Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer

Gordon G A Hutchins; Darren Treanor; Alexander Wright; Kelly Handley; Laura Magill; Emma Tinkler-Hundal; Katie Southward; Matthew Seymour; David Kerr; Richard Gray; Philip Quirke; QUASAR trial collaborators; UK National Cancer Research Institute Colorectal Cancer Clinical Studies Group

doi:10.1111/his.13326

Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer

Gordon G A Hutchins, Darren Treanor, Alexander Wright, Kelly Handley, Laura Magill, Emma Tinkler-Hundal, Katie Southward, Matthew Seymour, David Kerr, Richard Gray, Philip Quirke, QUASAR trial collaborators, UK National Cancer Research Institute Colorectal Cancer Clinical Studies Group

Birmingham Clinical Trials Unit

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Abstract

INTRODUCTION: The biological importance of tumour-associated stroma is increasingly apparent, yet clinical utility remains ill-defined. In stage-II / Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC MATERIALS AND METHODS: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses RESULTS: High tumour stroma (≥50%) was associated with increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1,343) if <50% [Rate ratio (RR)=1.62; 95%CI 1.30-2.02, p<0.0001)]. For stromal proportions of ≥65%, 40% (46/115) of patients had recurrent disease within 10 years. The adverse prognostic effect of high stroma was independent of established prognostic variables, and maintained in stage II / Dukes B patients (RR=1.62; 95%CI=1.26-2.08; p=0.0002). KRAS mutation in the presence of high stroma augmented recurrence risk (RR=2.93; 95%CI=1.87-4.59; p=0.0005). Stromal morphometry did not predict response to FUFA chemotherapy DISCUSSION: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with over 50% higher risk of disease recurrence. This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted. This article is protected by copyright. All rights reserved.

Original language	English
Journal	Histopathology
Early online date	26 Jul 2017
DOIs	https://doi.org/10.1111/his.13326
Publication status	E-pub ahead of print - 26 Jul 2017

Keywords

Colorectal
Stroma
Colon
Rectal
Cancer

UN SDGs

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

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Hutchins_et_al-2017-Histopathology
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/his.13326 This article is protected by copyright. All rights reserved.
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Hutchins, G. G. A., Treanor, D., Wright, A., Handley, K., Magill, L., Tinkler-Hundal, E., Southward, K., Seymour, M., Kerr, D., Gray, R., Quirke, P., QUASAR trial collaborators, & UK National Cancer Research Institute Colorectal Cancer Clinical Studies Group (2017). Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer. Histopathology. Advance online publication. https://doi.org/10.1111/his.13326

@article{d9cda72ffd77411eb9288ddadf4d7889,

title = "Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer",

abstract = "INTRODUCTION: The biological importance of tumour-associated stroma is increasingly apparent, yet clinical utility remains ill-defined. In stage-II / Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC MATERIALS AND METHODS: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses RESULTS: High tumour stroma (≥50%) was associated with increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1,343) if <50% [Rate ratio (RR)=1.62; 95%CI 1.30-2.02, p<0.0001)]. For stromal proportions of ≥65%, 40% (46/115) of patients had recurrent disease within 10 years. The adverse prognostic effect of high stroma was independent of established prognostic variables, and maintained in stage II / Dukes B patients (RR=1.62; 95%CI=1.26-2.08; p=0.0002). KRAS mutation in the presence of high stroma augmented recurrence risk (RR=2.93; 95%CI=1.87-4.59; p=0.0005). Stromal morphometry did not predict response to FUFA chemotherapy DISCUSSION: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with over 50% higher risk of disease recurrence. This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted. This article is protected by copyright. All rights reserved.",

keywords = "Colorectal , Stroma , Colon , Rectal , Cancer",

author = "Hutchins, {Gordon G A} and Darren Treanor and Alexander Wright and Kelly Handley and Laura Magill and Emma Tinkler-Hundal and Katie Southward and Matthew Seymour and David Kerr and Richard Gray and Philip Quirke and {QUASAR trial collaborators} and {UK National Cancer Research Institute Colorectal Cancer Clinical Studies Group}",

year = "2017",

month = jul,

day = "26",

doi = "10.1111/his.13326",

language = "English",

journal = "Histopathology",

issn = "0309-0167",

publisher = "Wiley",

}

Hutchins, GGA, Treanor, D, Wright, A, Handley, K , Magill, L, Tinkler-Hundal, E, Southward, K, Seymour, M, Kerr, D, Gray, R, Quirke, P, QUASAR trial collaborators & UK National Cancer Research Institute Colorectal Cancer Clinical Studies Group 2017, 'Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer', Histopathology. https://doi.org/10.1111/his.13326

TY - JOUR

T1 - Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer

AU - Hutchins, Gordon G A

AU - Treanor, Darren

AU - Wright, Alexander

AU - Handley, Kelly

AU - Magill, Laura

AU - Tinkler-Hundal, Emma

AU - Southward, Katie

AU - Seymour, Matthew

AU - Kerr, David

AU - Gray, Richard

AU - Quirke, Philip

AU - QUASAR trial collaborators

AU - UK National Cancer Research Institute Colorectal Cancer Clinical Studies Group

PY - 2017/7/26

Y1 - 2017/7/26

N2 - INTRODUCTION: The biological importance of tumour-associated stroma is increasingly apparent, yet clinical utility remains ill-defined. In stage-II / Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC MATERIALS AND METHODS: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses RESULTS: High tumour stroma (≥50%) was associated with increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1,343) if <50% [Rate ratio (RR)=1.62; 95%CI 1.30-2.02, p<0.0001)]. For stromal proportions of ≥65%, 40% (46/115) of patients had recurrent disease within 10 years. The adverse prognostic effect of high stroma was independent of established prognostic variables, and maintained in stage II / Dukes B patients (RR=1.62; 95%CI=1.26-2.08; p=0.0002). KRAS mutation in the presence of high stroma augmented recurrence risk (RR=2.93; 95%CI=1.87-4.59; p=0.0005). Stromal morphometry did not predict response to FUFA chemotherapy DISCUSSION: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with over 50% higher risk of disease recurrence. This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted. This article is protected by copyright. All rights reserved.

AB - INTRODUCTION: The biological importance of tumour-associated stroma is increasingly apparent, yet clinical utility remains ill-defined. In stage-II / Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC MATERIALS AND METHODS: Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified using digitised haematoxylin and eosin sections derived from 1,800 patients enrolled in QUASAR which randomised 3,239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic/predictive value of PoT/PoS measures were determined by stratified log-rank analyses RESULTS: High tumour stroma (≥50%) was associated with increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1,343) if <50% [Rate ratio (RR)=1.62; 95%CI 1.30-2.02, p<0.0001)]. For stromal proportions of ≥65%, 40% (46/115) of patients had recurrent disease within 10 years. The adverse prognostic effect of high stroma was independent of established prognostic variables, and maintained in stage II / Dukes B patients (RR=1.62; 95%CI=1.26-2.08; p=0.0002). KRAS mutation in the presence of high stroma augmented recurrence risk (RR=2.93; 95%CI=1.87-4.59; p=0.0005). Stromal morphometry did not predict response to FUFA chemotherapy DISCUSSION: Simple digital morphometry applied to a single representative H&E section identifies CRC patients with over 50% higher risk of disease recurrence. This technique can reliably partition patients into sub-populations with differential risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted. This article is protected by copyright. All rights reserved.

KW - Colorectal

KW - Stroma

KW - Colon

KW - Rectal

KW - Cancer

U2 - 10.1111/his.13326

DO - 10.1111/his.13326

M3 - Article

C2 - 28746977

SN - 0309-0167

JO - Histopathology

JF - Histopathology

ER -

Intra-tumoural stromal morphometry predicts disease recurrence but not response to 5-fluorouracil - results from the QUASAR trial of colorectal cancer

Abstract

Keywords

UN SDGs

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