Virgili Manrique Anna C, Salazar Juliana, Arranz María Jesús, Bagué Silvia, Orellana Ruth, López-Pousa Antonio, Cerdà Paula, Gracia Isidre, Majercakova Katarina, Peiró Ana, Trullols Laura, Fernández Manuel, Valverde Sandra, Quintana María Jesús, Bell Olga, Artigas-Baleri Alícia, Sebio Ana
Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain.
Department of Medicine, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.
J Pers Med. 2022 Apr 11;12(4):618. doi: 10.3390/jpm12040618.
Neoadjuvant chemotherapy based on anthracyclines and ifosfamide for high-risk soft tissue sarcomas (STS) of the extremities and trunk is a controversial treatment option. There are substantial interindividual differences in clinical outcomes in patients treated with neoadjuvant chemotherapy. The aim of this study was to evaluate, as biomarkers, polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, or drug targets and their association with toxicity and survival in STS patients treated with neoadjuvant chemotherapy. We analysed variants in genes involved in anthracycline metabolism (, , , , and ) and in ifosfamide catabolism () in 79 treated patients. Two genes showed significant association after adjusted multivariate analysis: and . In patients treated with anthracyclines, rs3740066 was associated with risk of febrile neutropenia ( = 0.031), and with decreased overall survival (OS) ( = 0.024). rs2273697 was associated with recurrence-free survival (RFS) ( = 0.024). In patients treated with ifosfamide, rs3764435 was associated with RFS ( = 0.046). Our pharmacogenetic study shows for the first time that variants in genes regulating the metabolism of neoadjuvant chemotherapy may be helpful to predict toxicity and survival benefit in high-risk STS treated with neoadjuvant chemotherapy. Further validation studies are needed to establish their clinical utility.
基于蒽环类药物和异环磷酰胺的新辅助化疗用于治疗四肢和躯干的高危软组织肉瘤（STS）是一种存在争议的治疗选择。接受新辅助化疗的患者临床结局存在显著的个体差异。本研究的目的是评估编码药物代谢酶、药物转运体或药物靶点的基因多态性作为生物标志物及其与接受新辅助化疗的STS患者毒性和生存的相关性。我们分析了79例接受治疗患者中参与蒽环类药物代谢（、、、、和）以及异环磷酰胺分解代谢（）的基因变异。经过校正的多变量分析后，两个基因显示出显著相关性：和。在接受蒽环类药物治疗的患者中，rs3740066与发热性中性粒细胞减少风险相关（=0.031），并与总生存期（OS）降低相关（=0.024）。rs2273697与无复发生存期（RFS）相关（=0.024）。在接受异环磷酰胺治疗的患者中，rs3764435与RFS相关（=0.046）。我们的药物遗传学研究首次表明，调节新辅助化疗代谢的基因变异可能有助于预测接受新辅助化疗的高危STS患者的毒性和生存获益。需要进一步的验证研究来确定它们的临床实用性。
