Data from A <i>let-7</i> microRNA-Binding Site Polymorphism in <i>KRAS</i> Predicts Improved Outcome in Patients with Metastatic Colorectal Cancer Treated with Salvage Cetuximab/Panitumumab Monotherapy

Abstract

<div>Abstract<p><b>Purpose:</b> An inherited mutation in <i>KRAS</i> (LCS6-variant or rs61764370) results in altered control of the <i>KRAS</i> oncogene. We studied this biomarker's correlation to anti-EGFR monoclonal antibody (mAb) therapy response in patients with metastatic colorectal cancer.</p><p><b>Experimental Design:</b> LCS6-variant and <i>KRAS/BRAF</i> mutational status was determined in 512 patients with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-variant allele to therapy exposure.</p><p><b>Results:</b> In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-variant (TG/GG), which was found twice as frequently in the <i>BRAF</i>-mutated versus the wild-type (WT) group (<i>P</i> = 0.03). LCS6-variant patients had significantly longer progression- free survival (PFS) with anti-EGFR mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; <i>P</i> = 0.019) and in the double WT (<i>KRAS</i> and <i>BRAF</i>) patient population (18 vs. 10.4 weeks; <i>P</i> = 0.039). Combination therapy (mAbs plus chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.</p><p><b>Conclusions:</b> LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm the importance of this mutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation. <i>Clin Cancer Res; 20(17); 4499–510. ©2014 AACR</i>.</p></div>