Azienda Policlinico Umberto I Roma, Roma, Italy.
Azienda Ospedaliera Sant'Andrea, Roma, Lazio, Italy.
J Oncol Pharm Pract. 2020 Dec;26(8):1836-1842. doi: 10.1177/1078155220904999. Epub 2020 Mar 4.
Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3-4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II-IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3-4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1-37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3-4 adverse events (OR = 10.40 [95% IC: 1.48-7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3-4 toxicity occurrence (OR = 10.9 [95% IC 1.2-96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity.
卡培他滨是一种 5-氟尿嘧啶的口服前体药物，在乳腺癌的治疗中具有重要作用。卡培他滨相关的严重和意外毒性并不罕见，且生物标志物的鉴定具有挑战性。我们评估了二氢嘧啶脱氢酶、胸苷酸合成酶增强子区和亚甲基四氢叶酸还原酶多态性、5-氟尿嘧啶降解率与乳腺癌患者 G3-4 毒性发生之间的关系。本研究回顾性研究了接受卡培他滨治疗的乳腺癌患者的遗传多态性和 5-氟尿嘧啶降解率。遗传标记物和 5-氟尿嘧啶降解率与报告的毒性相关。本研究纳入了 37 名中位年龄为 58 岁的接受卡培他滨治疗 II-IV 期乳腺癌的患者。总体而言，34 名（91.9%）患者至少发生了任何级别毒性，9 名患者发生了 G3-4 毒性。纯合子亚甲基四氢叶酸还原酶 677TT 与血液学毒性显著相关（OR=6.5[95%CI 1.1-37.5]，P=0.04）。有 3 名患者的 5-氟尿嘧啶降解率小于 0.86ng/mL/106 细胞/分钟，3 名患者大于 2.1ng/mL/106 细胞/分钟。在单变量逻辑回归分析中，5-氟尿嘧啶降解率的改变值（<0.86 或>2.10ng/mL/106 细胞/分钟）增加了 G3-4 不良事件的风险（OR=10.40[95%CI：1.48-7.99]，P=0.02）。在调整年龄、合并症和 CAPE 方案后进行多变量逻辑回归分析，确认 5-氟尿嘧啶降解率作为 G3-4 毒性发生的预测因子（OR=10.9[95%CI 1.2-96.2]，P=0.03）。5-氟尿嘧啶降解率的治疗前评估可识别出发生严重 5-FU 毒性风险较高的乳腺癌患者。
