Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada; Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Division of Medical Oncology, Cross Cancer Institute, Edmonton, AB, Canada.
Clin Breast Cancer. 2021 Oct;21(5):e584-e593. doi: 10.1016/j.clbc.2021.03.001. Epub 2021 Mar 6.
Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients.
We studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FEC in the (neo)adjuvant setting. Patients received standard-dose FEC during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m or to 120 and 140 mg/m for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes.
Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin.
Pharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.
表阿霉素由尿苷二磷酸葡萄糖醛酸转移酶 2B7（UGT2B7）代谢。UGT2B7-161 启动子多态性中，纯合子（CC）患者清除率较低，与野生型纯合子（TT）或杂合子（CT）患者相比，白细胞减少症发生率显著较高。本研究旨在确定 TT 和 CT 基因型患者是否能耐受比 CC 基因型患者更高的表阿霉素剂量。
我们研究了组织学证实的非转移性、浸润性乳腺癌女性患者，她们计划在（新）辅助环境中接受至少三个周期的 FEC 治疗。患者在第 1 个 21 天周期中接受标准剂量的 FEC。根据基因型，在第 2 和第 3 个周期中，将表阿霉素剂量分别递增至 115 和 130 mg/m2，或递增至 CT 和 TT 基因型患者的 120 和 140 mg/m2。主要终点测量是骨髓抑制和剂量限制毒性。对这些终点与三种基因型进行了分析。
共纳入 45 例患者（10 例 CC、21 例 CT 和 14 例 TT 基因型），在第 1 个周期接受 100 mg/m2 表阿霉素治疗。第 2 和第 3 个周期分别有 12 例和 10 例 TT 患者进行剂量递增；第 2 和第 3 个周期分别有 16 例 CT 患者进行剂量递增。白细胞减少症，但非发热性中性粒细胞减少症，与基因型和剂量相关，且在 CT 和 TT 基因型患者中，随着剂量的增加而增加。然而，第 3 个周期的白细胞减少症发生率与接受标准剂量表阿霉素的 CC 基因型患者相似。
基于遗传药理学的表阿霉素剂量调整具有良好的耐受性，并允许在不增加毒性的情况下进行剂量递增。
