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Susanne Klein-Scory, Swetlana Ladigan-Badura, Thomas Mika, Berlinda Verdoodt, Andrea Tannapfel, Michael Pohl, Roland Schroers, Alexander Baraniskin

• \(\underline {Gastric}\) \(\underline {carcinomas}\) are among the most common cancers in Germany, with approximately 18,000 new cases per year. About 10 years ago, based on results of the \(\underline {Trastuzumab}\) for gastric cancer (ToGA) trial, the addition of the \(\underline {monoclonal}\) \(\underline {antibody}\) trastuzumab to a platinum-fluoropyrimidine chemotherapy \(\underline {backbone}\) became the standard-of-care 1st-line \(\underline {therapy}\) for human \(\underline {epidermal}\) \(\underline {growth}\) \(\underline {factor}\) \(\underline {receptor}\) 2 (\(\it HER2\))-positive gastric cancers. Only patients with primary \(\it HER2\) \(\underline {gene}\) \(\underline {amplification}\) benefit from this therapy. Thus, accurate \(\it HER2\) gene amplification detection is predictive and critical for therapy selection. As a gold standard the \(\it HER2\) status is currently determined in tumor tissue specimens using immune \(\underline {histochemistry}\) and \(\underline {fluorescent}\) \(\underline {in}\) \(\underline {situ}\) \(\underline {hybridisation}\). However, \(\it HER2\) amplification is detectable in only about 20 % of gastric carcinomas. The recent approval of an antibody-drug conjugate \(\underline {Trastuzumab}\) \(\underline {deruxtecan}\) (T-DXd) and the establishment of a new subgroup of \(\it HER2\)-low tumors due to the \(\underline {bystander}\) \(\underline {effect}\) associated with T-DXd increases the relevance of precise \(\it HER2\) diagnostics. Aim of this analysis was to determine the \(\it HER2\) amplification status from circulating DNA fragments in blood using a \(\it HER2\) \(\underline {Copy}\) \(\underline {Number}\) \(\underline {Variation}\) assay to establish a minimal invasive approach. For the present study, a digital droplet PCR-based method was validated relative to established tissue-based methods. Furthermore and most importantly, the changes of \(\it HER2\) status during therapy were investigated in seven patients indicating that the changes of \(\it HER2\) status and number of \(\it HER2\) copies detected in blood can reflect on therapy efficiency and uncover treatment resistance.