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.
The pharmacogenomics journal. 2024 Mar 04*** epublish ***
Jai N Patel, Chen Jiang, Kouros Owzar, Daniel L Hertz, Janey Wang, Flora A Mulkey, William K Kelly, Susan Halabi, Yoichi Furukawa, Cameron Lassiter, Susan G Dorsey, Paula N Friedman, Eric J Small, Michael A Carducci, Michael J Kelley, Yusuke Nakamura, Michiaki Kubo, Mark J Ratain, Michael J Morris, Howard L McLeod
Department of Cancer Pharmacology & Pharmacogenomics, Atrium Health Levine Cancer Institute, Charlotte, NC, USA. ., Alliance Statistics and Data Management Center, Duke University, Durham, NC, USA., Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA., Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA., Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA., Institute of Medical Science, The University of Tokyo, Tokyo, Japan., University of Maryland School of Nursing (Miltenyi Biotech at time of publication), Baltimore, MD, USA., Department of Pharmacology and Center for Pharmacogenomics, Northwestern University, Evanston, IL, USA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA., Durham VA Medical Center/Duke University Medical Center, Durham, NC, USA., Center for Personalized Therapeutics, University of Chicago (Japanese Foundation for Cancer Research, Ariake, Tokyo at time of publication), Chicago, IL, USA., Riken Center for Integrative Medical Sciences (Haradoi Hospital, Fukuoka, Japan at time of publication), Kanagawa, Japan., Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Utah Tech University, St. George, UT, USA.