GABRP as a biomarker for predicting anti-PD1 therapeutic efficacy in advanced gastric cancer (WJOG10417GTR study).

Abstract

4035 Background: GABRP, Gamma-aminobutyric acid type A receptor subunit π, is a key molecule that influences tumor properties and patient prognosis in various cancers, including gastric cancer (GC): GABRP is significantly upregulated in tumor tissues, and promotes tumor progression and metastasis via chemokine signaling and macrophage recruitment, leading to poor prognosis. Thus, GABRP seems to be a promising potential target for cancer treatment. However, it remains unclear whether the GABRP-targeting strategy can contribute to GC treatment, especially anti-PD1/PDL1 therapy, which has recently attracted great attention. Methods: We collected biopsy tumor tissues from 96 patients with advanced GC before and one month after nivolumab monotherapy in the WJOG10417GTR study according to the protocol (No. 2017-473) approved by the IRB, and analyzed for GABRP expression by RNA-sequencing (RNAseq) and immunohistochemical staining (IHC; only at pre-treatment). Progression-free survival (PFS) and overall survival (OS) were compared between high and low groups divided by the cutoff value determined by change point of the larger log hazard ratios (HRs) based on the method for modeling continuous-scale covariates. This study was supported by Ono Pharmaceutical and Bristol Myers Squibb. Results: RNAseq data revealed that high levels of GABRP gene expression in tumors at baseline were significantly associated with shorter PFS (median PFS [mPFS] 1.643 months [95% CI = 1.281 - 3.253] vs 3.170 months [1.971 - 10.251], HR = 2.798, P = 0.005) and shorter OS (median mOS [mOS] 5.092 months [3.450 - NA] vs 15.409 months [13.733 - NA], HR = 5.145, P < 0.001), and the high post-treatment levels were significantly associated with shorter PFS (mPFS 1.873 months [1.511 - 3.253] vs 4.123 months [2.073 - NA], HR = 3.333, P = 0.009) and shorter OS (mOS 7.162 months [5.092 - 15.310] vs NA [13.733 - NA], HR = 4.524, P = 0.015), as compared to low levels. This was confirmed by IHC data that showed similar results, albeit only baseline data: patients with high baseline levels of GABRP protein expression in tumors had significantly shorter PFS (mPFS 1.528 months [0.986 - 1.971] vs 3.121 months [1.873 - 4.238], HR = 1.727, P = 0.016). Conclusions: These results suggest that GABRP expressed in tumors is a significant poor prognostic factor for nivolumab monotherapy in advanced GC. GABRP may be a promising biomarker for predicting anti-PD1/PDL1 therapeutic efficacy in advanced GC, and targeting it may contribute to improving the clinical outcomes in GC as a new therapeutic strategy.