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Br J Cancer. 2017 Oct 24;117(9):1286-1294. doi: 10.1038/bjc.2017.294. Epub 2017 Aug 31.

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

Author information

1
Department of Oncology, North Wales Cancer Treatment Centre, Bodelwyddan, Denbighshire LL18 5UJ, UK.
2
Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
3
St James' Institute of Oncology, University of Leeds, Leeds LS9 7TF, UK.
4
Clatterbridge Cancer Centre, Clatterbridge Road, Wirral CH63 4JY, UK.
5
The Christie NHS Foundation Trust, Withington, Manchester M20 4BX, UK.
6
Royal Preston Hospital, Fulwood, Preston PR2 9HT, UK.
7
Pathology and Tumour Biology, Level 4 Wellcome Trust Brenner Building, St James University Hospital, Beckett Street, Leeds LS9 7TF, UK.
8
St Luke's Cancer Centre, Egerton Road, Guildford GU2 7XX, UK.
9
Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK.
10
Colchester General Hospital, Turner Road, Colchester CO4 5JL, UK.
11
University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry CV2 2DX, UK.
12
Cancer Research UK & UCL Cancer Trials Centre, University College London, 90 Tottenham Court Road, London W1T 4TJ, UK.

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.

PMID:
28859058
PMCID:
PMC5672930
DOI:
10.1038/bjc.2017.294
[Indexed for MEDLINE]
Free PMC Article

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