Journal
ONCOLOGIST
Volume 17, Issue 6, Pages 823-829Publisher
WILEY
DOI: 10.1634/theoncologist.2012-0081
Keywords
Colorectal cancer; KRAS; MicroRNA; Let-7; Cetuximab; Prognosis
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Funding
- Merck-Serono
- Roche
- Amgen
- PROJECT INTEROMICS, Ministero dell' Istruzione, dell'Universiti e della Ricerca (MIUR), Italy
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Preclinical and experimental data in vivo indicate that Lethal-7 (Let-7) microRNA downregulates KRAS with anti-tumor 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 (EGER) 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 wild-type LCS6 patients (excluding 14 carriers of the LCS6 G allele variant). All survival associations were confirmed after excluding patients with KRAS codon 13 mutations. Among the clinicopathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p = .002). In patients with KRAS mutations, Let-7a analysis may serve to identify subgroups of patients who may still benefit from EGFR inhibition and this may open up new perspectives for alternative treatment strategies. The Oncologist 2012;17:823-829
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