title: Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients.
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.
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Sclafani
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Chau
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.affiliation: Department of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lampis
authors.affiliation: Department of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Jens Claus
authors.initials: JC
authors.lastname: Hahne
authors.affiliation: Department of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Ghidini
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK, Department of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Lote
authors.affiliation: Department of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Domenico
authors.initials: D
authors.lastname: Zito
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, University of Uppsala, Uppsala 78751 85, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Department of Haematology and Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia 46010, Spain and.
authors.forename: Andres
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Ruwaida
authors.initials: R
authors.lastname: Begum
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: David Gonzalez
authors.initials: DG
authors.lastname: De Castro
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Sanna Hulkki
authors.initials: SH
authors.lastname: Wilson
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Peckitt
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Eltahir
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wotherspoon
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Tait
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Gina
authors.initials: G
authors.lastname: Brown
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Oates
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK, Department of Cancer Therapeutics, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Braconi
authors.affiliation: Department of Medicine, The Royal Marsden NHS Foundation Trust, Surrey SM2 5PT, UK, Department of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK, nicola.valeri@icr.ac.uk.
authors.forename: Nicola
authors.initials: N
authors.lastname: Valeri
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D059248:Chemoradiotherapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020641:Polymorphism, Single Nucleotide; D012004:Rectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D012189:Retrospective Studies
chemical_list: C000591804:MIRN608 microRNA, human; D035683:MicroRNAs