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Ann Oncol. 2015 Sep;26(9):1936-41. doi: 10.1093/annonc/mdv285. Epub 2015 Jul 10.

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

Author information

1
Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey.
2
Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton.
3
Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, UK.
4
Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain.
5
Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden.
6
Department of Hematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
7
Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton nicola.valeri@icr.ac.uk.

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.

KEYWORDS:

KRAS; LCS-6 KRAS variant; cetuximab; let-7; rectal cancer; single-nucleotide polymorphism

PMID:
26162609
PMCID:
PMC4551162
DOI:
10.1093/annonc/mdv285
[Indexed for MEDLINE]
Free PMC Article

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