Abstract 2508: Characteristics and clinical correlations of PI3K/AKT/mTOR pathway genetic variations in Chinese endometrial carcinoma
Authors: Xue Fengxia , Wang Yingmei , Wang Haifang , Zhang Jun , Meng Li , Guo Honglin , Shi Junping 
Published: September 2020

Abstract
Background: Next-generation sequencing (NGS) and the resulting target-based precision therapy has shown promising efficacy in many tumors. The PI3K/AKT/mTOR pathway is the most common abnormal pathway in endometrial carcinoma. Here we report the genetic characteristics of the PI3K/AKT/mTOR pathway in Chinese endometrial cancer and explored their clinical application to support further precision therapy strategy studies.
Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples and matched peripheral blood samples of 76 Chinese endometrial adenocarcinoma patients were collected for YuansuTM NGS-panel assay (OrigiMed, Shanghai). Pathological diagnosis was confirmed by independent pathologists. Genomic alterations (GAs) included single base substitution, short and long insertions/deletion (Indel), copy number variation, gene fusion, and rearrangement. Tumor mutational burden (TMB) and microsatellite instability (MSI) were assessed. FIGO stage, age, gender, and differentiation degree were collected for clinical application analysis.
Results: GAs in the PI3K/AKT/mTOR pathway were found in 93.4% (71/76) of patients and were mostly substitution/Indels (75.0%) and truncations (24.5%). The most common GAs were PTEN (72.4%), PIK3CA (51.3%), PIK3R1 (32.9%), FBXW7 (9.2%), and AKT1 (7.9%). Hotspot mutation sites were p.R130X (17.9%) of PTEN and p.H1047X (21.2%) and p.R88Q (15.4%) of PIK3CA. The median TMB was 7.55 Muts/Mb, but patients with PTEN, PIK3CA, and PIK3R1 mutations had a significantly higher TMB (PTEN: 20.9 vs 2.5 Muts/Mb, respectively, p &lt; 0.001; PIK3CA: 23.2 vs 5 Muts/Mb, respectively, p = 0.003; PIK3R1: 25.5 vs 6.2 Muts/Mb, respectively, p = 0.037). MSI-high was found in 9.2% of patients. PIK3R1 mutation patients were younger compared to wild type patients (51 vs 56 years old, respectively, p = 0.024), whereas FBXW7 mutation patients were older (63 vs 54 years old, respectively, p = 0.040). The rates of PTEN mutations and truncation variations were lower in FIGO IV stage (33.3% and 41.7%, p = 0.023 and p = 0.002, respectively) and higher in highly differentiated tissues (92% and 92%, p = 0.009 and p = 0.035, respectively), indicating that these GAs were associated with low grade phenotypes. A 56-year-old female with metastatic endometrial cancer, who could not tolerate a needle biopsy and standard treatment protocols, had ctDNA testing. A PTEN deletion was found and she received mTOR inhibitor everolimus treatment and achieved a partial response which lasted for more than 12 months.
Conclusions: Our study revealed gene variation characteristics of the PI3K/AKT/mTOR pathway in Chinese endometrial adenocarcinoma patients and the clinical correlations of these variations. PTEN mutations and truncation variations were associated with low grade phenotypes. This study was helpful for optimizing the usage of mTOR inhibitor everolimus.
Citation Format: Fengxia Xue, Yingmei Wang, Haifang Wang, Jun Zhang, Li Meng, Honglin Guo, Junping Shi. Characteristics and clinical correlations of PI3K/AKT/mTOR pathway genetic variations in Chinese endometrial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2508.