Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations

Simon Gollins, Nick West, David Sebag-Montefiore, Arthur Sun Myint, Mark Saunders, Shabbir Susnerwala, Phil Quirke, Sharadah Essapen, Leslie Samuel, Bruce Sizer, Jane Worlding, Katie Southward, Gemma Hemmings, Emma Tinkler-Hundal, Morag Taylor, Daniel Bottomley, Philip Chambers, Emma Lawrie, Andre Lopes, Sandy Beare

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Abstract

BACKGROUND: The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. METHODS: In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. RESULTS: Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73-88%) (four patients with clinical complete response declined surgery). Twenty-four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05-1.03, P=0.055). CONCLUSIONS: This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss.
Original languageEnglish
Pages (from-to)1286-1294
Number of pages9
JournalBritish Journal of Cancer
Volume117
Early online date31 Aug 2017
DOIs
Publication statusPublished - 24 Oct 2017

Keywords

  • locally advanced rectal cancer
  • cetuximab-containing chemoradiation
  • RAS mutations
  • intra-tumoural clonal heterogeneity
  • treatment response
  • next generation sequencing

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    Gollins, S., West, N., Sebag-Montefiore, D., Myint, A. S., Saunders, M., Susnerwala, S., Quirke, P., Essapen, S., Samuel, L., Sizer, B., Worlding, J., Southward, K., Hemmings, G., Tinkler-Hundal, E., Taylor, M., Bottomley, D., Chambers, P., Lawrie, E., Lopes, A., & Beare, S. (2017). Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations. British Journal of Cancer, 117, 1286-1294. https://doi.org/10.1038/bjc.2017.294