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

Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRASoncogene.We studied this biomarker’s correlation to anti-EGFRmonoclonal antibody (mAb) therapy response in patients with metastatic colorectal cancer. Experimental Design: LCS6-variant and KRAS/BRAFmutational status was determined in 512 patients with metastatic colorectal cancer treated with salvage anti-EGFRmAb therapy, and findings correlated with outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6variant allele to therapy exposure. Results: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6variant (TG/GG),whichwas found twice as frequently in theBRAF-mutated versus thewild-type (WT) group (P 1⁄4 0.03). LCS6-variant patients had significantly longer progressionfree survival (PFS) with anti-EGFR mAbmonotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P1⁄4 0.019) and in the double WT (KRAS and BRAF) patient population (18 vs. 10.4 weeks; P 1⁄4 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 orOS for LCS6-variant patients. Cell line studies confirmed a unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy. Conclusions: LCS6-variantpatientswithmetastatic colorectal cancerhaveanexcellent response toanti-EGFR mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm the importanceof thismutationas abiomarkerof anti-EGFRmAb response inpatientswithmetastatic colorectal cancer, and warrant further prospective confirmation. Clin Cancer Res; 20(17); 4499–510. 2014 AACR.