High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease.

The Oncologist
Annamaria RuzzoMauro Magnani

Abstract

Preclinical and experimental data in vivo indicate that Lethal-7 (Let-7) microRNA downregulates KRAS with antitumor effects in the presence of activating KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas from patients who received salvage cetuximab plus irinotecan. The study population was retrospectively identified among metastatic colorectal cancer patients who underwent third-line therapy with cetuximab plus irinotecan in a period when only epidermal growth factor receptor (EGFR) expression was required for anti-EGFR therapy. In 59 patients harboring KRAS mutations, Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS) times. An exploratory subgroup analysis was performed using the rs61764370 (LCS6 T>G) polymorphism that experimentally impairs Let-7 binding to KRAS mRNA. In the whole group, higher Let-7a levels were significantly associated with better survival outcomes. For the primary OS endpoint, the multivariate hazard ratio was 0.82 (95% confidence interval, 0.73-0.91; p = .01). The same findings with an accentuated positive effect of high Let-7a levels on both OS and PFS times were observed in an exploratory analysis of the 45 wil...Continue Reading

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