RAS mutations and cetuximab in locally advanced rectal cancer: Results of the EXPERT-C trial

F. Sclafani, D. Gonzalez, D. Cunningham, S. Hulkki Wilson, C. Peckitt, J. Giralt, B. Glimelius, S. Roselló Keränen, A. Wotherspoon, G. Brown, D. Tait, J. Oates, I. Chau

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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 63.8 months, 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. © 2014 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)1430-1436
JournalEuropean Journal of Cancer
Volume50
Issue number8
DOIs
Publication statusPublished - 1 Jan 2014

Keywords

  • BRAF
  • Cetuximab
  • KRAS
  • Neoadjuvant chemotherapy
  • NRAS
  • RAS
  • Rectal cancer

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    Sclafani, F., Gonzalez, D., Cunningham, D., Hulkki Wilson, S., Peckitt, C., Giralt, J., Glimelius, B., Roselló Keränen, S., Wotherspoon, A., Brown, G., Tait, D., Oates, J., & Chau, I. (2014). RAS mutations and cetuximab in locally advanced rectal cancer: Results of the EXPERT-C trial. European Journal of Cancer, 50(8), 1430-1436. https://doi.org/10.1016/j.ejca.2014.02.002