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

作者：Saridaki Zenia; Weidhaas Joanne B^*; Lenz Heinz Josef; Laurent Puig Pierre; Jacobs Bart; De Schutter Jef; De Roock Wendy; Salzman David W; Zhang Wu; Yang Dongyun; Pilati Camilla; Bouche Olivier; Piessevaux Hubert; Tejpar Sabine

来源：Clinical Cancer Research, 2014, 20(17): 4499-4510.

DOI：10.1158/1078-0432.CCR-14-0348

Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. Westudied this biomarker%26apos;s correlation to anti-EGFR monoclonal antibody (mAb) therapy response in patients with metastatic colorectal cancer. %26lt;br%26gt;Experimental Design: LCS6-variant and KRAS/BRAF 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. %26lt;br%26gt;Results: 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 BRAF-mutated versus the wild-type (WT) group (P = 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; P = 0.019) and in the double WT (KRAS and BRAF) patient population (18 vs. 10.4 weeks; P = 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. %26lt;br%26gt;Conclusions: 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 thismutation as a biomarker of anti-EGFRmAbresponse in patients with metastatic colorectal cancer, and warrant further prospective confirmation.

• 出版日期2014-9-1