Background: AVAGAST showed regional bevacizumab (Bev) efficacy difference (RBED), namely, Asian (Asi) patients (pts) with gastric cancer (GC) had no benefit whereas European and Pan-American patients had more benefit from Bev. Recently, germline gene polymorphisms in angiogenesis have been recognized as predictive marker for Bev efficacy. Allele frequency (AF) in gene polymorphisms may vary depending on ethnicity. We tested the hypothesis whether angiogenic pathway gene polymorphisms may have different AF among Asi, Caucasian (Cau), and Hispanic (Hisp) in GC and this disparity may explain RBED. Methods: Three-hundred pts [Japanese (Jap), Cau, and Hisp, 100 from each race] with histopathologically confirmed GC were collected from Japan, USA, Austria, and Italy between 1991 and 2011. These pts were divided into 2 groups as training set (n=50) and validation set (n=50) in each race. Seven functional gene polymorphisms previously reported as predictive marker were selected. All samples were analyzed using PCR-based direct DNA- sequencing. Fisher's exact test was used to compare the distribution of AF among races. Results: Significant disparate distributions in favorable AF for Bev were shown among races in Table. Jap GC pts had significant lower AF of 5 predictive gene polymorphisms in training set, and among these 5, three predictive gene polymorphisms were also validated. Conclusions: Our preliminary results showed significant disparate AF distributions in predictive gene polymorphisms for Bev, and these disparities may explain RBED in AVAGAST. Further investigation is warranted to elucidate RBED.

The favorable allele frequencies for bevacizumab.

	Training set				Validation set
	Cau (%)	Hisp (%)	Jap (%)	P value	Cau (%)	Hisp (%)	Jap (%)	P value
VEGFR2 rs12505758 T/C	84.0	85.0	68.8	0.009	87.0	83.3	64.3	0.004
VEGFR1 rs9582036 C/A	79.0	86.0	82.7	0.660	75.0	80.0	83.0	0.740
VEGF-A rs699946 A/G	78.0	60.2	49.0	0.001	78.0	76.0	58.0	0.021
VEGFR2 rs11133360 C/T	55.1	43.8	70.8	0.002	60.0	35.9	68.0	<0.001
VEGF-A rs833061 C/T	52.0	35.0	29.6	0.020	50.0	40.0	33.0	0.200
VEGF-A rs699947 A/C	51.0	34.0	27.6	0.013	51.0	36.0	29.0	0.026
VEGF-A rs1570366 A/G	39.0	17.0	14.6	0.001	37.0	22.0	20.4	0.130