Antitumor activities of bevacizumab for KRAS, BRAF, and PIK3CA mutated human colorectal cancer xenograft models.

Abstract

362 Background: In colorectal cancer, it has been reported that mutations (mts) in KRAS, BRAF, or PIK3CA can have a negative impact on molecular target therapies. Especially, a KRAS mt represents a predictive biomarker for resistance to anti-EGFR antibodies. Bevacizumab (BV), an anti-VEGF-A antibody, has been demonstrated to have clinical benefits in colorectal cancers; however, the impact of mts in especially BRAF or PIK3CA on the efficacy of BV remains unknown. In this study, we examined the antitumor activity of BV in human colorectal cancer xenograft models harboring these mts. Methods: BALB-nu/nu mice were subcutaneously inoculated with 15 colorectal cancer cell lines. BV was intraperitoneally administered every week for 3 weeks at a dose of 5 mg/kg. Antitumor activity was evaluated by determining tumor volume and tumor growth inhibition (TGI) on day 22. The colorectal cancer cell lines used were screened for KRAS, BRAF, and PIK3CA mts by direct sequencing of hot spots. Statistical analysis was performed using Wilcoxon test for tumor volume and TGI and Fisher's exact test for the correlation of genotype and antitumor effect. Results: Genotypes of KRAS, BRAF, and PIK3CA were all wild-type (wt) in COLO320DM, KM-12 and SW48 and in other cell lines were, respectively, as follows: COLO205, HT-29, WiDr and LS411N: wt, mt, and wt; SW620 and LoVo: mt, wt, and wt; HCT-8, HCT116, DLD-1, T84 and LS174T: mt, wt, and mt; RKO: wt, mt and mt. BV as a non-responder (NR) showed no significant antitumor activity in 3 cell lines (WiDr, LoVo and DLD-1), whereas as a responder (R) significant activity was observed in the other 12 cell lines. There was no significant difference in the antitumor effect of BV between cell lines depending on KRAS, BRAF or PIK3CAmutational status in terms of TGI and R/NR ratio (Table). Conclusions: BV shows antitumor effect regardless of mutational status of KRAS, BRAF, or PIK3CA in colorectal cancers. [Table: see text]