目的:在标准剂量下,携带某些DPYD基因变异的患者中,氟嘧啶相关毒性和死亡风险显著增加。我们在多中心癌症中心实施了DPYD基因分型,并评估了其对剂量的影响。毒性,和住院。
方法:在这项前瞻性观察研究中,接受(反应性)或计划接受(预处理)基于氟嘧啶的化疗的患者根据提供者的判断对5种DPYD变异体进行基因分型,作为标准实践.主要终点是接受氟嘧啶修饰的变体载体的比例。次要终点包括平均相对剂量强度,氟嘧啶相关的3级+毒性,和住院。费希尔精确检验比较了预处理载体之间的毒性和住院率,反应性载流子,和野生型患者。单变量和多变量逻辑回归确定了与毒性和住院风险相关的因素。Kaplan-Meier方法估计到一级3+毒性事件和住院的时间。
结果:在接受DPYD基因分型的757名患者中(中位年龄63岁,男性54%,74%白色,19%黑色,88%的胃肠道恶性肿瘤),45例(5.9%)为杂合携带者。93%的开始治疗的携带者对氟嘧啶进行了修饰。在442例3个月随访的患者中,64%,31%,和30%的活性载体,预处理载体,野生型患者有3+级毒性,分别为(P=0.085);64%,25%,13%住院(P<.001)。与野生型患者相比,反应携带者的住院几率高10倍(P=0.001),而治疗前携带者和野生型患者之间没有显著差异.发生毒性事件的时间和住院时间在基因型组之间存在显着差异(P<0.001),反应性携带者发病最早,发病率最高。
结论:DPYD基因分型在大多数携带者中促进了氟嘧啶修饰。与反应性测试相比,治疗前测试降低了毒性和住院率,从而使野生型患者的风险正常化,应被视为标准做法。
OBJECTIVE: Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization.
METHODS: In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher\'s exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization.
RESULTS: Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence.
CONCLUSIONS: DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.