fcγriia and iiia polymorphisms predict clinical outcome of trastuzumab-treated metastatic gastric cancer

De-shen Wang,1,* Xiao-li Wei,1,* Zhi-qiang Wang,1,* Yun-xin Lu,1 Si-mei Shi,1 Niu Wang,1 Miao-zhen Qiu,1 Feng-hua Wang,1 Rong-jiao Wang,2 Yu-hong Li,1 Rui-hua Xu1 1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 2Oncology BU, BGI-Shenzhen, Shenzhen, China *These authors contributed equally to this work Abstract: Trastuzumab has substantial antitumor activity in metastatic gastric cancer. One such mechanism by which it exerts its antitumor activity is antibody-dependent cell-mediated cytotoxicity, which has been reported to be influenced by FcγRIIA and IIIA polymorphisms. This study is the first to assess their impact on trastuzumab efficacy in patients with metastatic gastric cancer. We retrospectively examined 42 Her-2-positive patients receiving fluorouracil and platinum-based chemotherapy and trastuzumab, and 68 Her-2-negative patients receiving fluorouracil and platinum-based chemotherapy only as the first-line treatment. FcγRIIA and IIIA polymorphisms were assessed, and their associations with efficacy in both settings were analyzed. In patients treated with trastuzumab, the FcγRIIA H/H genotype was associated with significantly superior progression-free survival (PFS) (hazard ratio [HR] [95% CI]: 0.36 [0.16–0.82], adjusted HR [95% CI]: 0.18 [0.07–0.48], P=0.001). When combining FcγRIIA and IIIA polymorphisms, the FcγRIIA H/H or FcγRIIIA V/V genotype was associated with a significantly improved disease control rate (P=0.04) and PFS (HR [95% CI]: 0.29 [0.13–0.67], adjusted HR [95% CI]: 0.17 [0.07–0.45], P<0.001). As expected, no association of FcγRIIA and IIIA polymorphisms with efficacy was found in patients receiving chemotherapy only. We concluded that FcγRIIA and IIIA polymorphisms might predict disease control rate and PFS in metastatic gastric cancer patients receiving trastuzumab treatment. Keywords: gastric cancer, trastuzumab, antibody-dependent cell-mediated cytotoxicity, FcγRIIA polymorphism, FcγRIIIA polymorphism, human epidermal growth factor receptor-2