F Sclafani1, D Gonzalez1, D Cunningham2, S Hulkki Wilson1, C Peckitt1, J Giralt3, B Glimelius4, S Roselló Keränen5, A Wotherspoon1, G Brown1, D Tait1, J Oates1, I Chau1. 1. The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. 2. The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. Electronic address: david.cunningham@rmh.nhs.uk. 3. Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 4. Akademiska Sjukhuset Uppsala, Uppsala, Sweden. 5. Institute of Health Research Hospital Clinic of Valencia, University of Valencia, Valencia, Spain.
Abstract
BACKGROUND: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial. METHODS:Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed. RESULTS: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n=40; CAPOX-C, n=38). In this population, after a median follow-up of 63.8months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p=0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p=0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p=0.20). CONCLUSIONS: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.
RCT Entities:
BACKGROUND: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancerpatients treated with or without cetuximab within the 31 EXPERT-C trial. METHODS: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed. RESULTS: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n=40; CAPOX-C, n=38). In this population, after a median follow-up of 63.8months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p=0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p=0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p=0.20). CONCLUSIONS: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancerpatients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.
Authors: Stuart J Wong; Jennifer Moughan; Neal J Meropol; Pramila Rani Anne; Lisa A Kachnic; Asif Rashid; James C Watson; Edith P Mitchell; Jondavid Pollock; R Jeffrey Lee; Michael Haddock; Beth A Erickson; Christopher G Willett Journal: Int J Radiat Oncol Biol Phys Date: 2014-11-05 Impact factor: 7.038
Authors: F Sclafani; I Chau; D Cunningham; C Peckitt; A Lampis; J C Hahne; C Braconi; J Tabernero; B Glimelius; A Cervantes; R Begum; D Gonzalez De Castro; S Hulkki Wilson; Z Eltahir; A Wotherspoon; D Tait; G Brown; J Oates; N Valeri Journal: Ann Oncol Date: 2015-07-10 Impact factor: 32.976
Authors: M Kripp; K Horisberger; S Mai; P Kienle; T Gaiser; S Post; F Wenz; K Merx; R-D Hofheinz Journal: Gastroenterol Res Pract Date: 2015-03-15 Impact factor: 2.260