Background: KRAS is down-regulated by Let-7 microRNA isoforms and this effect may be clinically relevant to patients harboring KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas of patients who received salvage irinotecan/cetuximab. The Let-7a levels were characterized and studied for association with survival outcomes. Methods: The study population was retrospectively identified among metastatic colorectal cancer (mCRC) patients who underwent third-line cetuximab/irinotecan before 2008. At that time epidermal growth factor receptor (EGFR) expression only was required for adopting the anti-EGFR therapy. In 59 eligible patients harboring KRAS mutations, tumoral Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS). An exploratory sub-group analysis was performed to detect the single nucleotide polymorphism (SNP) rs61764370 G/A (LCS6) in the region that experimentally impairs the Let-7 binding to the KRAS mRNA. Results: Among clinico-pathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p=0.002). Differences in Let-7a levels were not found between paired tumor and non-tumor samples in 39 cases (66%) with availability of both tissues. Increased Let-7a levels were significantly associated with improved survival (multivariate Hazard Ratio=0.88; 95%CI=0.79-0.98; p=0.02). In the exploratory analysis the variant G allele of the LCS6 occurred in 14 patients and among the 45 A/A LCS6 homozygous patients, there was a significantly favorable association between high Let-7a levels and both OS and PFS. Conclusions: Replication of these data is warranted. In patients with KRAS mutation, Let-7 analysis may serve for identifying subgroups who may still gain some benefit from EGFR inhibition and it may open new perspectives for alternative treatment strategies.
Let-7a microRNA levels in KRAS-mutated colorectal carcinomas determine survival differences in patients treated with anti-EGFR
RUZZO, ANNAMARIA;ANDREONI, FRANCESCA;MAGNANI, MAURO;
2011
Abstract
Background: KRAS is down-regulated by Let-7 microRNA isoforms and this effect may be clinically relevant to patients harboring KRAS mutations. We quantified the Let-7a isoform in KRAS-mutated colorectal carcinomas of patients who received salvage irinotecan/cetuximab. The Let-7a levels were characterized and studied for association with survival outcomes. Methods: The study population was retrospectively identified among metastatic colorectal cancer (mCRC) patients who underwent third-line cetuximab/irinotecan before 2008. At that time epidermal growth factor receptor (EGFR) expression only was required for adopting the anti-EGFR therapy. In 59 eligible patients harboring KRAS mutations, tumoral Let-7a levels were analyzed for association with overall survival (OS) and progression-free survival (PFS). An exploratory sub-group analysis was performed to detect the single nucleotide polymorphism (SNP) rs61764370 G/A (LCS6) in the region that experimentally impairs the Let-7 binding to the KRAS mRNA. Results: Among clinico-pathologic features, high Let-7a levels were associated with grade 2-3 skin toxicity (p=0.002). Differences in Let-7a levels were not found between paired tumor and non-tumor samples in 39 cases (66%) with availability of both tissues. Increased Let-7a levels were significantly associated with improved survival (multivariate Hazard Ratio=0.88; 95%CI=0.79-0.98; p=0.02). In the exploratory analysis the variant G allele of the LCS6 occurred in 14 patients and among the 45 A/A LCS6 homozygous patients, there was a significantly favorable association between high Let-7a levels and both OS and PFS. Conclusions: Replication of these data is warranted. In patients with KRAS mutation, Let-7 analysis may serve for identifying subgroups who may still gain some benefit from EGFR inhibition and it may open new perspectives for alternative treatment strategies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.