Cremolini Chiara, Del Re Marzia, Antoniotti Carlotta, Lonardi Sara, Bergamo Francesca, Loupakis Fotios, Borelli Beatrice, Marmorino Federica, Citi Valentina, Cortesi Enrico, Moretto Roberto, Ronzoni Monica, Tomasello Gianluca, Zaniboni Alberto, Racca Patrizia, Buonadonna Angela, Allegrini Giacomo, Ricci Vincenzo, Di Donato Samantha, Zagonel Vittorina, Boni Luca, Falcone Alfredo, Danesi Romano
Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Istituto Toscano Tumori, Pisa, Italy.
Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Oncotarget. 2017 Dec 21;9(8):7859-7866. doi: 10.18632/oncotarget.23559. eCollection 2018 Jan 30.
Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e., FOLFIRI or FOLFOXIRI) plus bevacizumab in the randomized clinical trial TRIBE by GONO (clinicaltrials.gov: NCT00719797), in which adverse events were carefully and prospectively collected at each treatment cycle. Here we show that patients bearing c.1905+1G/A and c.2846A/T genotypes, together with UGT1A1*28 variant carriers, have an increased risk of experiencing clinically relevant toxicities, including hematological AEs and stomatitis. No carrier of the c.1679T>G minor allele was identified. Present results support the preemptive screening of mentioned and variants to identify patients at risk of clinically relevant 5-fluoruracil- and irinotecan-related AEs, in order to improve treatments' safety through a "genotype-guided" approach.
我们的研究探讨了三种候选二氢嘧啶脱氢酶（DPYD）和一种尿苷二磷酸葡萄糖醛酸基转移酶（UGT）单核苷酸多态性在预测5-氟尿嘧啶和伊立替康相关不良事件方面的临床可靠性问题。为此，我们利用了一大群转移性结直肠癌患者，这些患者在GONO进行的随机临床试验TRIBE（clinicaltrials.gov：NCT00719797）中接受了一线基于5-氟尿嘧啶和伊立替康的化疗方案（即FOLFIRI或FOLFOXIRI）加贝伐单抗治疗，在每个治疗周期中都仔细且前瞻性地收集了不良事件。在此我们表明，携带c.1905 +1G/A和c.2846A/T基因型的患者以及UGT1A1 *28变异携带者发生临床相关毒性的风险增加，包括血液学不良事件和口腔炎。未鉴定出c.1679T>G次要等位基因的携带者。目前的结果支持对上述变异进行前瞻性筛查，以识别有临床相关5-氟尿嘧啶和伊立替康相关不良事件风险的患者，以便通过“基因型指导”方法提高治疗的安全性。
