Pharmacogenetics of epirubicin and uridine glucuronosyltransferase 2B7 in early breast cancer patients
John R. MackeyS. DamarajuEdith PituskinAndrew ScarfeK. TonkinH. AuSheryl KoskiA. A. JoyJane HansonMichael B. Sawyer
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2015 Background: Anthracyclines are widely used for the treatment of breast cancer. Unlike doxorubicin, the major mechanism of epirubicin inactivation is metabolism to inactive glucuronides by uridine glucuronosyltransferase (UGT) 2B7. A polymorphism has been discovered at position -161 T to C in the enhancer region which correlated with efficacy of morphine glucuronidation (Sawyer et al. Clin Pharmcol Ther 2003). Methods: We have carried out a prospective pharmacogenetic study of epirubicin metabolism in M0 breast cancer patients treated with adjuvant or neoadjuvant FEC100 (5-fluorouracil 500 mg/m2, Epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2) given every 3 weeks. Patients did not receive prophylactic G-CSF. Drug levels were drawn at 1 and 24 hours. Patients were followed during cycle 1 for toxicity, graded according to the NCIC CTC criteria. To date 102 patients have been enrolled to date out of a planned sample of 120. Patient characteristics-median (range): age 50 (28 - 67), sex 101 F/ 1 M, baseline AST 22 U/L (13–66), ALT 21 U/L (5–90), bilirubin 7 μmol/L (2–24), creatinine 73 μmol/L (51 - 126). Results: 24 patients were TT homozygotes, 55 were CT heterozygotes, and 23 were CC homozygotes. There was no relationship between nausea, vomiting or mucositis and UGT2B7 genotype. The mean neutrophil survival fraction was 14%, 11% and 8% for TT, CT, and CC genotypes (p=0.3, ANOVA test). There was a trend for increased grade 3/4neutropenia in patients having at least one deficient allele (i.e. CT or CC) vs. wild type homozygous (TT) (p=0.1, Chi square test). Patients with a deficient allele (CT or CC) were at increased risk for grade 3/4 leucopenia compared to TT homozygotes (p=0.01, Chi square test). Conclusions: The preliminary analysis of this prospective pharmacogenetic study suggested that the UGT2B7 -161 C/T SNP predicts for grade 3/4 leucopenia in women treated with FEC100. Studies of this UGT2B7 polymorphism as a predictor of epirubicin toxicity and efficacy are warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer PfizerKeywords:
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Limited evidence suggests that inherited predisposing risk variants might affect the disease outcome. In this study, we analyzed the effect of genome-wide association studies—identified breast cancer-risk single nucleotide polymorphisms on survival of early-stage breast cancer patients in a Chinese population. This retrospective study investigated the relationship between 21 GWAS-identified breast cancer-risk single nucleotide polymorphisms and the outcome of 1177 early stage breast cancer patients with a long median follow-up time of 174 months. Cox proportional hazards regression models were used to estimate the hazard ratios and their 95% confidence intervals. Primary endpoints were breast cancer special survival and overall survival while secondary endpoints were invasive disease free survival and distant disease free survival. Multivariate survival analysis showed only the rs2046210 GA genotype significantly decreased the risk of recurrence and death for early stage breast cancer. After grouping breast cancer subtypes, significantly reduced survival was associated with the variant alleles of rs9485372 for luminal A and rs4415084 for triple negative breast cancer. Importantly, all three single-nucleotide polymorphisms, rs889312, rs4951011 and rs9485372 had remarkable effects on survival of luminal B EBC, either individually or synergistically. Furthermore, statistically significant multiplicative interactions were found between rs4415084 and age at diagnosis and between rs3803662 and tumor grade. Our results demonstrate that breast cancer risk susceptibility loci identified by GWAS may influence the outcome of early stage breast cancer patients’ depending on intrinsic tumor subtypes in Chinese women.
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The French Epirubicin Study Group carried out a randomized trial comparing epirubicin alone 75 mg/m2 with fluorouracil (5FU) 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 50 mg/m2 (FEC 50) and 5FU 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 75 mg/m2 (FEC 75) as first treatment for advanced breast cancer patients. Patients were stratified according to whether or not there were bone metastases only. Four hundred twelve patients entered this trial; 378 were assessable for tolerability and 365 for efficacy. The overall response rates were comparable between FEC 50 (44.6%) and FEC 75 (44.7%), but both were better than the epirubicin alone (30.6%) (P = .04 and P = .0006, respectively). The complete response rate was better in FEC 75 (15.5%) than in FEC 50 (7%) (P = .025) or epirubicin (4%) (P = .002). Similar results were obtained in the group of patients without bone-only metastases. No difference in the three treatments was observed in the patients with bone metastases only. Mean durations of response were similar in the three groups, being 412 days, 440 days, and 350 days for FEC 50, FEC 75, and epirubicin, respectively. Patients without previous adjuvant chemotherapy fared better than those with previous treatment (without anthracyclines). Tolerability was fair in the three groups. Overall, the epirubicin-alone group showed better tolerance than the two other groups, which did not differ significantly. Time to progression and survival were not different among the three groups, but more early relapses occurred in the epirubicin and FEC 50 groups; survival seemed to be better during the first 8 months in the FEC 75 group, and the survival difference between the epirubicin group and the FEC 75 group was of borderline significance. No difference in survival was observed between epirubicin- and FEC 50-group patients, even though the response rate was significantly worse in the monochemotherapy group.
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Objective To develop a method of determining the characteristics of epirubicin resistance and to study the reversal of such resistance in the intravesical treatment of superficial bladder cancer, using sensitive and resistant derivatives of a bladder cancer cell line in vitro . Materials and methods Epirubicin fluorescence and flow cytometry were used to measure the intracellular levels of epirubicin in both sensitive and resistant live cultured bladder tumour cells, with and without different doses of the resistance‐reversing agent verapamil. Results There was a reliable, highly significant and consistent difference in intracellular epirubicin concentration between the resistant and sensitive bladder tumour cells. In addition, it was possible to substantially reverse the features of resistant cell subline with additional verapamil. Conclusion Application of this assay to clinical specimens should allow better targeting of epirubicin intravesical chemotherapy and avoid the premature termination of such treatment in patients whose tumours remain sensitive to this agent. Furthermore, the addition of verapamil to intravesical epirubicin may permit effective treatment of those patients whose tumours have inherent or acquired resistance to epirubicin.
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進行乳癌に対するepirubicinの動脈内注入療法(以下,動注)中に動脈支配領域に一致して皮膚病変のみられた56歳女性例を報告した。右乳癌の術前動注療法として,右鎖骨下動脈及び内胸動脈へのepirubicin 70 mgの週1回のone shot動注療法を3回施行後より右前胸部に紅斑が出現し当科を受診。初診時,動脈支配領域に一致して壊死性潰瘍,紅斑および色素沈着が認められ,紅斑部の生検で表皮に加え汗腺の壊死性変化が認められた。epirubicinはdoxorubicin(ADM)の副作用を軽減する目的で開発されたADMの誘導体で,近年局所進行乳癌に対する動注療法において,ADMにとって代わる薬剤となっている。血管内カテーテルや動注リザーバーの開発と進歩により,動注化学療法は多用される傾向にあり今回のような症例が増加するものと考えられる。
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Abstract Breast cancer is a frequent female malignant tumor with high mortality and poor prognosis. Peroxidasin like (PXDNL) has many biological functions, including characteristic activity of hormone biosynthesis, host defense, and cell motility. In addition, PXDNL is closely connected with the progression of breast cancer. In this study, we found that PXDNL may be an independent prognostic biomarker of breast cancer. We tested the mRNA expression of PXDNL in breast cancer by detecting The Cancer Genome Atlas (TCGA) database. The chi-squared test was used to evaluate clinical correlation. The receiver operating characteristic (ROC) curves were drawn to evaluate diagnosis potential in breast cancer. Subsequently, survival analyses were performed to identify the relevance between the expression of PXDNL and the overall survival/relapse-free survival of patients with breast cancer. Univariate/multivariate Cox regression model was executed to detect risk factors affecting the prognosis of patients with breast cancer. PXDNL is highly expressed in breast cancer tissues and is related to survival status of patients. The ROC curve showed that PXDNL had beneficial diagnostic ability in breast cancer. Survival analysis indicated that patients with breast cancer with high PXDNL expression generally had decreased overall survival/relapse-free survival. Univariate/multivariate Cox model analyses further suggested an association between PXDNL expression and prognosis of patients with breast cancer. High PXDNL expression is a potential and independent prognostic biomarker in breast cancer.
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ΣΤΗΝ ΠΑΡΟΥΣΑ ΕΛΕΓΧΟΜΕΝΗ ΜΕΛΕΤΗ ΜΕ ΠΡΟΟΠΤΙΚΗ ΕΚΤΙΜΗΘΗΚΕ Η ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ ΤΩΝΕΝΔΟΚΥΣΤΙΚΩΝ ΕΓΧΥΣΕΩΝ EPIRUBICIN ΣΤΗΝ ΠΡΟΦΥΛΑΞΗ ΑΠΟ ΤΙΣ ΥΠΟΤΡΟΠΕΣ ΤΩΝ ΕΠΙΦΑΝΕΙΑΚΩΝ ΟΓΚΩΝ ΤΗΣ ΟΥΡΟΔΟΧΟΥ ΚΥΣΤΕΩΣ (ΣΤΑΔΙΟ ΤΑ, Τ1). ΑΠΟ ΤΟΥΣ 99 ΣΥΝΟΛΙΚΑ ΑΣΘΕΝΕΙΣ, ΟΙ 67 ΥΠΟΒΛΗΘΗΚΑΝ ΣΕ 6 ΕΒΔΟΜΑΔΙΑΙΕΣ ΕΓΧΥΣΕΙΣ 50 MG EPIRUBICIN ΜΕΤΑ ΤΗ ΔΙΟΥΡΗΘΡΙΚΗ ΑΦΑΙΡΕΣΗ ΟΛΩΝ ΤΩΝ ΝΕΟΠΛΑΣΜΑΤΩΝ(ΟΜΑΔΑ Α), ΕΝΩ ΣΤΟΥΣ ΥΠΟΛΟΙΠΟΥΣ 32 (ΟΜΑΔΑ Β) ΕΓΙΝΕ ΜΟΝΟ ΔΙΟΥΡΗΘΡΙΚΗ ΑΦΑΙΡΕΣΗ. ΤΟ ΠΟΣΟΣΤΟ ΤΩΝ ΥΠΟΤΡΟΠΩΝ ΗΤΑΝ 40% ΓΙΑ ΤΗΝ ΟΜΑΔΑ Α ΚΑΙ 59% ΓΙΑ ΤΗΝ ΟΜΑΔΑ Β ΚΑΙ ΓΙΑ ΣΥΝΟΛΙΚΟ ΧΡΟΝΟ ΠΑΡΑΚΟΛΟΥΘΗΣΕΩΣ1307 ΚΑΙ 393 ΜΗΝΕΣ ΓΙΑ ΤΙΣ ΔΥΟ ΟΜΑΔΕΣ, ΑΝΤΙΣΤΟΙΧΑ. ΑΥΤΗ Η ΔΙΑΦΟΡΑ ΔΕΝ ΗΤΑΝ ΣΤΑΤΙΣΤΙΚΑ ΣΗΜΑΝΤΙΚΗ (Ρ>0.05), ΟΤΑΝ ΟΜΩΣ ΟΙ ΑΣΘΕΝΕΙΣ ΕΞΕΤΑΣΤΗΚΑΝ ΜΕ ΔΙΑΦΟΡΕΤΙΚΟΤΡΟΠΟ, ΔΗΛΑΔΗ ΟΤΑΝ ΣΥΓΚΡΙΘΗΚΑΝ Ο ΣΧΕΤΙΚΟΣ ΚΙΝΔΥΝΟΣ ΥΠΟΤΡΟΠΩΝ, Η ΣΥΧΝΟΤΗΤΑ ΤΩΝ ΝΕΟΠΛΑΣΜΑΤΙΚΩΝ ΥΠΟΤΡΟΠΩΝ ΑΝΑ 100 ΜΗΝΕΣ ΑΣΘΕΝΩΝ ΗΤΑΝ 1.55 ΚΑΙ 3.15 ΑΝΤΙΣΤΟΙΧΑ, ΕΝΩ Ο ΜΕΣΟΣ ΧΡΟΝΟΣ ΕΜΦΑΝΙΣΕΩΣ ΤΩΝ ΥΠΟΤΡΟΠΩΝ ΗΤΑΝ 16.2 ΚΑΙ 11.05 ΜΗΝΕΣ, ΑΝΤΙΣΤΟΙΧΑ. ΤΟΤΕ ΤΑ ΑΠΟΤΕΛΕΣΜΑΤΑ ΗΤΑΝ ΣΤΑΤΙΣΤΙΚΩΣ ΣΗΜΑΝΤΙΚΑ ΥΠΕΡ ΤΗΣ ΟΜΑΔΑΣ ΤΟΥ EPIRUBICIN (ΟΜΑΔΑ Α). Η ΚΥΡΙΟΤΕΡΗ ΠΑΡΕΝΕΡΓΕΙΑ ΤΩΝ ΕΓΧΥΣΕΩΝ EPIRUBICIN ΗΤΑΝ Η ΧΗΜΙΚΗ ΚΥΣΤΙΤΙΔΑ, Η ΣΥΧΝΟΤΗΤΑ ΚΑΙ Ο ΒΑΘΜΟΣ ΤΗΣ ΟΠΟΙΑΣ ΑΥΞΑΝΕ ΣΗΜΑΝΤΙΚΑ ΜΕΤΑ ΤΗΝ 4Η ΕΓΧΥΣΗ ΤΟΥ ΦΑΡΜΑΚΟΥ. ΣΥΜΠΕΡΑΙΝΕΤΑΙ, ΟΤΙ Η EPIRUBICIN ΕΛΑΤΤΩΝΕΙ ΣΗΜΑΝΤΙΚΑ ΤΟ ΠΟΣΟΣΤΟ ΤΩΝ ΥΠΟΤΡΟΠΩΝ ΚΑΙ ΤΟΝ ΑΡΙΘΜΟ ΤΩΝ ΥΠΟΤΡΟΠΙΑΖΟΝΤΩΝ ΟΓΚΩΝ, ΕΝΩ ΣΑΦΩΣΕΠΙΜΗΚΥΝΕΙ ΤΟ ΧΡΟΝΟ ΕΜΦΑΝΙΣΕΩΣ ΤΩΝ ΤΕΛΕΥΤΑΙΩΝ.
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