Journal
BRITISH JOURNAL OF CANCER
Volume 117, Issue 9, Pages 1286-1294Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2017.294
Keywords
locally advanced rectal cancer; cetuximab-containing chemoradiation; RAS mutations; intra-tumoural clonal heterogeneity; treatment response; next generation sequencing
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Funding
- Cancer Research UK Bobby Moore Fund [C23134A9353]
- Merck Serono
- Pfizer
- Yorkshire Cancer Research
- Pathological Society of Great Britain and Ireland
- Academy of Medical Sciences
- Medical Research Council
- National Institute of Health
- Cancer Research UK [15953] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0514-10070, CL-2011-02-004] Funding Source: researchfish
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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.
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