The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19–12.28; P = 9.40 × 10⁻⁸) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

本研究的目的是发现癌症和白血病 B 组（联盟）90401 中与贝伐单抗相关的胃肠道出血相关的临床和药物遗传学因素。转移性去势抵抗性前列腺癌患者接受多西他赛和泼尼松±贝伐单抗治疗。使用 Illumina HumanHap610-Quad 对患者进行基因分型，并使用单核苷酸多态性 (SNP) 与胃肠道出血之间关联的特定原因风险进行评估。在 1008 名患者中，接受贝伐珠单抗 ( n  = 503) 和安慰剂 ( n = 505) 治疗的患者分别有 9.5% 和 3.8% 发生 2 级或以上胃肠道出血 。贝伐单抗（P  <0.001）和年龄（P  =0.002）与胃肠道出血相关。在 616 名经过基因评估的欧洲人中（n  = 314 名接受贝伐珠单抗治疗的患者和n  = 302 名接受安慰剂治疗的患者），分别有 9.6% 和 2.0% 的患者发生 2 级或以上胃肠道出血。一个 SNP（rs1478947；HR 6.26；95% CI 3.19–12.28；P  = 9.40 × 10 ^-8）超过了 Bonferroni 校正的显着性。接受贝伐珠单抗治疗的 AA/AG 和 GG 基因型患者的 2 级或以上胃肠道出血发生率分别为 33.3% 和 6.2%，而安慰剂组的这一比例分别为 2.9% 和 1.9%。需要对这些发现进行前瞻性验证和功能分析，以更好地了解遗传对治疗相关胃肠道出血的影响。