Abstract 2037: A discovery study to identify clinical and genetic risk factors for bevacizumab (BEV)-related gastrointestinal (GI) hemorrhage (HEM) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated on CALGB 90401 (Alliance)
Authors: Patel Jai N. , Jiang Chen , Owzar Kouros , Hertz Daniel L. , Mulkey Flora A. , Kelly William K. , Halabi Susan , Furukawa Yoichi , Lassiter Cameron , Dorsey Susan G. , Friedman Paula N. , Small Eric J. , Carducci Michael A. , Mahoney John F. , Kelley Michael J. , Nakamura Yusuke , Kubo Michiaki , Ratain Mark J. , Morris Michael J. , McLeod Howard L. 
Published: July 2016

Background: Treatment-related GI HEM is a major health concern with few known predictive risk factors. The objective of this analysis was to discover clinical and genetic factors that modulate GI HEM risk in a large randomized phase III study.

Methods: Chemotherapy-naïve mCRPC pts were randomized 1:1 to receive docetaxel and prednisone ± BEV once every 21 days for up to two years (N = 1008). Cause-specific time-to-event analysis using a Cox regression model was used to investigate the association between grade 2+ GI HEM (designated as at least “probably” related to therapy) and BEV, age, history (hx) of peptic ulcer disease (PUD), hx of HEM, antiplatelet/anticoagulant use, hx of smoking, and hemoglobin. Genetically-defined Caucasian pts who provided consent for the genomic companion study (CALGB 60404) were genotyped using the Illumina HumanHap610-Quad platform (N = 616). Log rank test was used to investigate the association of single nucleotide polymorphisms (SNPs) and GI HEM, and results were adjusted for significant clinical covariates.

Results: The overall incidence of grade 2+ GI HEM was 9.5% (48/503) and 3.8% (19/505) in the BEV and placebo arms, respectively. Of the clinical covariates, only BEV (HR = 5.77; 95% CI 2.20-15.11; P&lt;0.001) and age (HR = 1.06; 95% CI 1.01-1.11; P = 0.01) were significantly associated with GI HEM in the multivariable analysis, while a trend was noted for hx of PUD (P = 0.08). Of 498,081 SNPs tested, one intergenic SNP (rs1478947; HR 6.26; 95% CI 3.00-14.4; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance (1.0 × 10-7) for association with GI HEM (minor allele frequency = 0.06). The incidence of GI HEM in the BEV arm was 33.3% (13/39) and 6.2% (17/275) for pts with the AA/AG and GG genotypes, while the incidence in the placebo arm was 2.9% (1/35) and 1.9% (5/267), respectively.

Conclusion: BEV, age, and one putative intergenic SNP (rs1478947) were associated with cause-specific GI HEM risk in CALGB 90401. The effect of rs1478947 appears to be specific to pts receiving BEV. Although the mechanism by which rs1478947 increases GI HEM risk remains unclear, rs1478947 is in complete LD (r2 = 1) with rs1478948, variations of which may alter the binding motif for transcription factor hepatocyte nuclear factor-4 (HNF4). HNF4 exerts a major regulatory effect on clotting factor VII (fVII) expression and function. Altered binding of HNF4 to fVII promoter may result in reduced fVII function and an increased risk of bleeding. It is unclear how much weight each identified risk factor contributes to the overall incidence of GI HEM, which in absolute terms was not dramatically different between arms. Exploratory studies from large trials of BEV-treated pts are needed to better understand the genetic contribution to and biological basis of GI HEM. Support: U10CA180821

Citation Format: Jai N. Patel, Chen Jiang, Kouros Owzar, Daniel L. Hertz, Flora A. Mulkey, William K. Kelly, Susan Halabi, Yoichi Furukawa, Cameron Lassiter, Susan G. Dorsey, Paula N. Friedman, Eric J. Small, Michael A. Carducci, John F. Mahoney, Michael J. Kelley, Yusuke Nakamura, Michiaki Kubo, Mark J. Ratain, Michael J. Morris, Howard L. McLeod. A discovery study to identify clinical and genetic risk factors for bevacizumab (BEV)-related gastrointestinal (GI) hemorrhage (HEM) in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated on CALGB 90401 (Alliance). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2037.