Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients.

Francesco Sclafani,Nicola Valeri,Clare Peckitt,Chiara Braconi,Ian Chau,Domenico Zito,Bengt Glimelius,Ruwaida Begum,Josep Tabernero,Diana Tait,Hazel Lote,Andrew Wotherspoon,Zakaria Eltahir,David Cunningham,Sanna Hulkki Wilson,Michele Ghidini,J Oates ,Andrea Lampis ,David González De Castro ,Gina Brown ,Jens C Hahne ,Andrés Cervantes

doi:10.1093/carcin/bgw073

Abstract

Single nucleotide polymorphisms (SNPs) in microRNA genes have been associated with colorectal cancer (CRC) risk, survival and response to treatment. Conflicting results are available on the association between rs4919510, a SNP in mature miR-608 and clinical outcome in CRC. Here, we analyzed the association between rs4919510 and benefit from perioperative treatment in a randomised phase II trial of neoadjuvant Capecitabine and Oxaliplatin (CAPOX) followed by chemo-radiotherapy, surgery and adjuvant CAPOX ± Cetuximab in high-risk locally advanced rectal cancer (LARC). A total of 155/164 (94.5%) patients were assessable. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG. Median follow-up was 64.9 months. In the CAPOX arm the 5-year progression-free survival (PFS) and overall survival (OS) rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12-0.83, P = 0.02; HR OS 0.38, 95% CI: 0.14-1.01, P = 0.05). In the CAPOX-C arm PFS and OS were 73.2 and 82.2%, respectively for CC carriers and 64.6 and 73.1% for CG/GG carriers (HR PFS 1.38, 95% CI: 0.61-3.13, P = 0.44; HR OS 1.34, 95% CI: 0.52-3.48, P = 0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (P = 0.02) and OS (P = 0.07). This is the first study investigating rs4919510 in LARC. The CC genotype appeared to be associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy and chemo-radiotherapy alone. Addition of Cetuximab to chemotherapy and chemo-radiotherapy in CC carriers appeared to improve clinical outcome.

Highlights

Management of locally advanced rectal cancer (LARC) is largely based on a number of clinical–radiological factors identified on baseline staging
LARC patients were classified as high risk and eligible for the EXPERT-C trial based on the presence of at least one of the following factors on high-resolution pelvic Magnetic Resonance Imaging (MRI): (a) predicted circumferential resection margin involvement, (b) T3 distal tumor, (c) T3c or T3d tumor, (d) T4 tumor, (e) extramural vascular invasion (EMVI)
Genotyping of the rs4919510 locus was performed on DNA extracted from pre (n = 113) and post (n = 122) neo-adjuvant treatment formalin-fixed paraffin-embedded tumor tissue (FFPE) biopsies in 155 out of 164 eligible patients enrolled in the EXPERT-C trial: this cohort represents 94.5% and is representative of the trial population as we have previously shown [15]

Summary

Introduction

Management of locally advanced rectal cancer (LARC) is largely based on a number of clinical–radiological factors identified on baseline staging. It is clear that patients with similar risk factors at baseline can have different outcomes and may require tailored treatment approaches and surveillance strategies [1]. A number of key cellular processes including proliferation, differentiation and response to anticancer treatments are influenced by this regulatory mechanism [3]. Single nucleotide polymorphisms (SNPs) in microRNA genes have been increasingly analysed for their functional implications. A single base pair change in the nucleoside sequence can affect microRNA biogenesis, processing, and target site binding. Growing evidence supports a link between SNPs in microRNA genes and colorectal cancer (CRC) risk, prognosis and drug response [5,6]

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Results

Conclusion