Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial
A partir d'échantillons tumoraux fixés au formol et inclus en paraffine après prélèvement sur 151 patients atteints d'un cancer localement avancé du rectum, cette étude met en évidence une association entre un polymorphisme à simple nucléotide du gène codant le micro-ARN let-7, qui régule notamment l'expression du gène KRAS, et la réponse à un traitement néoadjuvant
Background : Let-7 is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single nucleotide polymorphism (rs61764370, T>G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early stage colorectal cancer and benefit from anti-EGFR monoclonal antibodies in metastatic colorectal cancer.
Materials and Methods : We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms.
Results : A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response after neoadjuvant therapy (28.1% versus 10.6%; p=0.020) and a trend for better 5-year progression-free (PFS) (77.4% versus 64.5%: HR 0.56; p=0.152) and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; p=0.234). Both complete response and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, p=0.078; HR OS 1.79, p=0.082) compared to those with the LCS-6 TG genotype (HR PFS 1.33, p=0.713; HR OS 1.01, p=0.995).
Conclusion : This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.
Annals of Oncology , article en libre accès, 2015