Abstract

<div>AbstractPurpose:<p>Approximately 8% to 10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in <i>KRAS.</i> Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents.</p>Experimental Design:<p>We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multigene sequencing panel and identified 73 patients (9.2%) with <i>KRAS</i> wild-type (WT) pancreatic cancer.</p>Results:<p>Overall, 43.8% (32/73) of <i>KRAS</i> WT cases had evidence of an alternative driver of the MAPK pathway, including <i>BRAF</i> mutations and in-frame deletions and receptor tyrosine kinase fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative <i>KRAS</i> WT cases (12/41) demonstrated activating alterations in other oncogenic drivers, such as <i>GNAS</i>, <i>MYC</i>, <i>PIK3CA</i>, and <i>CTNNB1</i>. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid models carrying <i>BRAF</i> in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a <i>KRAS</i> WT tumor with a <i>ROS1</i> fusion. Clinically, patients with <i>KRAS</i> WT tumors were significantly younger in age of onset (median age: 62.6 vs. 65.7 years; <i>P</i> = 0.037). <i>SMAD4</i> mutations were associated with a particularly poor prognosis in <i>KRAS</i> WT cases.</p>Conclusions:<p>This study defines the genomic underpinnings of <i>KRAS</i> WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-2221" target="_blank">See related commentary by Kato et al., p. 4527</a></i></p></div>

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