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Introduction

A Micro RNA Polymorphism (MiRSNP) in 3’UTR of K-ras gene was associated with clinical outcome in mCRC patients treated with either single agent cetuximab (IMCL-0144) or in combination with irinotecan (EPIC)

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Introduction

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  1. A Micro RNA Polymorphism (MiRSNP) in 3’UTR of K-ras gene was associated with clinical outcome in mCRC patients treated with either single agent cetuximab (IMCL-0144) or in combination with irinotecan (EPIC) Thomas Winder1, Wu Zhang1, Anthony El-Khoueiry1, Dongyun Yang1, Alexandra Pohl1, Georg Lurje1, Eric Rowinsky2, Shirin Khambata-Ford3, Christiane Langer3, Melissa Awad3 and Heinz-Josef Lenz1 1.USC/Norris Comprehensive Cancer Center, Los Angeles, CA 2. Imclone Systems, New York, NY 3. Bristol Myers Squibb Pharmaceutical Res Ins., New York, NY Introduction Results Recent studies have found K-ras mutation status predict resistance to EGFR inhibitors in mCRC(1,2). An in vitro study demonstrated let-7 family of microRNAs can regulate RAS expression by binding to the 3’-UTR of RAS gene(3). Several studies had shown a MicroRNA single nucleotide polymorphism (MiRSNP) in a let-7 microRNA complementary site (lcs6) in the K-ras 3’-UTR region was associated with increased cancer risk in NSCLC and reduced overall survival in oral cancers(4,5). We tested the hypothesis whether this MiRSNP will be associated with response and progression free survival in 130 mCRC patients treated with single agent cetuximab(IMCL-0144) and in 186 mCRC patients treated with cetuximab in combination irinotecan (EPIC) independent of K-ras mutation status. Progression-free survival by K-ras lcs6 MiRSNP in mutant K-ras of EPIC Arm A(cetuximab+irinotecan) Baseline characteristics in patients enrolled in either EPIC or IMCL-0144 correlative study EPIC IMCL-0144 Patients and method K-ras lcs6 SNP was tested in 130 mCRC patients enrolled in IMC-0144 phase II clinical trial (single agent cetuximab) and in 186 mCRC patients enrolled in a second line phase III trial of cetuximab plus irinotecan versus irinotecan alone (EPIC). Patients enrolled in the correlative studies had similar clinical characteristics with the patients enroll in the IMCL-0144 trial but no tissue available. For EPIC trial, the analyzed population is not representative of the treated population. A small percentage of the overall population was analyzed, which is reflected in the efficacy data for the ITT versus analyzed population. In contrast to the results from the overall population, the PFS in the analyzed population is not significantly different between the arms (RR and PFS favor the Cetuximab arm in overall population) and the OS too trends the opposite way. Genomic DNA was extracted from dissected formalin fixed paraffin embedded tumor tissue. K-ras mutation status and the polymorphism were analyzed using direct sequencing and PCR-RFLP technique. Briefly, forward 5’-TTAGGAGAGACGGGGTTTCA-3’ and reverse primer 5’-AAATGAGTTCTGCAAAACAGG-3’ were used for PCR amplification, PCR products were digested by restriction enzyme TfiI (New England Biolab), and alleles were separated on 4% NuSieve ethidium bromide stained agarose gel. Tumor response by K-ras lcs6 MiRSNP in wild type K-ras mCRC treat with single agent cetuximab(IMCL-0144) Conclusion Our data suggest for the first time that the functional germline polymorphism in K-ras lcs6 may be a potential predictive marker in mCRC patients treated with cetuximab-based chemotherapy independent of K-ras mutation status. This finding warranted further confirmative clinical trials. • Reference: • Khambata-Ford S, Garrett CR, Meropol NJ, et al:. J Clin Oncol 25:3230-7, 2007 • Van Cutsem E, Lang I, D'haens G, et al:. J Clin Oncol 26:5s; 2008 (suppl) abstr 2 • Johnson SM, Grosshans H, Shingara J, et al: Cell 120:635-47, 2005 • Chin LJ, Ratner E, Leng S, et al: Cancer Res 68:8535-40, 2008 • Christensen BC, Moyer BJ, Avissar M et al: Carcinogenesis April 20 2009

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