Department of Cancer Pharmacology & Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, NC, USA.
Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA.
Pharmacogenomics J. 2024 Mar 4;24(2):6. doi: 10.1038/s41397-024-00328-z.
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) 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.
本研究旨在发现与癌症和白血病组 B（联盟）90401 中贝伐珠单抗相关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±贝伐珠单抗治疗。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）与胃肠道出血之间的因果风险评估进行评估。在 1008 名患者中，贝伐珠单抗（n=503）和安慰剂（n=505）治疗患者中分别有 9.5%和 3.8%发生 2 级或更高级别的胃肠道出血。贝伐珠单抗（P<0.001）和年龄（P=0.002）与胃肠道出血相关。在 616 名遗传估计为欧洲人的患者中（n=314 名贝伐珠单抗和 n=302 名安慰剂治疗患者），分别有 9.6%和 2.0%的患者发生 2 级或更高级别的胃肠道出血。一个 SNP（rs1478947；HR 6.26；95%CI 3.19-12.28；P=9.40×10）超过了 Bonferroni 校正的显著性。贝伐珠单抗治疗患者中 AA/AG 和 GG 基因型的 2 级或更高级别的胃肠道出血发生率分别为 33.3%和 6.2%，安慰剂组分别为 2.9%和 1.9%。需要对这些发现进行前瞻性验证和功能分析，以更好地了解遗传因素对治疗相关胃肠道出血的贡献。
