Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach—A Real World Data Analysis

SIMPLE SUMMARY: Molecular tumor signatures are becoming increasingly important in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC). There are few studies available analyzing data from the Caucasian population regarding molecular signatures and biomarkers. In the presented study, we investigated the distribution of gene variants in outpatients with advanced disease at the onset of diagnosis and correlated them with clinically relevant biomarkers according to ESCAT levels. In addition, we compared the results of conventional diagnostics (IHC/ISH) with NGS findings of gene amplifications. We were able to detect clinically relevant biomarkers according to ESCAT level I in approximately one-third of our patients, which have immediate therapeutic implications. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment. ABSTRACT: After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.