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.
This work was funded by Cancer Research UK Bobby Moore Fund (ref C23134A9353). Merck Serono supplied free cetuximab and an educational grant and Pfizer gave free irinotecan and an educational grant. Neither Merck Serono or Pfizer was involved in study design, data analysis or manuscript preparation or had access to study data. Central trial coordination was by Cancer Research UK and University College London Cancer Trials Centre, including data collection and statistical analyses. The Pathology and Tumour Biology laboratory is supported by grants from Yorkshire Cancer Research, the Pathological Society of Great Britain and Ireland, the Academy of Medical Sciences, The Medical Research Council and a National Institute of Health Research Senior Investigator Award. SG was a National Institute for Social Care and Health Research Academic Health Science Collaboration Clinical Research Fellow.
- locally advanced rectal cancer
- cetuximab-containing chemoradiation
- RAS mutations
- intra-tumoural clonal heterogeneity
- treatment response
- next generation sequencing