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

Oncologist. 2012;17(6):823-9. doi: 10.1634/theoncologist.2012-0081. Epub 2012 May 14.


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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / therapeutic use
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Endpoint Determination
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Male
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mutation
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Real-Time Polymerase Chain Reaction
  • Retrospective Studies
  • Specimen Handling
  • Survival Analysis
  • ras Proteins / genetics*


  • Antineoplastic Agents
  • KRAS protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • mirnlet7 microRNA, human
  • ErbB Receptors
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins