Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy and precision oncology treatment options may improve patient outcomes. Next-generation sequencing (NGS) is an established tool that enables multigene panel analysis. Methods: This NGS tissue-based analysis, conducted at a German pancreatic cancer center, included 128 patients between January 2016 and January 2021. Results: A targetable lesion was detected in 15.6% of patients. BRCA1/2 mutations were identified in 16 patients, of whom 13 had germline mutations; 8 of these patients received olaparib. In 41.4% of patients, homologous recombination repair genes were affected. Two cases of ATP1B1-NRG1 fusions and seven cases of dMMR tumors were found, leading to individualized treatment. KRAS mutations were present in 70.3%, and TP53 mutations were present in 63.3%. A total of 80.5% of patients received platinum-based chemotherapy, predominantly FOLFIRINOX. Conclusion: The high frequency of targetable alterations in our cohort underscores upfront NGS testing in PDAC. Younger patients, those with a positive family history, and KRAS WT patients should be of particular interest.

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