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

doi:10.1038/bjc.2017.294

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

Health Services Research Unit (HSRU)

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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 language	English
Pages (from-to)	1286-1294
Number of pages	9
Journal	British Journal of Cancer
Volume	117
Early online date	31 Aug 2017
DOIs	https://doi.org/10.1038/bjc.2017.294
Publication status	Published - 24 Oct 2017

Bibliographical note

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.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations
© The Author(s) named above. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Final published version, 295 KBLicence: CC BY

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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

Gollins, S, West, N, Sebag-Montefiore, D, Myint, AS, 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, vol. 117, pp. 1286-1294. https://doi.org/10.1038/bjc.2017.294

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

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.",

keywords = "locally advanced rectal cancer, cetuximab-containing chemoradiation, RAS mutations, intra-tumoural clonal heterogeneity, treatment response, next generation sequencing",

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

note = "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.",

year = "2017",

month = oct,

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doi = "10.1038/bjc.2017.294",

language = "English",

volume = "117",

pages = "1286--1294",

journal = "British Journal of Cancer",

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T1 - Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer

T2 - significance of pre-treatment and post-resection RAS mutations

AU - Gollins, Simon

AU - West, Nick

AU - Sebag-Montefiore, David

AU - Myint, Arthur Sun

AU - Saunders, Mark

AU - Susnerwala, Shabbir

AU - Quirke, Phil

AU - Essapen, Sharadah

AU - Samuel, Leslie

AU - Sizer, Bruce

AU - Worlding, Jane

AU - Southward, Katie

AU - Hemmings, Gemma

AU - Tinkler-Hundal, Emma

AU - Taylor, Morag

AU - Bottomley, Daniel

AU - Chambers, Philip

AU - Lawrie, Emma

AU - Lopes, Andre

AU - Beare, Sandy

N1 - 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.

PY - 2017/10/24

Y1 - 2017/10/24

N2 - 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.

AB - 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.

KW - locally advanced rectal cancer

KW - cetuximab-containing chemoradiation

KW - RAS mutations

KW - intra-tumoural clonal heterogeneity

KW - treatment response

KW - next generation sequencing

U2 - 10.1038/bjc.2017.294

DO - 10.1038/bjc.2017.294

M3 - Article

SN - 0007-0920

VL - 117

SP - 1286

EP - 1294

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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