Abstract
Simple SummaryMolecular 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.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.
Highlights
After a long period of therapeutic stagnation, a breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is becoming evident with Her2neu, PDL1 or FGFR2 directed therapies [1]
Multigene sequencing analysis for Her2neu was available for all 54 patients
We found a Her2neu amplification in 8/54 (14.8%) patients analyzed by nextgeneration sequencing (NGS), while 10/54 (18.5%) showed overexpression in the conventional diagnostics (IHC/in situ hybridization (ISH))
Summary
After a long period of therapeutic stagnation, a breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is becoming evident with Her2neu, PDL1 or FGFR2 directed therapies [1]. Based on phase III trials such as CheckMate 649, Checkmate 577, Attraction 4 and KEYNOTE 590 showing convincing clinical improvement, the addition of ICIs (nivolumab or pembrolizumab) to chemotherapy or chemoradiation therapy (CRT) is becoming the standard of care in the first-line setting of metastatic disease [3,4,5,6]. Another new treatment option is the addition of ICI therapy to Her2neu directed regimens in patients with ErbB2 overamplification. The identification of patients who qualify for targeted therapy based on appropriate biomarkers remains a major challenge
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