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Amphiregulin and Epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with Cetuximab

(2009) JOURNAL OF CLINICAL ONCOLOGY. 27(30). p.5068-5074
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Abstract
Purpose: To study the power of the epidermal growth factor receptor (EGFR) epiregulin (EREG) and amphiregulin (AREG) ligands' expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab and irinotecan. Patients and Methods: Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting. Results: In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95% CI, 0.274 to 0.609; P < .001; time-dependent c-index [C tau index], 0.640), and AREG PFS HR was 0.43 (95% CI, 0.29 to 0.64; P < .001; C tau index, 0.627). EREG OS HR was 0.42 (95% CI, 0.28 to 0.63; P < .0001; C tau index, 0.639), and AREG OS HR was 0.40 (95% CI, 0.27 to 0.64; P < .0001; C tau index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation. Conclusion: Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.
Keywords
IRINOTECAN, CARCINOMA, MUTATIONS, SURVIVAL

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Chicago
Jacobs, Bart, Wendy De Roock, Hubert Piessevaux, Robin Van Oirbeek, Bart Biesmans, Jef De Schutter, Steffen Fieuws, et al. 2009. “Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated with Cetuximab.” Journal of Clinical Oncology 27 (30): 5068–5074.
APA
Jacobs, Bart, De Roock, W., Piessevaux, H., Van Oirbeek, R., Biesmans, B., De Schutter, J., Fieuws, S., et al. (2009). Amphiregulin and Epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with Cetuximab. JOURNAL OF CLINICAL ONCOLOGY, 27(30), 5068–5074.
Vancouver
1.
Jacobs B, De Roock W, Piessevaux H, Van Oirbeek R, Biesmans B, De Schutter J, et al. Amphiregulin and Epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with Cetuximab. JOURNAL OF CLINICAL ONCOLOGY. 2009;27(30):5068–74.
MLA
Jacobs, Bart, Wendy De Roock, Hubert Piessevaux, et al. “Amphiregulin and Epiregulin mRNA Expression in Primary Tumors Predicts Outcome in Metastatic Colorectal Cancer Treated with Cetuximab.” JOURNAL OF CLINICAL ONCOLOGY 27.30 (2009): 5068–5074. Print.
@article{862710,
  abstract     = {Purpose: To study the power of the epidermal growth factor receptor (EGFR) epiregulin (EREG) and amphiregulin (AREG) ligands' expression in primary tumors to predict the outcome in patients with chemorefractory metastatic colorectal cancer (cmCRC) treated with the combination of cetuximab and irinotecan.
Patients and Methods: Gene expression measurements and KRAS mutation analysis were performed on archival formalin-fixed paraffin-embedded primary tumors of 220 cmCRC patients. Response was measured using RECIST (Response Evaluation Criteria in Solid Tumors) criteria. The relation between ligand expression levels and outcome was evaluated using logistic regression for response and Cox regression for survival data. Receiver operating characteristics analysis was performed for response and survival data. CIs for the performance indices were obtained with a nonparametric bootstrap procedure. Findings were externally validated on a series of 67 samples treated in a similar setting.
Results: In KRAS wild type (WT) patients, there was a significant association between log-transformed ligand expression and response for EREG (odds ratio for objective response, 1.90; 95\% CI, 1.27 to 2.83; P = .0005; concordance index [c-index], 0.681) and for AREG (odds ratio for objective response, 1.862; 95\% CI, 1.22 to 2.72; P = .0017; c-index, 0.673). In a Cox regression model, dichotomized ligand expression was significantly associated with progression-free survival (PFS) and overall survival (OS). EREG PFS hazard ratio (HR) was 0.41 (95\% CI, 0.274 to 0.609; P {\textlangle} .001; time-dependent c-index [C tau index], 0.640), and AREG PFS HR was 0.43 (95\% CI, 0.29 to 0.64; P {\textlangle} .001; C tau index, 0.627). EREG OS HR was 0.42 (95\% CI, 0.28 to 0.63; P {\textlangle} .0001; C tau index, 0.639), and AREG OS HR was 0.40 (95\% CI, 0.27 to 0.64; P {\textlangle} .0001; C tau index, 0.625). There was no predictive power of ligand expression in patients with KRAS mutation.
Conclusion: Expression of EGFR ligands in primary tumors significantly predicts outcome in KRAS WT cmCRC treated with cetuximab and irinotecan.},
  author       = {Jacobs, Bart and De Roock, Wendy and Piessevaux, Hubert and Van Oirbeek, Robin and Biesmans, Bart and De Schutter, Jef and Fieuws, Steffen and Vandesompele, Jo and Peeters, Marc and Van Laethem, Jean-Luc and Humblet, Yves and Penault-Llorca, Frederique and De Hertogh, Gert and Laurent-Puig, Pierre and Van Cutsem, Eric and Tejpar, Sabine},
  issn         = {0732-183X},
  journal      = {JOURNAL OF CLINICAL ONCOLOGY},
  keyword      = {IRINOTECAN,CARCINOMA,MUTATIONS,SURVIVAL},
  language     = {eng},
  number       = {30},
  pages        = {5068--5074},
  title        = {Amphiregulin and Epiregulin mRNA expression in primary tumors predicts outcome in metastatic colorectal cancer treated with Cetuximab},
  url          = {http://dx.doi.org/10.1200/JCO.2008.21.3744},
  volume       = {27},
  year         = {2009},
}

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