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Background:

Epirubicin dosing affects important clinical outcomes in breast cancer, with higher dose regimens improving efficacy but producing more myelosuppression. Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). We previously reported relationships between UGT2B7’s promoter polymorphisms and epirubicin clearance and clinical outcomes in the (neo)adjuvant breast cancer setting; we identified a trend for increased grade 3/4 neutropenia but better efficacy outcomes in patients having at least one deficient allele (i.e. CT or CC) vs. patients who were wild type homozygotes. Patients homozygous for the deficient allele (CC) were at statistically significant increased risk for leucopenia compared to patients who were wild type homozygotes or heterozygotes. In this study we hypothesized patients with CT and TT genotypes would tolerate a higher epirubicin dose compared to CC genotype patients.

We designed this study to determine the safety of pharmacogenetic-guided epirubicin dosing for each UGT2B7 genotype.

Methods:

Female breast cancer patients with histologically confirmed non-metastatic invasive breast cancer scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting were enrolled into the study. Peripheral blood was analyzed for UGT2B7 genotype. Patients received standard dose IV FE100C during the first 21 day cycle. Based on genotype, epirubicin dosing was escalated in the 2nd and 3rd cycles.

Epirubicin Dose Escalation Scheme

 Dose of Epirubicin per Cycle (mg/m2) 
 Cycle 
Genotype 
CC 100 100 100 
CT 100 115 130 
TT 100 120 140 
 Dose of Epirubicin per Cycle (mg/m2) 
 Cycle 
Genotype 
CC 100 100 100 
CT 100 115 130 
TT 100 120 140 

Results:

To date 32 patients are evaluable for pharmacogenetic guided epirubicin dosing (8 CC genotypes, 14 CT genotypes and 10 TT genotypes). All 32 patients received epirubicin100 mg/m2 in cycle one and a single patient in each of the CC and CT genotypes experienced grade 3 febrile neutropenia and were not dose escalated. All other patients with CT and TT genotypes were dose escalated in cycle 2 and all but two patients in the CT and TT genotypes were dose escalated in cycle 3.

The incidence of febrile neutropenia was not dose dependent as all three genotypes had similar incidence in each cycle whereas leucopenia was genotype and dose dependent. The incidence of leukopenia increased in patients with CT and TT genotypes as their dose was increased and cycle 3 leukopenia rates were similar to patients with the CC genotype receiving standard dose epirubicin.

Conclusions:

Pharmacogenetic guided epirubicin dosing is well tolerated. This study is ongoing and updated data will be presented.

Citation Format: John R Mackey, Edith Pituskin, Ann Vlahadamis, Katia Tonkin, Karen King, Sanraj Basi, Maria Ho, Judith Meza-Junco, Anil Joy, Dick Au, Sambasivarao Damaraju, Michael B Sawyer. Pharmacogenetic dosing of epirubicin in FEC chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-48.

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