Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer : results of the EXPERT-C trial
Sclafani, Francesco (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Chau, Ian (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Cunningham, David (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Peckitt, C. (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Lampis, Andrea (The Institute of Cancer Research. Division of Molecular Pathology (UK))
Hahne, Jens Claus (The Institute of Cancer Research. Division of Molecular Pathology (UK))
Braconi, Chiara (The Institute of Cancer Research. Division of Cancer Therapeutics (UK))
Tabernero, Josep (Hospital Universitari Vall d'Hebron)
Glimelius, B. (University of Uppsala. Department of Immunology, Genetics and Pathology (Sweden))
Cervantes, Andrés (Universitat de València. Departament d'Hematologia i Oncologia Mèdica)
Begum, Ruwaida (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
González De Castro, David (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Hulkki Wilson, Sanna (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Eltahir, Zakaria (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Wotherspoon, Andrew (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Tait, D. (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Brown, Gina (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Oates, J. (The Royal Marsden NHS Foundation Trust. Department of Medicine (UK))
Valeri, Nicola (The Institute of Cancer Research. Division of Molecular Pathology (UK))
Universitat Autònoma de Barcelona

Data:	2015
Resum:	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. 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. 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). 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.
Ajuts:	European Commission 334261
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	LCS-6 KRAS variant ; Single-nucleotide polymorphism ; Let-7 ; KRAS ; Cetuximab ; Rectal cancer
Publicat a:	Annals of oncology, Vol. 26, Issue 9 (September 2015) , p. 1936-1941, ISSN 1569-8041

DOI: 10.1093/annonc/mdv285
PMID: 26162609

6 p, 225.1 KB

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