Ethnic gene profile of genes involved in angiogenesis may predict regional bevacizumab efficacy difference in gastric cancer Takeru Wakatsuki 1 , Wu Zhang 1 , Dongyun Yang 2 , Fotios Loupakis 1 , Mizutomo Azuma 3 , Francisco Graziano 5 , Yan Ning 1 , Melissa J Labonte 1 , Peter M Wilson 1 ,
Ethnic gene profile of genes involved in angiogenesis
may predict regional bevacizumab efficacy difference in gastric cancer
Takeru Wakatsuki1, Wu Zhang1, Dongyun Yang2, Fotios Loupakis1, Mizutomo Azuma3, Francisco Graziano5, Yan Ning1, Melissa J Labonte1, Peter M Wilson1,
Rita El-Khoueiry1 , Pierre Bohanes1, Armin Gerger1, Leonor Benhime1, David Paez1, Masahiko Watanabe4, Wasaburou Koizumi3, and Heinz-Josef Lenz1,2
1. Department of Medical Oncology, 2. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA
3. Department of Gastroenterology, 4. Department of Surgery, Kitasato University East Hospital, Sagamihara, Japan
5. Medical Oncology Unit, Hospital of Uribino, Uribino, Italy
AVAGAST showed regional bevacizumab (Bev) efficacy difference, namely, Asian patients with gastric cancer had no benefit, whereas European and Pan-American patients had more benefit from Bev.1
Germline gene polymorphisms involved in angiogenesis have been recognized as candidate predictive marker for Bev efficacy and allele frequency in gene polymorphisms varies depending on ethnicity.
We hypothesized that these polymorphisms have different allele frequency among Asian, Caucasian, and Hispanic patients with gastric cancer, and this disparity may have contributed to regional Bev efficacy difference in AVAGAST.
Seven candidate predictive markers were selected. These polymorphisms and favorable allele frequency for Bev were shown in Table1. Significant disparate distributions of allele frequency were seen among three races in both sets (Table2). Caucasian was more likely to have favorable allele for Bev (Red region), whereas Asian and Hispanic were more likely to have unfavorable allele (Blue one) in Figure1. According to SNP profile, we assumed that 25% of Asian, 52% of Caucasian, and 28% Hispanic patients carried favorable allele and benefited from Bev. 1000 simulated trials reproduced similar median PFS and HR to AVAGAST in Asian and Europe, however shorter PFS and higher HR were estimated in Pan-America.
A candidate predictive marker for Bev was defined that gene polymorphism predicted superior outcome only in Bev treatment group, but not control group.
Candidate polymorphisms were collected through Medline, ASCO and EMCC websites until December 31th, 2011, regardless type of cancer.
Three-hundred patients (Asian, Caucasian, and Hispanic, 100 from each race) with histopathologically confirmed gastric cancer were collected from Japan, the U.S.A., and Italy.
Genomic DNA was extracted from peripheral blood or tissue samples, and all samples were analyzed using PCR-based direct DNA- sequencing.
One hundred samples in each race were divided to training set and validation set (50 samples in each set). Fisher’s exact test were undergone for comparison of allele frequency among races.
We performed a Monte Carlo study (1,000 simulations) to test the efficacy of Bev in patients with gastric cancer by race. 1,000 simulated trials were conducted based on the observed median PFS in the control arm and the sample size by arm in each region of AVAGAST trial. The percentage of simulated trials with a significant log-rank test on PFS by arm (P<0.05 and HR<1) was calculated in each region.
1. Significant disparate distributions of allele frequency in candidate predictive markers for Bevwere shown among Asian, Caucasian, and Hispanic.
2. These disparities may have contributed to regional bevacizumab efficacy difference in AVAGAST.
1. Ohtsu A, et al. JCO 29: 3968-76, 2011
3. Loupakis F, et al. BMC Cancer Epub, 2011
2. Lambrechts D, et al. Eur J Cancer 47:s173, 2011
4. Schneider BP, et al. JCO 26: 4672-8, 2008