Search

Pharmacogenetic variants of the steroid hormone‐metabolizing enzyme cytochrome P450 2B6 (CYP2B6) were reported to be associated with breast cancer (BC) risk and prognosis. CYP2B6 expression is inducible by estradiol (E2) but induction was demonstrated only under steroid hormone‐deprived medium conditions. Physiological conditions, however, even under endocrinological BC treatment, do not correspond to complete steroid hormone depletion. The aim of this study was to investigate the E2‐mediated CYP2B6 and CYP1B1 regulation under various steroid hormone conditions, including physiological concentrations, in human oestrogen receptor positive (T47D, MCF‐7) and negative (MDA‐MB‐231) BC cell lines. We confirm that steroid‐deprived pre‐cultivation led to CYP2B6 upregulation in T47D, but not in MCF‐7. However, when pre‐cultivated with steroid‐containing medium CYP2B6 was downregulated in T47D and MCF‐7, while the addition of physiological E2 concentrations to steroid‐deprived medium resulted in a downregulation in T47D. In contrast, CYP1B1 was never downregulated in any culture condition. Thus, we show that E2‐mediated CYP2B6 regulation in BC cells depends on steroid hormone exposure in a cell line‐specific manner. Our data indicates the importance of being careful with conclusions drawn from CYP2B6 induction findings in vitro, as we demonstrate potential influences of hormonal changes on CYP2B6 expression, which could impact steroid hormone homeostasis and, consequently, BC risk. [ABSTRACT FROM AUTHOR]

Aims: Adverse drug reactions (ADRs) are known to show sex‐specific differences in occurrence and phenotype. The aim of this study was to analyse sex‐specific differences in ADR–drug combinations that required hospitalization based on two different datasets. Methods: We performed a complementary analysis of (i) spontaneously reported (n = 12 564, female = 51.7%) and (ii) systematically collected ADR reports from a prospective multicentre observational study (ADRED, n = 2355, female = 48.2%) from Germany in the ADR database EudraVigilance (EV). Both datasets were analysed separately concerning the suspected drugs, ADRs and ADR–drug combinations more frequently reported for females or males by calculating reporting odds ratios (ROR) with 95% confidence intervals. ADR–drug combinations more frequently reported for either females or males in EV reports were related to prescription data. Finally, the results from both datasets were discussed with regard to their (dis‐)concordance. Results: In both datasets, some antineoplastic agents and nervous system drugs were found to be reported more often for females than males (RORs ranging from 1.5 [1.1–2.1] for quetiapine in spontaneous reports to 41.3 [13.1–130.0] for trastuzumab in spontaneous reports). ADRs of the respiratory system, and haemorrhages were described predominantly for males in both datasets. In spontaneous reports the ADR–drug combination self‐injurious behaviour–quetiapine was more often reported for females without and with consideration of drug prescriptions (ROR: 3.8 [1.3–11.0]). Quetiapine and psychiatric disorders (superordinate level) was exclusively reported for females in ADRED reports. Conclusions: Our results can contribute to raise awareness and further knowledge regarding sex‐specific ADRs. The findings require further in‐depth investigation. [ABSTRACT FROM AUTHOR]

Introduction: Epirubicin is a common adjuvant treatment for breast cancer. It is mainly eliminated after glucuronidation through uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7). The present study aimed to describe the impact of the UGT2B7His268Tyr polymorphism on invasive disease-free survival in breast cancer patients after epirubicin treatment. Methods: This is a pharmacogenetic study based on samples collected from 745 breast cancer patients of the Austrian Tumor of breast tissue: Incidence, Genetics, and Environmental Risk factors (TIGER) cohort who did not present metastases at baseline. This cohort included 205 women with epirubicin-based combination chemotherapy, 113 patients having received chemotherapy without epirubicin and 427 patients having received no chemotherapy at all. Of the epirubicin-treated subgroup, 120 were subsequently treated with tamoxifen. For all women UGT2B7His268Tyr was genotyped. Invasive disease-free survival was assessed using Kaplan-Meier and Cox's proportional hazard regression analysis. Results: Among the 205 epirubicin-treated patients, carriers of two UGT2B7268Tyr alleles had a mean invasive disease-free survival of 8.6 (95% confidence interval (CI) 7.9 to 9.3) years as compared to 7.5 (95% CI 6.9 to 8.0) years in carriers of at least one UGT2B7268His allele (adjusted hazard ratio (HR) = 2.64 (95% CI 1.22 to 5.71); P = 0.014). In addition, the impact of the UGT2B7His268Tyr polymorphism became even more pronounced in patients subsequently treated with tamoxifen (adjusted HR = 5.22 (95% CI 1.67 to 26.04); P = 0.015) whereas no such difference in invasive disease-free survival was observed in patients not receiving epirubicin. Conclusions: Breast cancer patients carrying the UGT2B7268Tyr/Tyr genotype may benefit most from adjuvant epirubicin-based chemotherapy. These results warrant confirmation in further studies. [ABSTRACT FROM AUTHOR]