Abstract 4727: Analysis of <i>PIK3CA</i> mutations and PI3K signaling proteins as prognostic biomarkers for advanced gastric cancer
Authors: Satoshi S. Nishizuka, Chie Ito, Kohei Kume, Takeshi Iwaya, Keisuke Koeda, Akira Sasaki
Journal: Cancer Research (2017)

Abstract Although surgery and chemotherapy has extended the survival of patients with advanced gastric cancer, some patients experience relapse. In cases of potentially curative gastrectomy, no visible tumor mass should be present at the time of post-operative chemotherapy. Therefore, relapse may be attributed to very small cancer cell populations that survive and develop drug resistance. Previously, we found that changes in the phosphatidylinositide 3-phosphate kinase (PI3K) pathway protein levels were responsible for the growth of drug-resistant cancer cells. In the present study, we postulated that the oncogenic mutations in PIK3CA and PI3K pathway proteins could be prognostic biomarkers for patients with advanced gastric cancer. A retrospective cohort of 160 patients with advanced gastric cancer, receiving potentially curative surgery with/without chemotherapy was investigated for PIK3CA mutations and PI3K pathway protein levels in the context of 5-year overall survival (OS) and relapse-free survival (RFS). Mutations were screened by direct sequencing followed by validation through allele-specific quantitative real-time PCR, digital PCR, and ultra-deep sequencing. Tissue microarrays were produced from tumor-rich areas of surgically removed specimens. Protein levels were assessed by incubation with specific primary antibodies against total and phosphorylated proteins including PI3K (p85), AKT, mTOR, and PTEN, followed by colorimetric detection. Samples were deemed to have positive staining when more than 5% of the cancer cells were stained. OS and RFS periods were estimated using the Kaplan-Meier method. A log-rank test and Cox proportional hazards model was used to compare the survival and hazards ratio, respectively. Subgroup analysis was also performed. Thirteen patients (13/111 11.7%) had PIK3CA mutations in codon 545, whereas one patient (1/94 1.1%) had a mutation in the PIK3CA codon 1047. Phosphorylated-AKT positive (p-AKT(+)) patients in the surgery-only group showed good prognosis in terms of OS and RFS. Both OS and RFS of PTEN(+) patients were higher than those of PTEN(-) patients in both surgery-only and chemotherapy groups although statistical significance was not confirmed. PTEN(+) patients showed similar survival curves for up to 2 years post-operation, and separated thereafter. No significant association was observed between PIK3CA mutations and PI3K pathway protein levels. Subgroup analysis demonstrated that both p-AKT(+) and PTEN(+) were better prognostic factors for survival. There was no interaction between the protein levels and any clinicopathological/mutational factors. This study revealed that: (i) PIK3CA hotspot mutations occurred with low frequency in gastric cancer; (ii) PIK3CA hotspot mutations were not directly associated with PI3K pathway activation; and (iii) p-AKT(+) may be a biomarker for better outcomes in gastric cancer patients undergoing gastrectomy. Citation Format: Satoshi S. Nishizuka, Chie Ito, Kohei Kume, Takeshi Iwaya, Keisuke Koeda, Akira Sasaki. Analysis of PIK3CA mutations and PI3K signaling proteins as prognostic biomarkers for advanced gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4727. doi:10.1158/1538-7445.AM2017-4727