The Prognostic Role of Ephrin A2 and Endothelial Growth Factor Receptor Pathway Mediators in Patients With Advanced Colorectal Cancer Treated With Cetuximab
Abstract
Background Patients with colorectal cancer (CRC) with wild-type KRAS mutations are often treated with the endothelial growth factor receptor (EGFR) monoclonal antibody cetuximab. Despite the presence of a specific molecular target, most patients still do not derive benefit from this biological treatment. Our study explores the role of ephrin A2 (EphA2) receptor expression and of EGFR pathway mediators as predictors of cetuximab benefit.Patients and methods Formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 226 cetuximab-treated patients with CRC were studied for mRNA expression of insulin growth factor binding protein 2 (IGFBP2), insulin growth factor receptor 1 (IGF1R), cMET, EphA2, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 by means of TaqMan reverse-transcribed polymerase chain reaction (RT-PCR).Results Of the 226 patients evaluable for exploratory analysis, 222 had complete data from follow-up visits. The univariate analysis revealed the following significant adverse prognostic factors for risk of death: high EphA2 mRNA levels (hazard ratio [HR], 1.61; P = .015), high HER2 mRNA levels (HR, 1.51; P = .045), and high IGF1R mRNA levels (HR, 1.56; P = .021). Low EphA2 tumor expression was significantly associated with objective response to cetuximab therapy. In multivariate analysis of a broad biomarker panel, factors with independent prognostic value included EphA2 mRNA levels (HR, 1.67; P = .029), high amphiregulin (AREG) mRNA levels in KRAS wild-type tumors (HR, 0.17; P < .0001), and high epiregulin (EREG) mRNA levels (HR, 0.38; P = .006).Conclusion High EphA2 receptor expression in CRC was associated with a worse outcome in patients treated with cetuximab-based therapy. Prospective validation in treated and control patients is required to dissect the predictive from prognostic role in advanced CRC.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
High levels of EphA2 are associated with poor outcome in metastatic colorectal cancer patients treated with cetuximab-based therapy.
“high levels of EphA2, a pro-angiogenic RTK [123, 124], have been associated with poor outcome in mCRC patients treated with cetuximab-based therapy [125].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [125]
Cites
Jemal, A., Siegel, R., Xu, J., & Ward, E. (2010) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.20073 · Cited by 12,596 · see citing works
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer
Hurwitz, H., Fehrenbacher, L., Novotny, W., Cartwright, T., Hainsworth, J., Heim, W., Berlin, J., Baron, A., Griffing, S., Holmgren, E., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa032691 · Cited by 10,968 · see citing works
Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., Verslype, C., et al. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033025 · Cited by 5,035 · see citing works
de Gramont, A., Figer, A., Seymour, M., Homerin, M., Hmissi, A., Cassidy, J., Boni, C., Cortes-Funes, H., Cervantes, A., Freyer, G., et al. (2000) · Journal of Clinical Oncology · doi:10.1200/jco.2000.18.16.2938 · Cited by 3,815 · see citing works
Self-citation<i>K-ras</i> Mutations and Benefit from Cetuximab in Advanced Colorectal Cancer
Karapetis, C. S., Khambata-Ford, S., Jonker, D. J., O'Callaghan, C. J., Tu, D., Tebbutt, N. C., Simes, R. J., Chalchal, H., Shapiro, J. D., Robitaille, S., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0804385 · Cited by 3,622 · see citing works
<i>KRAS</i> Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G., Penna, C., Ducreux, M., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0191 · Cited by 2,229 · see citing works
Eph receptors and ephrins in cancer: bidirectional signalling and beyond
Pasquale, E. B. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2806 · Cited by 1,216 · see citing works
Khambata-Ford, S., Garrett, C. R., Meropol, N. J., Basik, M., Harbison, C. T., Wu, S., Wong, T. W., Huang, X., Takimoto, C. H., Godwin, A. K., et al. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2006.10.5437 · Cited by 1,125 · see citing works
Brown, L. F., Berse, B., Jackman, R. W., Tognazzi, K., Manseau, E. J., Senger, D. R., & Dvorak, H. F. (1993) · PubMed · Cited by 635 · see citing works
Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members
Wheeler, D. L., Huang, S., Kruser, T. J., Nechrebecki, M. M., Armstrong, E. A., Benavente, S., Gondi, V, Hsu, K.-T., & Harari, P. M. (2008) · Oncogene · doi:10.1038/onc.2008.19 · Cited by 550 · see citing works
Lenz, H., Cutsem, E. V., Khambata‐Ford, S., Mayer, R. J., Gold, P. J., Stella, P. J., Mirtsching, B. C., Cohn, A. L., Pippas, A. W., Azarnia, N., et al. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.06.7595 · Cited by 522 · see citing works
Impact of EGFR expression on colorectal cancer patient prognosis and survival
Spano, J., Lagorce, C., Atlan, D., Milano, G. A., Dômont, J., Benamouzig, R., Attar, A., Bénichou, J., Martin, A., Morère, J., et al. (2004) · Annals of Oncology · doi:10.1093/annonc/mdi006 · Cited by 462 · see citing works
Nishino, M., Jagannathan, J. P., Ramaiya, N. H., & den Abbeele, A. D. V. (2010) · American Journal of Roentgenology · doi:10.2214/ajr.09.4110 · Cited by 378 · see citing works
Jacobs, B., De Roock, W., Piessevaux, H., Van Oirbeek, R., Biesmans, B., De Schutter, J., Fieuws, S., Vandesompele, J., Peeters, M., Van Laethem, J.-L., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.21.3744 · Cited by 368 · see citing works
Self-citationManfrédi, S., Bouvier, A., Lepage, C., Hatem, C., Dancourt, V., & Faivre, J. (2006) · British journal of surgery · doi:10.1002/bjs.5349 · Cited by 316 · see citing works
Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo
Brantley, D. M., Cheng, N., Thompson, E. J., Lin, Q. F., Brekken, R. A., Thorpe, P. E., Muraoka, R. S., Cerretti, D. P., Pozzi, A., Jackson, D., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205679 · Cited by 314 · see citing works
Bossi, P., Viale, G., Lee, A. K. C., Alfano, R. M., Coggi, G., & Bòsari, S. (1995) · PubMed · Cited by 243 · see citing works
McKay, J., Murray, L. J., Curran, S., Ross, V. G., Clark, C., Murray, G. I., Cassidy, J., & McLeod, H. L. (2002) · European Journal of Cancer · doi:10.1016/s0959-8049(02)00234-4 · Cited by 220 · see citing works
Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior.
Carles‐Kinch, K., Kilpatrick, K. E., Stewart, J. C., et al. (2002) · PubMed · Cited by 198 · see citing works
EphA2 Receptor Tyrosine Kinase as a Promising Target for Cancer Therapeutics
Ireton, R. C., & Chen, J. (2005) · Current Cancer Drug Targets · doi:10.2174/1568009053765780 · Cited by 178 · see citing works
Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients
Cappuzzo, F., Varella-Garcia, M., Finocchiaro, G., Skokan, M., Gajapathy, S., Carnaghi, C., Rimassa, L., Rossi, E., Ligorio, C., Di Tommaso, L., et al. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604439 · Cited by 178 · see citing works
Himanen, J., & Nikolov, D. B. (2002) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00096-1 · Cited by 169 · see citing works
Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression
Héroult, M., Schaffner, F., & Augustin, H. G. (2005) · Experimental Cell Research · doi:10.1016/j.yexcr.2005.10.028 · Cited by 160 · see citing works
Martin, V, Landi, L., Molinari, F., Fountzilas, G., Geva, R., Riva, A., Saletti, P., De Dosso, S., Spitale, A., Tejpar, S., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.4 · Cited by 156 · see citing works
Self-citationEpidemiology, disease Progression, and Economic Burden of Colorectal Cancer
Benson, A. B. (2007) · Journal of Managed Care Pharmacy · doi:10.18553/jmcp.2007.13.s6-c.5 · Cited by 149 · see citing works
Saridaki, Z., Tzardi, M. N., Papadaki, C., Sfakianaki, M., Pega, F., Kalikaki, A., Tsakalaki, E., Trypaki, M., Messaritakis, I., Stathopoulos, E. N., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015980 · Cited by 127 · see citing works
Ligation of EphA2 by Ephrin A1-Fc inhibits pancreatic adenocarcinoma cellular invasiveness
Duxbury, M. S., Ito, H., Zinner, M. J., Ashley, S. W., & Whang, E. E. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.06.054 · Cited by 109 · see citing works
Baker, J. B., Dutta, D., Watson, D., Maddala, T., Munneke, B., Shak, S., Rowinsky, E. K., Xu, L.-A., Harbison, C. T., Clark, E. A., et al. (2011) · British Journal of Cancer · doi:10.1038/sj.bjc.6606054 · Cited by 107 · see citing works
The role of Eph receptors and ephrin ligands in colorectal cancer
Herath, N. I., & Boyd, A. (2009) · International Journal of Cancer · doi:10.1002/ijc.25147 · Cited by 96 · see citing works
Cunningham, D., & Glimelius, B. L. G. (1999) · PubMed · Cited by 94 · see citing works
Expression of EphA2 and E-cadherin in colorectal cancer: Correlation with cancer metastasis
Saito, T., Masuda, N., Miyazaki, T., Kanoh, K., Suzuki, H., Shimura, T., Asao, T., & Kuwano, H. (2004) · Oncology Reports · doi:10.3892/or.11.3.605 · Cited by 88 · see citing works
Prognostic significance of HER3 and HER4 protein expression in colorectal adenocarcinomas
Kountourakis, P., Pavlakis, K., Psyrri, A. K., Rontogianni, D. P., Xiros, N., Patsouris, E., Pectasides, D. G., & Economopoulos, T. (2006) · BMC Cancer · doi:10.1186/1471-2407-6-46 · Cited by 85 · see citing works
Self-citationInno, A., Di Salvatore, M., Cenci, T., Martini, M., Orlandi, A., Strippoli, A., Ferrara, A. M., Bagalà, C., Cassano, A., Larocca, L. M., et al. (2011) · Clinical Colorectal Cancer · doi:10.1016/j.clcc.2011.03.028 · Cited by 83 · see citing works
Scartozzi, M., Mandolesi, A., Giampieri, R., Pierantoni, C., Loupakis, F., Zaniboni, A., Galizia, E., Giustini, L., Silva, R. R., Bisonni, R., et al. (2010) · International Journal of Cancer · doi:10.1002/ijc.25193 · Cited by 74 · see citing works
Sánchez‐Navarro, I., Gámez‐Pozo, A., González-Barón, M., Pinto-Marín, Á., Hardisson, D., López, R., Madero, R., Cejas, P., Mendiola, M., Espinosa, E., et al. (2010) · BioTechniques · doi:10.2144/000113388 · Cited by 65 · see citing works
Scartozzi, M., Mandolesi, A., Giampieri, R., Bittoni, A., Pierantoni, C., Zaniboni, A., Galizia, G., Giustini, L., Silva, R. R., Bisonni, R., et al. (2011) · The Oncologist · doi:10.1634/theoncologist.2010-0119 · Cited by 63 · see citing works
Koutras, A. K., Kalogeras, K. T., Dimopoulos, M. A., et al. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604769 · Cited by 61 · see citing works
Mishra, L., Bass, B., Ooi, B. S., et al. (1998) · Growth Hormone & IGF Research · doi:10.1016/s1096-6374(98)80300-6 · Cited by 53 · see citing works
Herath, N. I., Spanevello, M., Doecke, J. D., et al. (2011) · European Journal of Cancer · doi:10.1016/j.ejca.2011.07.003 · Cited by 51 · see citing works
Winder, T., Zhang, W., Yang, D., Ning, Y., Bohanes, P., Gerger, A., Wilson, P. M., Pohl, A., Mauro, D. J., Langer, C., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2092 · Cited by 46 · see citing works
Scartozzi, M., Giampieri, R., Maccaroni, E., Mandolesi, A., Giustini, L., Silva, R., Zaniboni, A., Biscotti, T., Biagetti, S., Galizia, E., et al. (2012) · Annals of Oncology · doi:10.1093/annonc/mdr558 · Cited by 43 · see citing works
Heindl, S., Eggenstein, E., Keller, S., Kneißl, J., Keller, G., Mutze, K., Rauser, S., Gasteiger, G., Drexler, I., Hapfelmeier, A., et al. (2012) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-011-1128-4 · Cited by 41 · see citing works
Huang, F., Xu, L.-A., & Khambata-Ford, S. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1135 · Cited by 33 · see citing works
Horndler, C., Gallego, R., García‐Albéniz, X., et al. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.11.2.13839 · Cited by 7 · see citing works
Kotoula, V., Lambaki, S., Televantou, D., Kalogera‐Fountzila, A., Nikolaou, A. C., Markou, K. D., Misailidou, D., Syrigos, K. N., & Fountzilas, G. (2011) · Translational Oncology · doi:10.1593/tlo.10217 · Cited by 7 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Leto, S. M., & Trusolino, L. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1161-2 · Cited by 87 · see citing works
- Authors
- Strimpakos, A., Pentheroudakis, G., Kotoula, V., De Roock, W., Kouvatseas, G., Papakostas, P., Makatsoris, T., Papamichael, D., Andreadou, A., Sgouros, J., Zizi-Sermpetzoglou, A., Kominea, A., Televantou, D., Razis, E., Galani, E., Pectasides, D., Tejpar, S., Syrigos, K., & Fountzilas, G.
- Affiliations
- National and Kapodistrian University of Athens (GR)
- University Hospital of Ioannina (GR)
- Aristotle University of Thessaloniki (GR)
- University of Patras (GR)
- Bank of Cyprus Oncology Center (CY)
- Tzaneion General Hospital (GR)
- Hygeia Hospital (GR)
- Metropolitan Hospital (GR)
- Hippocration General Hospital (GR)
- KU Leuven (BE)
- Sotiria General Hospital (GR)
- Corresponding author
- Strimpakos, Alexios
- ORCID
- Venue
- Clinical Colorectal Cancer
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 12
- Issue
- 4
- Pages
- 267-274.e2
- ISSN
- 1533-0028 (ISSN-L)
- OpenAlex
- W1978720618
- Cited by
- 27
- References
- 45
- Citations by year
- 2024: 5 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 1 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 2
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Colorectal Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- ephrin-A2, EGFR signaling, cetuximab, advanced colorectal cancer, KRAS wild-type, prognostic factors, HER2, IGF-1 receptor, amphiregulin, epiregulin, treatment response, mRNA expression
- MeSH terms
- Cetuximab, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Female, Humans, Male, Middle Aged, Biomarkers, Tumor, Colorectal Neoplasms, Signal Transduction, Reverse Transcriptase Polymerase Chain Reaction, Ephrin-A2, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
