Centers and Institutes
Published March 4, 2024 | Version v1
Journal article Open

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance)

Creators

  • 1. Atrium Health Levine Cancer Institute
  • 2. Duke University
  • 3. University of Michigan
  • 4. Vanderbilt University
  • 5. Thomas Jefferson University
  • 6. University of Tokyo
  • 7. Miltenyi Biotech
  • 8. Northwestern University
  • 9. University of California, San Francisco
  • 10. Sidney Kimmel Comprehensive Cancer Center
  • 11. Durham VA Medical Center
  • 12. University of Chicago
  • 13. Haradoi Hospital
  • 14. Memorial Sloan Kettering Cancer Center
  • 15. Utah Tech University

Description

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.

Data availability

Genotype data are available at dbGap (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id¼phs001002.v1.p1). Details regarding the CALGB 90401 parent study can be found at: Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol. 2012;30: 1534-1540. Additional data may be requested from the corresponding author (JNP).

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Additional details

Identifiers

DOI
10.1038/s41397-024-00328-z
Other
oai:uchicago.tind.io:11304

Funding

National Cancer Institute
U10CA180821
National Cancer Institute
U10CA180882
National Cancer Institute
U24CA196171
National Cancer Institute
UG1CA233160
National Cancer Institute
UG1CA233253
National Cancer Institute
UG1CA233270
National Cancer Institute
UG1CA233290
National Cancer Institute
UG1CA233320
National Cancer Institute
UG1CA233327
National Cancer Institute
UG1CA233341
National Cancer Institute
UG1CA233373
Pharmacogenomics Research Network
GM61390
National Institute of General Medical Sciences
Pharmacogenomics of Anticancer Agents
National Institute of Nursing Research
P30NR014129
National Institute of Nursing Research
UG1CA233196
National Institute of Nursing Research
U10CA180820
Genentech
The Carolina Consortium

UChicago Information

Division(s)
Biological Sciences Division
Center(s) or Institute(s)
Center for Personalized Therapeutics