729P - Genomic profiling in Chinese biliary tract cancer patients with PI3K/AKT/mTOR pathway and RAS gene mutations

Abstract

BackgroundBiliary tract cancers (BTCs) are a group of relatively rare invasive carcinomas including gallbladder carcinoma (GBC), intrahepatic (ICC), hilar (HCCA) and extrahepatic (ECC) cholangiocarcinoma. Clinical trials of PI3K/AKT/mTOR inhibitors have revealed PI3K and PTEN mutations as effective biomarkers. This study aimed to analyze the gene mutations involved in this pathway and other gene mutations in Chinese BTC patients and to analyze the profiling characteristics of each subtype. MethodsA total of 661 (125 ECC, 159 GBC, 47 HCCA, and 330 ICC) BTC patients were included in this study. FFPE and matching blood samples from these patients were collected and sequenced using next-generation sequencing targeting 450 cancer genes. Genomic alterations including single nucleotide variants, insertions, and deletions, copy number variations and fusions were assessed. ResultsA total of 17.9% (118/661) of patients were identified harboring PI3K/AKT/mTOR pathway mutations. In preclinical data, RAS gene (KRAS/HRAS/NRAS) mutations might lead to reduced sensitivity to mTOR inhibitors. There was 11.8% (39/330) in ICC, 7.2% (9/125) in ECC, 12.8% (6/47) in HCCA and 25.2% (40/159) in GBC detected with PI3K pathway mutations and RAS wildtype, where the GBC proportion was statistically significantly higher than any other subtypes. A total of 3.6% (24/661) of patients presented co-occurrence of RAS and PI3K pathway mutations, but this was not found in HCCA. The percentages of co-occurrence in ICC, ECC and GBC were 3.6% (12/330), 4.0% (5/125) and 4.4% (7/159), respectively. The top 3 mutated genes in the PI3K/AKT/mTOR pathway were PIK3CA at 45.8% (54/118), PTEN at 22% (26/118) and TSC2 at 9.3% (11/118). PIK3CA mutations and amplification were discovered in 52 patients and 2 patients, respectively, including 23 ICC and 23 GBC patients, the most frequent being E542K (12/52) and52) mutations./52) mutations. ConclusionsIn Chinese BTC patients, the incidence (3.6%) of RAS and PI3K pathway mutation’s co-occurrence was generally low. Among BTC subtypes, GBC patients had the highest mutation proportion (25.2%) involved in the PI3K/AKT/mTOR pathway with wildtype RAS. Legal entity responsible for the studyDan Liu. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.