Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial

Sclafani, F. et al. (2015) Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial. Annals of Oncology, 26(9), pp. 1936-1941. (doi: 10.1093/annonc/mdv285) (PMID:26162609) (PMCID:PMC4551162)

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Background: Lethal-7 (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 (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients 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 (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR 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 with 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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Braconi, Dr Chiara and Valeri, Dr Nicola
Authors: Sclafani, F., Chau, I., Cunningham, D., Peckitt, C., Lampis, A., Hahne, J.C., Braconi, C., Tabernero, J., Glimelius, B., Cervantes, A., Begum, R., Gonzalez De Castro, D., Hulkki Wilson, S., Eltahir, Z., Wotherspoon, A., Tait, D., Brown, G., Oates, J., and Valeri, N.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Annals of Oncology
Publisher:Oxford University Press
ISSN (Online):1569-8041
Published Online:10 July 2015
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Annals of Oncology 26(9): 1936-1941
Publisher Policy:Reproduced under a Creative Commons License

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