Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial.
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Embargo End Date
ICR Authors
Authors
Sclafani, F
Chau, I
Cunningham, D
Peckitt, C
Lampis, A
Hahne, JC
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
Valeri, N
Chau, I
Cunningham, D
Peckitt, C
Lampis, A
Hahne, JC
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
Valeri, N
Document Type
Journal Article
Date
2015-09-01
Date Accepted
2015-06-26
Abstract
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.
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (9), pp. 1936 - 1941
Source Title
Publisher
OXFORD UNIV PRESS
ISSN
0923-7534
eISSN
1569-8041
Research Team
Signal Transduction & Molecular Pharmacology
Medicine (RMH Smith Cunningham)
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics
Medicine (RMH Smith Cunningham)
Evolutionary Genomics & Modelling
Gastrointestinal Cancer Biology and Genomics