Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR).

Monica Ganzinelli,Eliana Rulli,Sheila Piva,Roberto Labianca,Claudia Bareggi,Marina Chiara Garassino,Daniele Fagnani,Elisa Caiola,Elena Copreni,Ida Pavese,Massimo Broggini,Olga Martelli,Mirko Marabese,Maria Giuseppa Sarobba,Flavia Longo,M.c Locatelli ,A Bertolini ,Giuseppe Valmadre ,Anna Maria Calcagno ,Agnese Fabbri

doi:10.1038/srep16331

Abstract

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3′UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient’s baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15–0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52–1.01, p = 0.056) in terms of PFS.

Highlights

Protein with intrinsic GTPase activity, which is necessary for protein inactivation, and to tune the downstream effectors involved in pathways such as proliferation and differentiation
Since KRAS mutation demonstrated only a little impact on survival, as reported in TAILOR trial results[13], and KRAS activity can be regulated by microRNA, patients stratification based only on KRAS status could not be sufficient to evaluate the role of this biomarker
When we considered a KRAS mutated background, the TG/GG genotypes seemed to indicate a protective trend in both overall survival (OS) and PFS not statistically significant (HR(TT vs TG/GG) = 1.29, 95% confidence intervals (95% CIs) 0.61–2.74, p = 0.501 and Hazard Ratios (HRs)(TT vs TG/GG)

Summary

Introduction

Protein with intrinsic GTPase activity, which is necessary for protein inactivation, and to tune the downstream effectors involved in pathways such as proliferation and differentiation. The single nucleotide polymorphism (SNP) (rs61764370), named KRAS let-7 complementary site (KRAS-LCS6), was described as the change of the T-allele to a G-allele. This modification was seen to increase the KRAS expression and to activate the downstream pathways. The moderate smoker population harbouring the G-allele was shown to have an increased cancer risk[5] but the presence of infrequent allele did not reduce the survival rate of patients[12]. Since KRAS mutation demonstrated only a little impact on survival, as reported in TAILOR trial results[13], and KRAS activity can be regulated by microRNA, patients stratification based only on KRAS status could not be sufficient to evaluate the role of this biomarker. Given that the prognostic and predictive role of KRAS-LCS6 polymorphism was not yet investigated in lung cancer, we planned an ancillary study to assess the value of KRAS-LCS6 polymorphism on outcomes within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line NSCLC

Methods

Results

Conclusion