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Clinical Trial
. 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

Simon Gollins  1 , Nick West  2 , David Sebag-Montefiore  3 , Arthur Sun Myint  4 , Mark Saunders  5 , Shabbir Susnerwala  6 , Phil Quirke  7 , Sharadah Essapen  8 , Leslie Samuel  9 , Bruce Sizer  10 , Jane Worlding  11 , Katie Southward  2 , Gemma Hemmings  2 , Emma Tinkler-Hundal  2 , Morag Taylor  2 , Daniel Bottomley  2 , Philip Chambers  2 , Emma Lawrie  12 , Andre Lopes  12 , Sandy Beare  12
Affiliations
Clinical Trial

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

Simon Gollins et al. Br J Cancer. .

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.

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Conflict of interest statement

Outside of the submitted work SG has received research funding from Roche and Pfizer. NW reports grants from Yorkshire Cancer Research, grants from Pathological Society of Great Britain and Ireland, during the conduct of the study; grants from Academy of Medical Sciences, outside the submitted work. DS-M has received research funding from Roche and Sanofi-Aventis. PQ reports personal fees from Amgen, personal fees from Roche, personal fees from Ventana, during the conduct of the study; grants from Yorkshire Cancer Research programme grant, within and outside the submitted work. BS reports personal fees from Roche, personal fees and non-financial support from Sanofi and non-financial support from BMS, outside the submitted work. SB reports grants from Merck, grants from Pfizer Limited, during the conduct of the study. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Relationship between RAS mutation status and progression-free and overall survival. (A) progression-free survival and (B) overall survival in patients who were RAS mutated in either pre-treatment biopsy or resected specimen (‘anytime mutant’) versus patients whose specimens only ever tested RAS wild-type.
See this image and copyright information in PMC

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