Impact of Emergent Circulating Tumor DNA <i>RAS</i> Mutation in Panitumumab-Treated Chemoresistant Metastatic Colorectal Cancer.

Abstract

<b>Purpose:</b> The accumulation of emergent <i>RAS</i> mutations during anti-EGFR therapy is of interest as a mechanism for acquired resistance to anti-EGFR treatment. Plasma analysis of circulating tumor (ct) DNA is a minimally invasive and highly sensitive method to determine <i>RAS</i> mutational status.<b>Experimental Design:</b> This biomarker analysis of the global phase III ASPECCT study used next-generation sequencing to detect expanded <i>RAS</i> ctDNA mutations in panitumumab-treated patients. Plasma samples collected at baseline and posttreatment were analyzed categorically for the presence of <i>RAS</i> mutations by the Plasma<i>Select</i>-R 64-gene panel at 0.1% sensitivity.<b>Results:</b> Among panitumumab-treated patients with evaluable plasma samples at baseline (<i>n</i> = 238), 188 (79%) were wild-type (WT) <i>RAS</i>, and 50 (21%) were mutant <i>RAS</i> Of the 188 patients with baseline ctDNA WT <i>RAS</i> status, 164 had evaluable posttreatment results with a 32% rate of emergent <i>RAS</i> mutations. The median overall survival for WT and <i>RAS</i> mutant status by ctDNA at baseline was 13.7 (95% confidence interval, 11.5-15.4) and 7.9 months (6.4-9.6), respectively (<i>P</i> < 0.0001). Clinical outcomes were not significantly different between patients with and without emergent ctDNA <i>RAS</i> mutations.<b>Conclusions:</b> Although patients with baseline ctDNA <i>RAS</i> mutations had worse outcomes than patients who were WT <i>RAS</i> before initiating treatment, emergent ctDNA <i>RAS</i> mutations were not associated with less favorable patient outcomes in panitumumab-treated patients. Further research is needed to determine a clinically relevant threshold for baseline and emergent ctDNA <i>RAS</i> mutations. <i>Clin Cancer Res; 24(22); 5602-9. ©2018 AACR</i>.