Genome‐wide association studies of survival in 1520 cancer patients treated with bevacizumab‐containing regimens

Abstract

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta‐analysis of genome‐wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause‐specific Cox model was used to test the SNP‐OS association in both arms combined (prognostic), and the effect of SNPs‐bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta‐analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10−7, hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33‐1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07‐2.35). In the GWAS meta‐analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10−5, HR = 1.51, 95% CI 1.25‐1.82) as well as in TCGA (P = 1.39 × 10−4, HR = 3.09, 95% CI 1.73‐5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10−5). The largest GWAS meta‐analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.

PRUNE2 inhibits progression of colorectal cancer in vitro and in vivo

“…Although most prior studies have reported that PRUNE2 expression is decreased in various types of cancer ( 6 , 10 , 11 , 16 ), including prostate cancer, neuroblastoma and leiomyosarcoma, few studies have investigated PRUNE2 expression in CRC. Low PRUNE2 expression is associated with poor long-term clinical outcomes in patients with CRC ( 20 ). Meta-analysis of patients treated with bevacizumab identified PRUNE2 as a prognostic biomarker for CRC ( 20 ).…”

“…Low PRUNE2 expression is associated with poor long-term clinical outcomes in patients with CRC ( 20 ). Meta-analysis of patients treated with bevacizumab identified PRUNE2 as a prognostic biomarker for CRC ( 20 ). This supports the hypothesis that PRUNE2 serves as tumor suppressor gene of CRC.…”

ALOX12: A Novel Insight in Bevacizumab Response, Immunotherapy Effect, and Prognosis of Colorectal Cancer

“…Unfortunately, despite the dramatic benefits in mCRC treatment, the molecular mechanism of bevacizumab is still unclear. Recently, Quintanilha et al have reported that rs3795897 (G>A) in AGAP1 might be a potential predictor related to bevacizumab and patient survival (8). It is worth noting that no bevacizumab response biomarker for CRC was reported before (8,9).…”

“…Recently, Quintanilha et al. have reported that rs3795897 (G>A) in AGAP1 might be a potential predictor related to bevacizumab and patient survival ( 8 ). It is worth noting that no bevacizumab response biomarker for CRC was reported before ( 8 , 9 ).…”

“…have reported that rs3795897 (G>A) in AGAP1 might be a potential predictor related to bevacizumab and patient survival ( 8 ). It is worth noting that no bevacizumab response biomarker for CRC was reported before ( 8 , 9 ). Nevertheless, just as the authors said, this study displayed many limitations and a lack of further validation, which make the result questionable.…”