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A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

Zhang, W. ; Winder, T. ; Ning, Y. ; Pohl, A. ; Yang, D. ; Kahn, M. ; Lurje, G. ; LaBonte, M. J. ; Wilson, P. M. ; Gordon, M. A. ; Hu-Lieskovan, S. ; Mauro, D. J. ; Langer, C. ; Rowinsky, E. K. ; Lenz, H.-J

In: Annals of Oncology, 2011, vol. 22, no. 1, p. 104-109

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    Title
    • A let-7 microRNA-binding site polymorphism in 3′-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy
    Author
    • Zhang, W.. Division of Medical Oncology
    • Winder, T.. Division of Medical Oncology
    • Ning, Y.. Division of Medical Oncology
    • Pohl, A.. Division of Medical Oncology
    • Yang, D.. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA, USA
    • Kahn, M.. Division of Medical Oncology
    • Lurje, G.. Department of Visceral- and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
    • LaBonte, M. J.. Department of Pathology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
    • Wilson, P. M.. Department of Pathology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA
    • Gordon, M. A.. Division of Medical Oncology
    • Hu-Lieskovan, S.. Division of Medical Oncology
    • Mauro, D. J.. Oncology, Merck & Co., Inc., NJ
    • Langer, C.. Early Oncology, Bristol-Myers Squibb Pharmaceuticals Limited, New York
    • Rowinsky, E. K.. Oncology, ImClone Systems, New York, NY, USA
    • Lenz, H.-J. Division of Medical Oncology
    Document Type
    • Postprint
    Language
    • English
    Published in
    • Annals of Oncology, 2011, vol. 22, no. 1, p. 104-109. Oxford University Press
    Other Version
    OAI-PMH Identifier
    • oai:doc.rero.ch:294356
    Summary
    Purpose: Recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3′ untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy. Patients and methods: The presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique. Results: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes. Conclusions: These results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials