Amplification of mutant <i>KRAS</i>^G12D in a patient with advanced metastatic pancreatic adenocarcinoma detected by liquid biopsy: A case report

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancer types. Activating oncogenic <em>KRAS</em> mutations are commonly observed in PDAC; however, oncogenic <em>KRAS</em> amplification is rarely observed, and its significance in prognosis and resistance to therapy remains poorly characterized. The present report describes the case of a 52‑year‑old male patient diagnosed with advanced PDAC with liver metastasis. The patient received modified FOLFIRINOX (mFFX) therapy to which the patient became intolerant with a strong inflammatory response. Subsequent treatment with gemcitabine plus nab‑paclitaxel failed to control the disease. Targeted genetic analysis revealed <em>KRAS</em>^G12D and <em>TP53</em>^R248Q mutations in the primary tumor and liver metastases. Analysis of circulating tumor DNA (ctDNA) before the first line of treatment confirmed these genetic findings and revealed a &gt;4‑fold amplification of the mutant <em>KRAS</em>^G12D not detected in the primary tumor. Additionally, subsequent analysis confirmed a 5‑fold amplification of the KRASG12D allele in liver metastasis. Consecutive monitoring of ctDNA revealed an initial decrease in the tumor burden 2 weeks after the first cycle of mFFX. However, coinciding with treatment intolerance, a sharp increase in tumor mutational levels and <em>KRAS</em>^G12D amplification was observed 1 month later. The patient died 70 days after treatment initiation. Overall, amplification of oncogenic <em>KRAS</em>^G12D was not only associated with an aggressive phenotype, but also supported cancer resistance to chemotherapy. Importantly, this case suggests that plasma detection of <em>KRAS</em>^G12D amplification is feasible in the clinical routine and constitutes a powerful tool for assessing tumor aggressiveness.

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