The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer

Karen-Lise Garm Spindler, N Pallisgaard, Anders Aamann Rasmussen, J Lindebjerg, Rikke Fredslund Andersen, D Crüger, A Jakobsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Udgivelsesdato: 2009-Jan-29
OriginalsprogEngelsk
TidsskriftAnnals of Oncology
Vol/bind20
Udgave nummer5
Sider (fra-til)879-884
ISSN0923-7534
DOI
StatusUdgivet - 29. jan. 2009

Fingeraftryk

irinotecan
Colorectal Neoplasms
Mutation
Epidermal Growth Factor Receptor
Patient Selection
Single Nucleotide Polymorphism
erbB-1 Genes
Neoplasms
Homozygote
Cetuximab

Citer dette

@article{e485b290186e11deb27c000ea68e967b,
title = "The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer",
abstract = "BACKGROUND: The effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan. PATIENTS AND METHODS: The study included 71 patients referred to third-line cetuximab-irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases. RESULTS: There was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40{\%} response rate versus 0{\%}, P < 0.1(-3)), which translated into a significant difference in PFS. The EGF61A>G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19{\%} progression rate in KRASwt-EGF61 homozygote patients and 60{\%} in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002). CONCLUSION: The combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.",
author = "Spindler, {Karen-Lise Garm} and N Pallisgaard and Rasmussen, {Anders Aamann} and J Lindebjerg and Andersen, {Rikke Fredslund} and D Cr{\"u}ger and A Jakobsen",
year = "2009",
month = "1",
day = "29",
doi = "10.1093/annonc/mdn712",
language = "English",
volume = "20",
pages = "879--884",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Heinemann",
number = "5",

}

The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer. / Spindler, Karen-Lise Garm; Pallisgaard, N; Rasmussen, Anders Aamann; Lindebjerg, J; Andersen, Rikke Fredslund; Crüger, D; Jakobsen, A.

I: Annals of Oncology, Bind 20, Nr. 5, 29.01.2009, s. 879-884.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The importance of KRAS mutations and EGF61A>G polymorphism to the effect of cetuximab and irinotecan in metastatic colorectal cancer

AU - Spindler, Karen-Lise Garm

AU - Pallisgaard, N

AU - Rasmussen, Anders Aamann

AU - Lindebjerg, J

AU - Andersen, Rikke Fredslund

AU - Crüger, D

AU - Jakobsen, A

PY - 2009/1/29

Y1 - 2009/1/29

N2 - BACKGROUND: The effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan. PATIENTS AND METHODS: The study included 71 patients referred to third-line cetuximab-irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases. RESULTS: There was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40% response rate versus 0%, P < 0.1(-3)), which translated into a significant difference in PFS. The EGF61A>G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19% progression rate in KRASwt-EGF61 homozygote patients and 60% in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002). CONCLUSION: The combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.

AB - BACKGROUND: The effect of anti-epidermal growth factor receptor (EGFR) antibodies (mAb) in metastatic colorectal cancer seems limited to KRAS wild-type (wt) tumours, but still a major fraction of KRASwt patients are nonresponders and supplementary selection criteria are needed. We investigated methodological aspects of KRAS testing and the predictive and prognostic value of KRAS status combined with three EGFR-related gene polymorphisms [single-nucleotide polymorphisms (SNPs)] in patients treated with cetuximab and irinotecan. PATIENTS AND METHODS: The study included 71 patients referred to third-line cetuximab-irinotecan. Blood samples were analysed for SNPs. KRAS analysis was carried out by sequencing analysis and quantitative PCR (DxS kit) in primary tumour and distant metastases. RESULTS: There was a clear correlation between KRAS status in primary tumours and metastasis. The DxS kit presented the highest sensitivity. Response was confined to KRASwt patients (40% response rate versus 0%, P < 0.1(-3)), which translated into a significant difference in PFS. The EGF61A>G polymorphism showed relation to clinical outcome. A combined biomarker analysis showed a 19% progression rate in KRASwt-EGF61 homozygote patients and 60% in the EGF61A/G patients (P = 0.006) and a significant increase in overall survival (17.1 versus 5.9 months, log-rank, P = 0.002). CONCLUSION: The combined biomarker analysis maybe an attractive approach to selection of patients for third-line treatment including anti-EGFR mAbs.

U2 - 10.1093/annonc/mdn712

DO - 10.1093/annonc/mdn712

M3 - Journal article

VL - 20

SP - 879

EP - 884

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 5

ER -