5193, 2007). From this we conclude that genotyping of CYP2D6 disrupting gene variants allows the identification of breast cancer patients with PM and IM phenotypes who will have little or no benefit from adjuvant tamoxifen therapy.

Given alternative treatment options, i.e. tamoxifen versus aromatase inhibitor (AI), and based on available scientific and clinical evidence an individualized approach for the endocrine treatment of postmenopausal breast cancer is desirable. On the basis of the currently available evidence one might speculate that tamoxifen alone may be adequate for CYP2D6 EM/EM (wt/wt) carriers whereas postmenopausal patients with variant CYP2D6 alleles may fare better with upfront AI therapy. However, as of yet, formal recommendation on the integration of CYP2D6 genotypes in treatment decisions must await the validation in prospective clinical trials. Importantly, such validation studies in addition to the correlation of CYP2D6 genotype and clinical outcome must include the measurement of steady state endoxifen plasma levels as a surrogate of CYP2D6 phenotype in the patient group receiving tamoxifen. Moreover, the influence of co-medications such as antidepressants (for the relief of hot flashes frequently associated with tamoxifen treatment) known to inhibit CYP2D6 enzyme activity must be assessed. In Germany, we are currently recruiting postmenopausal ER positive breast cancer patients within the IKP211 observational study dedicated to the identification of tamoxifen and AI treatment outcome predictors. The study is part of the BMBF funded initiative „Improvement of Breast Cancer Diagnosis and Treatment Tübingen-Stuttgart“ and is supported by AGO-TraFo (Arbeitsgemeinschaft Gynäkologische Onkologie e.V., Kommission Translationale Forschung). Patients' inclusion criteria are adjuvant treatment with either tamoxifen (5 years or switch to AI after 2 years tamoxifen) or AI (5 years), respectively. It is expected, that these patient cohorts will allow a first confirmatory analysis of CYP2D6 genetics and metabolism, drug interaction and treatment outcome. Whether the determination of CYP2D6 genotype will be a diagnostic tool for the selection of the appropriate adjuvant hormonal therapy for the individual ER positive postmenopausal breast cancer patient awaits the validation in prospective clinical trials randomized for tamoxifen and AI treatment based on CYP2D6 genotypes. Such prospective clinical trials are currently being planned. Other open questions may address the clinical relevance of other cytochrome P450 isoenzymes and mutations as well as ethnic variation in the prevalence of their treatment outcome relevant genotypes.