CYP2D6 Genotype Predicts Tamoxifen Discontinuation and Prognosis in Patients With Breast Cancer

Abstract

PURPOSE To examine the association between CYP2D6 genotype, discontinuation of tamoxifen therapy, and prognosis for breast cancer. PATIENTS AND METHODS We conducted a prospective-retrospective study linking data from a clinical breast cancer register, the Swedish Prescribed Drug Register, and self-reported questionnaires. We genotyped CYP2D6 in 1,309 patients with breast cancer who were treated with tamoxifen and were diagnosed from 2005 to 2012; they were categorized as poor, intermediate, normal, or ultrarapid CYP2D6 metabolizers. We investigated whether metabolizer status was associated with tamoxifen discontinuation and prognosis for breast cancer using Cox regression analysis. RESULTS The 6-month discontinuation rates of tamoxifen among poor, intermediate, normal, and ultrarapid CYP2D6 metabolizers were 7.1%, 7.6%, 6.7%, and 18.8%, respectively. A U-shaped association was found between CYP2D6 metabolizer status and breast cancer–specific mortality, with adjusted hazard ratios of 2.59 (95% CI, 1.01 to 6.67) for poor, 1.48 (95% CI, 0.72 to 3.05) for intermediate, 1 (reference) for normal, and 4.52 (95% CI, 1.42 to 14.37) for ultrarapid CYP2D6 metabolizers. CONCLUSION Both poor and ultrarapid CYP2D6 metabolizers of tamoxifen have a worse prognosis for breast cancer compared with normal metabolizers after receiving a standard dose of tamoxifen. This U-shaped association might call for individualized tamoxifen dosage.

Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

“…30 More evidence for a concentration-dependent risk of adverse effects to the standard dose of tamoxifen comes from recent Swedish data, showing that patients genotyped as CYP2D6 UM, and thereby expected to have higher endoxifen levels at the standard dose of tamoxifen 31 seemed to experience more severe side effects 29,32 and that this would increase the risk of early treatment discontinuation during the first 6 months. 29 Our study has some important limitations. We believe that the obvious limitation of this study is the limited size, and therefore many of our statistically significant findings will require confirmation in larger study settings.…”

Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

“…This was significantly higher than the discontinuation rate of NMs (6.7%) [ 78 ]. At the same time point, no significant difference in tamoxifen discontinuation was found for PMs (7.1%) or IMs (7.6%), as compared to NMs (6.7%) [ 78 ].…”

“…Multivariate analyses showed that about 47% of tamoxifen plasma concentration variability is explained by patient adherence behavior; in addition, the combination of CYP2D6 genotype and adherence behavior explained 40% of endoxifen plasma concentration variability at 12 months [71]. He et al [78] investigated the relationship between CYP2D6 metabolizer status and tamoxifen discontinuation in a prospective-retrospective study, showing that UMs had a discontinuation rate of 18.8% at 6 months after the start of tamoxifen treatment. This was significantly higher than the discontinuation rate of NMs (6.7%) [78].…”

“…He et al [ 78 ] investigated the relationship between CYP2D6 metabolizer status and tamoxifen discontinuation in a prospective–retrospective study, showing that UMs had a discontinuation rate of 18.8% at 6 months after the start of tamoxifen treatment. This was significantly higher than the discontinuation rate of NMs (6.7%) [ 78 ]. At the same time point, no significant difference in tamoxifen discontinuation was found for PMs (7.1%) or IMs (7.6%), as compared to NMs (6.7%) [ 78 ].…”

Enriching Medication Review with a Pharmacogenetic Profile – A Case of Tamoxifen Adverse Drug Reactions

“…There are data suggesting that despite the enhanced activation of TAM to END in patients with UM status, this status is linked to a higher intake of symptom-relieving drugs (antinausea, anxiolytics, medications for relief from hot flushes), a higher frequency of early treatment discontinuation, and a worse prognosis for breast cancer compared to extensive metabolizers. 25 …”