2189 Early onset colorectal cancer - does the difference lie in epigenetics?

S396 CRC cells in vitro. The inhibition of proliferation is mediated by regulating extrinsic signalling pathway for apoptosis via Caspase-8. NOV can alter the sensitivity of CRC cells to 5-Fluorouracil in which the regulation of extrinsic apoptotic pathway may be involved. No conflict of interest. 2188 POSTER Prognostic role of the LCS-6 KRAS variant in locally advanced rectal cancer: Results of the EXPERT-C trial F. Sclafani1 , I. Chau1 , D. Cunningham1 , C. Peckitt2 , A. Lampis3 , J.C. Hahne3 , C. Braconi4 , J. Tabernero5 , B. Glimelius6 , A. Cervantes7 , R. Begum1 , D. Gonzalez De Castro8 , S. Hulkki Wilson8 , Z. Eltahir9 , A. Wotherspoon9 , D. Tait10 , G. Brown11 , J. Oates1 , N. Valeri3 . 1 The Royal Marsden NHS Foundation Trust, Medicine, London and Surrey, United Kingdom; 2 The Royal Marsden NHS Foundation Trust, Research and Development, London and Surrey, United Kingdom; 3 The Institute of Cancer Research, Molecular Pathology, London and Surrey, United Kingdom; 4 The Institute of Cancer Research, Cancer Therapeutics, London and Surrey, United Kingdom; 5 Vall d’Hebron University Hospital, ` Universitat Autonoma de Barcelona, Medical Oncology, Barcelona, Spain; 6 University of Uppsala, Oncology, Uppsala, Sweden; 7 Biomedical Research Institute INCLIVA, University of Valencia, Hematology and Medical Oncology, Valencia, Spain; 8 The Royal Marsden NHS Foundation Trust, Molecular Diagnostics, London and Surrey, United Kingdom; 9 The Royal Marsden NHS Foundation Trust, Histopathology, London and Surrey, United Kingdom; 10 The Royal Marsden NHS Foundation Trust, Radiotherapy, London and Surrey, United Kingdom; 11 The Royal Marsden NHS Foundation Trust, Radiology, London and Surrey, United Kingdom Background: Let-7 is a tumour suppressor miRNA which acts by downregulating 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 better prognosis in early stage colorectal cancer and clinical benefit from antiEGFR monoclonal antibodies in metastatic colorectal cancer. Although the prognostic relevance of KRAS mutation appears greater in rectal cancer compared to colon cancer, studies addressing the role of this polymorphism in a homogeneous series of rectal cancer patients are lacking. Materials 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 paraffinembedded tumour tissue and genotyped using a PCR based commercially available assay. Kaplan–Meier method and Cox regression analysis were used to estimate survival outcomes 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 after preoperative therapy (28.1% versus 10.6%, p = 0.020) and a trend for better 5-year progression-free (PFS) (77.4% versus 64.5%; HR 0.56, p = 0.152) and overall survival (OS) rates (80.3% versus 71.9%; HR 0.59, p = 0.234). Both complete response (treatment*LCS-6 p interaction=0.638) and survival outcomes (treatment*LCS-6 p interaction=0.937 for PFS and 0.973 for OS) were independent of the use of cetuximab. Liver recurrence was diagnosed in 15/123 (12.2%) patients with the LCS-6 TT genotype (accounting for 48.4% of all relapsed cases in this group) compared to 0/32 patients with the LCS-6 TG genotype (p = 0.038). In the overall study population a trend towards worse PFS (HR 1.56, p = 0.112) and OS (HR 1.57, p = 0.145) was observed for patients with KRAS mutant tumours. However, 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 to those with the LCS-6 TG genotype (HR PFS 1.33, p = 0.713; HR OS 1.01, p = 0.995). Conclusion: Our analysis suggests that in locally advanced rectal cancer rs61764370 may be a marker of response to neoadjuvant treatment and an indicator of favourable survival outcome possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit. Conflict of interest: Advisory Board: Ian Chau has had advisory roles with Merck Serono, Roche, Sanofi Oncology, Bristol Myers Squibb, EliLilly, Novartis, Gilead Science. Clare Peckitt has had advisory roles with Sanofi. Josep Tabernero has had advisory roles with Amgen, Roche, Sanofi-Aventis, and Merck. Andres Cervantes has had advisory roles with Merck-Serono and Roche. Other Substantive Relationships: Ian Chau has received research funding from Merck-Serono, Novartis, Roche and Sanofi Oncology, and honoraria from Roche, Sanofi-Oncology, Eli-Lilly, Taiho. David Cunningham received research funding from: Roche, Amgen,

Abstracts Celgene, Sanofi, Merck Serono, Novartis, AstraZeneca, Bayer, Merrimack and MedImmune. Andres Cervantes has received research funding from Roche and honoraria from Roche and Merck-Serono. 2189 POSTER Early onset colorectal cancer − does the difference lie in epigenetics? I. Ben-Aharon1 , R. Pelossof2 , M. Elkabets1 , F. Battaglin1 , K. Goodman3 , R. Yaeger1 , L. Saltz1 , N. Schultz4 , D. Solit1 , J. Garcia-Aguilar5 , A. Cercek1 . 1 Memorial Sloan Kettering Cancer Center, Medicine, New York, USA; 2 Memorial Sloan Kettering Cancer Center, Computational Biology, New York, USA; 3 Memorial Sloan Kettering Cancer Center, Radiation Oncology, New York, USA; 4 Memorial Sloan Kettering Cancer Center, Epidemiology-Biostatistics, New York, USA; 5 Memorial Sloan Kettering Cancer Center, Surgery, New York, USA Background: Large-scale epidemiological studies have shown a recent rise in the incidence of colorectal cancer (CRC) in patients younger than 50 years of age. Although hereditary syndromes play a role, the majority of early onset (EO) CRC cases are sporadic. We aimed to determine if EOCRC have a distinct molecular landscape compared to the averageonset (AO) CRC. Methods: Two cohorts of CRC patients were analyzed. The first, included patients treated at MSKCC and were consented for MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) using next generation sequencing. The second cohort included patients from the The Cancer Genome Atlas (TCGA) analyzed for somatic mutations, gene expression, and DNA methylation using standard TCGA Level 3 Illumina Human Methylation 450 array data. CpGs that were found to be differentially methylated in normal tissue were subtracted from the tumor analyses in each age group. Mutation profiles and DNA methylation were compared between patients 50 years of age and >50 years of age. Results: Mutation profile analysis included 346 patients with MSK-IMPACT information and 200 samples from the TCGA cohort, yielding a total of 126 young patients age 50 and 368 older pts age <50. Patients with MSI-H or hypermutated tumors were excluded from the analysis (n = 52). Several genes known to be associated with carcinogenesis, including ATRX, DIS3, RAD52 and SMO, had different mutation frequency in different age groups. DNA methylation profiles were different in EOCRC in that 154 genes were hypomethylated in EOCRC and demonstrated and increase in methylation with increase in age beyond naturally occurring variation in matching normal tissue (FDR corrected p-value 0.01). Conclusions: This exploratory study found differences in the somatic gene mutation and methylation landscape in the non-hypermutated EOCRC patients compared to AOCRC. Elucidating the unique features of EOCRC may enable the development of more effective preventive and therapeutic strategies for this population. No conflict of interest. 2190 POSTER Discovery of new molecular subtypes of non-hypermutated metastatic colorectal cancer (mCRC) through a next-generation sequencing (NGS) approach F. Pietrantonio1 , F. Perrone2 , C. Cremolini3 , A. Orlandi4 , M. Niger1 , M. Caporale1 , R. Berenato1 , C. Antoniotti3 , F. Loupakis3 , E. Tamborini2 , M. Milione2 , G. Settanni2 , A. Busico2 , F. De Braud1 , M. Di Bartolomeo1 . 1 Istituto Nazionale Tumori, ONCOLOGY, Milano, Italy; 2 Istituto Nazionale Tumori, Pathology and Molecular Biology, Milano, Italy; 3 Azienda Ospedaliero-Universitaria Pisana, Polo Oncologico, Pisa, Italy; 4 Policlinico Universitario “A. Gemelli”, Medical Oncology, Roma, Italy Background: In colorectal cancer, NGS has a role in the discovery of predictive biomarkers for targeted therapy, beyond offering valuable information on pathogenesis, disease biology and prognosis. The available data mostly revealed the frequency of genomic alterations in all-TNM stage CRC, with limited prognostic information. In this translational study, we aimed at exploring the pathogenic and prognostic role of common gene mutations in patients with mCRC. Materials and Methods: We included 74 BRAF codon 600 wild-type, microsatellite-stable mCRC patients treated at 2 Italian Institutions and consenting to tumor profiling for a wide phase 1 studies screening program. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples using the GeneRead DNA FFPE kit (Qiagen, Hilden, Germany). NGS was performed using the Ion AmpliSeq Cancer Panel (Life Technologies) targeting the coding sequences of 50 genes, the Ion AmpliSeq Library Kit2.0. and the Ion Torrent Personal Genome Machine platform (Life Technologies) according to the manufacturer’s instructions. NGS results were correlated with clinico-pathological variables by means of chi-square