Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: A fluorescent in situ hybridization study

Nicola Personeni, Steffen Fieuws, Hubert Piessevaux, Gert De Hertogh, Jef De Schutter, Bart Biesmans, Wendy De Roock, An Capoen, Maria Debiec-Rychter, Jean LucVan Laethem, Marc Peeters, Yves Humblet, Eric Van Cutsem, Sabine Tejpar

Research output: Contribution to journalArticle

Abstract

Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD. 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.

Original languageEnglish
Pages (from-to)5869-5876
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number18
DOIs
Publication statusPublished - Sep 15 2008

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erbB-1 Genes
Gene Dosage
Fluorescence In Situ Hybridization
Colorectal Neoplasms
Cetuximab
Area Under Curve
Neoplasms
Decision Making
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab : A fluorescent in situ hybridization study. / Personeni, Nicola; Fieuws, Steffen; Piessevaux, Hubert; De Hertogh, Gert; De Schutter, Jef; Biesmans, Bart; De Roock, Wendy; Capoen, An; Debiec-Rychter, Maria; Laethem, Jean LucVan; Peeters, Marc; Humblet, Yves; Van Cutsem, Eric; Tejpar, Sabine.

In: Clinical Cancer Research, Vol. 14, No. 18, 15.09.2008, p. 5869-5876.

Research output: Contribution to journalArticle

Personeni, N, Fieuws, S, Piessevaux, H, De Hertogh, G, De Schutter, J, Biesmans, B, De Roock, W, Capoen, A, Debiec-Rychter, M, Laethem, JL, Peeters, M, Humblet, Y, Van Cutsem, E & Tejpar, S 2008, 'Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: A fluorescent in situ hybridization study', Clinical Cancer Research, vol. 14, no. 18, pp. 5869-5876. https://doi.org/10.1158/1078-0432.CCR-08-0449
Personeni, Nicola ; Fieuws, Steffen ; Piessevaux, Hubert ; De Hertogh, Gert ; De Schutter, Jef ; Biesmans, Bart ; De Roock, Wendy ; Capoen, An ; Debiec-Rychter, Maria ; Laethem, Jean LucVan ; Peeters, Marc ; Humblet, Yves ; Van Cutsem, Eric ; Tejpar, Sabine. / Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab : A fluorescent in situ hybridization study. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 18. pp. 5869-5876.
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T1 - Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab

T2 - A fluorescent in situ hybridization study

AU - Personeni, Nicola

AU - Fieuws, Steffen

AU - Piessevaux, Hubert

AU - De Hertogh, Gert

AU - De Schutter, Jef

AU - Biesmans, Bart

AU - De Roock, Wendy

AU - Capoen, An

AU - Debiec-Rychter, Maria

AU - Laethem, Jean LucVan

AU - Peeters, Marc

AU - Humblet, Yves

AU - Van Cutsem, Eric

AU - Tejpar, Sabine

PY - 2008/9/15

Y1 - 2008/9/15

N2 - Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD. 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.

AB - Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored. Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction. Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD. 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005). Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.

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