Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Francesco Sclafani, Sanna Hulkki Wilson, David Cunningham, David Gonzalez De Castro, Eleftheria Kalaitzaki, Ruwaida Begum, Andrew Wotherspoon, Jaume Capdevila, Bengt Glimelius, Susana Roselló, Janet Thomas, Daina Tait, Gina Brown, Jacqui Oates, Ian Chau

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Abstract

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in non-metastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis-single strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinico-pathological characteristics and treatment outcomes were explored. 210/269 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43%, 9%, 4%, 9% and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs 65%, p=0.04), good pathological tumour regression (36% vs 23%, p=0.05) and a trend towards a better 5-year progression-free survival (74% vs 60%, HR 1.59, p=0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year progression-free survival than those with TP53/KRAS/NRAS wild-type tumours (54% vs 72%, HR 1.75, p=0.02). In univariate analysis BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs 73%, HR 3.29, p=0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis-generating and require validation in independent series. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalInternational Journal of Cancer
Early online date14 Jun 2019
DOIs
Publication statusEarly online date - 14 Jun 2019

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Rectal Neoplasms
Mutation
Disease-Free Survival
Neoplasms
Neoplasm Genes
Capillary Electrophoresis
Genes
Biomarkers
Biopsy
Polymerase Chain Reaction
Survival
Population

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Sclafani, Francesco ; Hulkki Wilson, Sanna ; Cunningham, David ; Gonzalez De Castro, David ; Kalaitzaki, Eleftheria ; Begum, Ruwaida ; Wotherspoon, Andrew ; Capdevila, Jaume ; Glimelius, Bengt ; Roselló, Susana ; Thomas, Janet ; Tait, Daina ; Brown, Gina ; Oates, Jacqui ; Chau, Ian. / Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients. In: International Journal of Cancer. 2019.
@article{daf960a6fb5c4d83bb2e57311db39eb4,
title = "Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients",
abstract = "Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in non-metastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis-single strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinico-pathological characteristics and treatment outcomes were explored. 210/269 (78{\%}) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43{\%}, 9{\%}, 4{\%}, 9{\%} and 60{\%} of patients, respectively. Concordance between paired biopsy and resection specimens was 82{\%} for KRAS, 95{\%} for NRAS, 99{\%} for BRAF, 96{\%} for PIK3CA and 63{\%} for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78{\%} vs 65{\%}, p=0.04), good pathological tumour regression (36{\%} vs 23{\%}, p=0.05) and a trend towards a better 5-year progression-free survival (74{\%} vs 60{\%}, HR 1.59, p=0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32{\%}) had a worse 5-year progression-free survival than those with TP53/KRAS/NRAS wild-type tumours (54{\%} vs 72{\%}, HR 1.75, p=0.02). In univariate analysis BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20{\%} vs 73{\%}, HR 3.29, p=0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis-generating and require validation in independent series. This article is protected by copyright. All rights reserved.",
author = "Francesco Sclafani and {Hulkki Wilson}, Sanna and David Cunningham and {Gonzalez De Castro}, David and Eleftheria Kalaitzaki and Ruwaida Begum and Andrew Wotherspoon and Jaume Capdevila and Bengt Glimelius and Susana Rosell{\'o} and Janet Thomas and Daina Tait and Gina Brown and Jacqui Oates and Ian Chau",
note = "This article is protected by copyright. All rights reserved.",
year = "2019",
month = "6",
day = "14",
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language = "English",
journal = "International Journal of Cancer",
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Sclafani, F, Hulkki Wilson, S, Cunningham, D, Gonzalez De Castro, D, Kalaitzaki, E, Begum, R, Wotherspoon, A, Capdevila, J, Glimelius, B, Roselló, S, Thomas, J, Tait, D, Brown, G, Oates, J & Chau, I 2019, 'Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients', International Journal of Cancer. https://doi.org/10.1002/ijc.32507

Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients. / Sclafani, Francesco; Hulkki Wilson, Sanna; Cunningham, David; Gonzalez De Castro, David; Kalaitzaki, Eleftheria; Begum, Ruwaida; Wotherspoon, Andrew; Capdevila, Jaume; Glimelius, Bengt; Roselló, Susana; Thomas, Janet; Tait, Daina; Brown, Gina; Oates, Jacqui; Chau, Ian.

In: International Journal of Cancer, 14.06.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

AU - Sclafani, Francesco

AU - Hulkki Wilson, Sanna

AU - Cunningham, David

AU - Gonzalez De Castro, David

AU - Kalaitzaki, Eleftheria

AU - Begum, Ruwaida

AU - Wotherspoon, Andrew

AU - Capdevila, Jaume

AU - Glimelius, Bengt

AU - Roselló, Susana

AU - Thomas, Janet

AU - Tait, Daina

AU - Brown, Gina

AU - Oates, Jacqui

AU - Chau, Ian

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/6/14

Y1 - 2019/6/14

N2 - Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in non-metastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis-single strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinico-pathological characteristics and treatment outcomes were explored. 210/269 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43%, 9%, 4%, 9% and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs 65%, p=0.04), good pathological tumour regression (36% vs 23%, p=0.05) and a trend towards a better 5-year progression-free survival (74% vs 60%, HR 1.59, p=0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year progression-free survival than those with TP53/KRAS/NRAS wild-type tumours (54% vs 72%, HR 1.75, p=0.02). In univariate analysis BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs 73%, HR 3.29, p=0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis-generating and require validation in independent series. This article is protected by copyright. All rights reserved.

AB - Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in non-metastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis-single strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinico-pathological characteristics and treatment outcomes were explored. 210/269 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43%, 9%, 4%, 9% and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs 65%, p=0.04), good pathological tumour regression (36% vs 23%, p=0.05) and a trend towards a better 5-year progression-free survival (74% vs 60%, HR 1.59, p=0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year progression-free survival than those with TP53/KRAS/NRAS wild-type tumours (54% vs 72%, HR 1.75, p=0.02). In univariate analysis BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs 73%, HR 3.29, p=0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis-generating and require validation in independent series. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ijc.32507

DO - 10.1002/ijc.32507

M3 - Article

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JO - International Journal of Cancer

JF - International Journal of Cancer

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ER -